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THE ALKALOIDS Chemistry and Pharmacology

Volume 30

This Page Intentionally Left Blank

THE ALKALOIDS Chemistry and Pharmacology Edited by Arnold Brossi National Institutes of Health Bethesda, Maryland

VOLUME 30

W ACADEMIC PRESS, INC. Harcoart Brace Jovanovich, Publishers San Diego London

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Berkeley Boston Tokyo Toronto

C O P Y R I G H T 0 1987 BY A C A D E M I C P R E S S , I N C ALL RIGHTS RESERVED. NO PART O F THIS PUBLICATION MAY BE REPRODUCED OR TRANSMITTED IN ANY FORM O R BY ANY MEANS. ELECTRONIC OR MECHANICAL, INCLUDING PHOTOCOPY. RECORDING, OR ANY INFORMATION STORAGE A N D RETRIEVAL SYSTEM, WITHOU’I PERMISSION IN WRITING FROM T H E PUBLISHER

ACADEMIC PRESS,

INC.

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United Kingdom Edition published by

ACADEMIC PRESS INC.

(LONDON) 24-28 Oval Road. London NW I 7DX

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(alk. paper)

PRINTED IN THE UNITED STATES OF AMERICA a788899o

9 8 7 6 5 4 3 2 1

IN MEMORY OF KAREL WIESNER Dr. Karel Wiesner, who died November 28, 1986, in Fredericton, New Brunswick, Canada, after a long illness, was a giant in the chemistry of natural products, particularly aconitum alkaloids and digitalis glycosides. Dr . Karel Wiesner, an organic chemist of Czechoslovakian descent, spent most of his career as a university professor at the University of New Brunswick in Fredericton, Canada, where since 1964 he headed the Natural Products Research Center. His profound knowledge of the basics in chemistry allowed him to synthesize complex molecules by uncomplicated but elegant schemes. It is with gratitude for having had the privilege of knowing Karel Wiesner personally that I dedicate Vol. 30 of “The Alkaloids” to his lasting memory. Arnold Brossi


CONTENTS ix

PREFACE .

Chapter 1 . The Bisbenzylisoquinoline Alkaloids KEITHT . BUCK

I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I1. Structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I11. Known Alkaloids from New Sources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IV . Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . V . Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . VI . Methods and Techniques .......................... ........... VII . Biosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . VIII . Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IX . Reviews of Bisbenzylisoquinoline Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . X . Tabulation of Bisbenzylisoquinoline Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . XI . Appendix . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1 2 101 104 115 123 131 142 154 155 173 202

Chapter 2 . The Alkaloids from Pauridiantha

R . A . JACQUESY AND J . LEVESQUE I . Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11. Taxonomic Position of the Genus Puuridiunthu . . . . . . . . . . . . . . . . . . . . . . . . . 111. Alkaloids in the Genus Pauridiantha . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IV . Biosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . V . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

223 224 225 241 246 247

Chapter 3 . The Amaryllidaceae Alkaloids STEPHENF . MARTIN I . Introduction and Botanical Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I1. Lycorine-Type Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii

252 262

... Vlll

CONTENTS

111. Lycorenine-Type Alkaloids . . . . . . . . ............................. IV . Narciclasine-Type Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . V . Galanthamine-Type Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . VI . Crinine-Type Alkaloids ............................ VII . Other Structural Types ............................................. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

CUMULATIVE INDEX OF TITLES .............................................. SUBJECT INDEX . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

289 296 308 321 358 369

311

. 383

PREFACE “The Bisbenzylisoquinoline Alkaloids,” reviewed in Vols. 7, 9, 13, and 16 of this treatise, represent the largest group among the isoquinoline alkaloids. Bisbenzylisoquinoline alkaloids tubocurarine, thalicarpine, tetrandrine, and cepharanthine also have interesting pharmacological properties, and for these reasons this group of alkaloids is again updated, covering in the Appendix the pertinent literature until 1985. Indole alkaloids of the rare genus Pauridiantha are presented here for the first time under the title “The Alkaloids from Pauridiantha’ ’; these alkaloids are found almost exclusively in Madagascar, where plant extracts are used by the natives for medicinal purposes. “The Amaryllidaceae Alkaloids,” reviewed in Vols. 6, 11, and 15 of this treatise, have been updated, and several new alkaloids of this class are listed. Occurrence, spectral properties, structure, synthesis, and biosynthesis of these alkaloids are covered in these chapters, and pharmacological properties whenever known are reported. Arnold Brossi

ix


-CHAPTER1 -

THE BISBENZYLISOQUINOLINE ALKALOIDS KEITHT. BUCK Fries and Fries Division Mullinckrodt, Inc. Cincinnati, Ohio 45216

I. Introduction 11. Structure A. Structure Revisions B. Confirmatoy and Additional Structural Data on Known Alkaloids C. New Alkaloids: Occurrence and Structure 111. Known Alkaloids from New Sources IV. Reactions A. Chemical Methods B , Biochemical Transformation V. Synthesis A. Total Synthesis B. Partial Synthesis VI. Methods and Techniques A. Spectrometry B. Analytical Methods C. Separation Techniques D. Biological Assay E. Classification VII. Biosynthesis A. Isotope Labeling Studies B. Other Biochemical Studies C. Circumstantial Evidence VIII. Pharmacology IX. Reviews of Bisbenzylisoquinoline Alkaloids X. Tabulation of Bisbenzylisoquinoline Alkaloids A. Alphabetical List B. Tabulation by Molecular Weight XI. Appendix References

I. Introduction

Although it is almost a clichC to point out the ever-accelerating pace of scientific development, since the last review on the bisbenzylisoquinoline alkaloids in 1

THE ALKALOIDS, VOL 30 Copynght 0 1987 by Academc Press, Inc All nghts of reproductmn in any form reserved

2

KEITH T.BUCK

this treatise (Vol. 16, 1977), which covered literature through the first half of 1975, the number of reported alkaloids of this class has more than doubled, and interest in them shows no sign of abating. A large part of this growth can be ascribed to the long-standing pharmaceutical interest in neuromuscular blocking agents such as tubocurarine and to a relatively recent flurry of research on a range of potential pharmaceutical applications for certain bisbenzylisoquinolines, notably thalicarpine, tetrandrine, and cepharanthine. Also important to this rapid expansion has been the development of facile instrumental techniques for identification and correlation of alkaloids. We have continued the practice in the last review of defining bisbenzylisoquinoline alkaloids as broadly as possible, thereby including biologically degraded dimers (e.g., thaliadine, dinklacorine), formally similar alkaloids (e.g., cancentrine, toddalidimerine, jolantinine), and alkaloids having biochemically modified subunits (e.g., pakistanamine, thalicarpine). No attempt has been made to cover the chemistry or pharmacology of analogs or derivatives that are not natural products. The main body of this chapter concentrates on the period 19751984 (Chemical Abstracts, Volumes 83-loo), and the appendix extends the coverage to 1986 (CA 101-104); earlier material is included only for continuity and in the interest of completeness. Because of the large body of new material, we have not expanded the discussion from the appendix to the previous chapter. The format follows that of the earlier review. The subject of synthesis, however, which formerly constituted a separate chapter, is included in this work, and other coverage has been expanded, particularly in the areas of plant biochemistry and pharmacology. The tabulation of all known bisbenzylisoquinoline alkaloids has been revised and updated. A section listing other major review articles on these alkaloids is also included, and the reader may wish to consult some of these for extensive physical data. In keeping with the original purpose of this treatise, we have tried for a comprehensive overview, with strong emphasis on the specific chemistry of the bisbenzylisoquinoline alkaloids, rather than an exhaustively detailed presentation.

11. Structure A. STRUCTURE REVISIONS

1. 0-Desmethyladiantifoline Comparison of the properties of the new alkaloid thaliadanine (1, Section II,C, 109) with those reported (1) for 0-desmethyladiantifoline (2) has shown that these materials are different. Notably, the NMR spectrum of 2 shows peaks at 6 5.78 and 3.56, which represent a 8’-H and 7’-OMe, respectively, as determined by comparison of the spectra of several aporphine-benzylisoquinoline

1. THE BISBENZYLISOQUINOLINE ALKALOIDS

3

OMe

OMe

L

O

1 R'=Me, R Z = H 2 R ' = H , RZ = M e

3 R'= Et. RZ = M e

dimers. O-Desmethyladiantifoline was therefore assigned the corrected structure 2; however, a direct comparison of samples has not been made (2). It is not clear why permanganate oxidation of the O-ethyl ether (3) was earlier claimed ( I ) to give 4 rather than the correct product 5.

4 5

R' = Me, RZ = Et R'=Et, R Z = M e

2. Magnolamine Magnolamine (6), mp 117-1 18°C (benzene or chloroform), first isolated in 1938, was originally assigned structure 7. A recent reinvestigation (3) showed that the alkaloid contains three rather than two methoxys (its NMR spectrum shows three sharp singlets at 6 3.74, 3.76, 3.78), and it failed to give a positive catechol reaction with FeC1,. Reaction with diazoethane afforded the O,O,Otriethyl derivative 8. The intense mle 192 base peak of the alkaloid (cleavage at a) was indicative that both isoquinoline rings are substituted with one methoxy . Oxidation of the triethyl derivative with KMnO, yielded the known isoquinolone 4 and the diacid 9, which was converted to 10 with CH,N,. Irradiation of the singlet aromatic protons adjacent to the methoxys in 4 and 10 showed

M H*I .ae

N

'ORZ

g

: '0

0 R'

6 7

R'=H.RZ=Me R'=RZ=H

8

R'= Et, R' = Me

a. y :H ' Me

4

KEITH T.BUCK

COOR' 0 Et@ o a C O C J R 1 OR'

9 R1=H,R2=Me 10 R'=R' = M e 11 R ' = H , R ' = E t

M H'e N T \:

/

: z 2 H M e

'

OMe

13

OEt

12

nuclear Overhauser effects (NOE) of, respectively, 19 and 25%, confirming the indicated substitution pattern of the alkaloid. The melting point of 9 (275276°C) differed significantly from that reported for 11 (245-247°C) (4); additionally, the properties of synthetic 7 (5) did not satisfactorily match those of magnolamine. Sodium/ammonia cleavage of 8 gave 12 and 13. A sample of 6 prepared by synthesis (see Section V,A, 1) was identical to magnolamine (6). 3. Phaeantharine

In 1957, structure 14 was proposed for phaeantharine (7). This assignment was based on spectrometric evidence, elemental analysis, and reduction of the alkaloid, followed by Na/NH, cleavage, to products that appeared to be

14

(R,S)-0-methylannepavine(15) and (R,S)-N-methylcoclaurine(16). A recent reexamination (8) of the alkaloid failed to confirm structure 14. No electronM

e

N

i

E

':? /

OMe

15

16

Me


5

impact MS could be obtained due to low volatility, but a field desorption MS showed mle 632 and 631, rather than the expected rnle 616. Sodium borohydride reduction gave material with MS identical to that of U-methyldauricine (17). The revised structure 18 was therefore suggested for phaeantharine, and it was confirmed by 300- and 500-MHz ‘H NMR in D,O and CD,OD, including homonuclear decoupling and NOE difference spectra, and by 13C NMR.

17

The original proposal of the incorrect structure 14 can be seen in hindsight as due mainly to misidentification of the NaINH, cleavage products, which must in fact be 15 and 19. The revised structure 18 for phaeantharine has been confirmed by total synthesis (9, see Section V,A).

18 Me0

MeoYMe HO

19

4. Thalibrunine Structure 20 was proposed for thalibrunine in 1974 (10).This assignment rested mainly on degradation (photooxidation-ZnIHC1 reduction) to 21 and cleavage (NaINH,) to (S)-N-methylcoclaurine (22). At that time no fragments

20

6

KEITH T. BUCK

21 HO

22

representing the linked lower rings of thalibrunine were isolated, and evidence for their substitution pattern consisted principally of spectral analogy, failure of the alkaloid to react with diazomethane, and an apparently positive Gibbs’ test (formation of a colored coupling product with 2,6-dibromoquinone-4-chloroimide, considered indicative of a para-unsubstituted phenol). A reexamination ( I I , I 2 ) of the NMR of thalibrunine in acetone-d,, rather than CDCl,, gave a more clearly resolved spectrum, which showed, among other things, only two rather than three, AB quartets for the aromatic hydrogens of the

23 24

R=OH R =OAc

24a R = H

lower rings, as well as a broad 1H singlet at 6 11.9, indicative of an internally hydrogen-bonded phenol. Consideration of steric factors suggested structure 23 for thalibrunine. Oxidation of thalibrunine acetate (24) with ceric ammonium nitrate gave in low yield the dialdehyde 25, which was independently synthesized. CHO

Me0

25

Finally, the stereochemistry of the left-hand portion of thalibrunine was established as (S) by a study of the CD curve of the Na/NH, cleavage product, 6demethoxydihydrothalibrunine (26). Although 26 shows an anomalous CD spectrum under neutral conditions, in dilute HC1 the hydrogen-bonding is disrupted and the spectrum reverts to that typical of an (S,S) dimer. Additionally, thalibrunine acetate (24) and hernandezine (24a) have similar CD curves. Thus


MeHN'

g

\

HO

:y /

'OMe

0

7

Me

1

26

thalibrunine should be reassigned as 23, and thalibrunimine (see Section II,C,ll2), later correlated (13) with 23, as 27.

27

B. CONFIRMATORY AND ADDITIONAL STRUCTURAL DATA ON KNOWNALKALOIDS This section includes those known alkaloids for which substantial new confirmatory data have been reported during the period under review. Additional data not bearing critically on structure proof are mentioned in appropriate (e.g., Spectrometry) sections. For alkaloids that have simply been reisolated from new sources, see Section 111. 1. Cancentrine

Details of the structure proof of cancentrine (28) have appeared ( 1 4 , and the absolute configuration has been determined by X-ray study of a derivative (15).

Me0 Me0 28

8

KEITH T. BUCK

The chemistry of the cancentrine family of alkaloids has been reviewed (16,17). (Also see 10-oxocancentrine, Section II,C,85.) la. Cocsuline, Efirine, Trigilletine, and N-Methyl- 12’-O-desmethyltrilobine Comparison of physical properties has shown the title alkaloids to have the identical structure 29. All samples gave isotrilobine (30) with diazomethane. The name ‘‘cocsuline” has priority (18). Additional spectral and degradative information on cocsuline has been published (19). Cocsuline gave a dimethiodide, which yielded an optically inactive Hofmann degradation product identical to that formed by similar treatment of isotrilobine (30). Cocsuline partially exchanged H-3”’ (by NMR) with D,O/t-BuOK, whereas U-methylcocsuline (= isotrilobine, 30) did not. However, H-5 of 30 could be completely exchanged on heating 125 hr at 110°C in a sealed tube with DCl/CH,OD. The stereochemistry of 29 was further confirmed as ( S , S ) by NalNH, cleavage of U-ethylcocsulineto fragments of (S) configuration (19).

-’% OMe

Me

.

4

/

\

\

13”‘

OR

0

29 R = H 30 R = M e

2. Cocsulinine and Cocsoline An expanded discussion of the structure proofs of cocsulinine (31) and cocsoline (32)has appeared (19). The biosynthesis of cocsulinine has been studied (see Section VILA). Cocsoline is the enantiomer of micranthine (see Section 11, c ,1) .

31


9

2a. Cycleahomine The structure of cycleahomine (33) has been unequivocally confirmed by partial synthesis as the N- (rather than N‘-) monoquaternary derivative of tetrandrine (see Section IV,A,l). The specific rotation of the chloride, (CHCl,, c 0.2), is +228”, rather than + 103”as earlier reported (20).

33

3. Dihydrowarifteine (34), Methyldihydrowarifteine (35), and Dimethyldihydrowarifteine (36)

These alkaloids were isolated, along with their unsaturated analogs (see Section II,B,4), from Cissampelos ovalifoEia D.C., an alleged component of “Macushi curare,’’ and characterized in 1970 by chemical interrelation and MS studies. At that time it was shown that the three bases have the same skeleton,

34 R ’ = R * = H 35 R’ = H. R 2 = Me

36

R’ = R 2 =Me

10

KEITH T. BUCK

differing only in the degree of methylation of the oxygen substituents, although it was not possible to specify the complete structures. The dihydro alkaloids were readily obtained by NaBH, reduction of the corresponding unsaturated alkaloids warifteine (37), methylwarifteine (38), and dimethylwarifteine (39) (21). Since the structures of these latter bases are now known (see Section II,B,4), the dihydrowarifteines are similarly identified (22,23), although the stereochemistry of ring E is not specified. The dihydrowarifteines show principal MS fragmentations at a, b, and c (21).

4. Dimethylwarifteine, Methylwarifteine, and Warifteine These alkaloids, also from Cissampelos ovalifolia D.C., show a mode of MS cleavage somewhat different from that of the dihydro bases (Section II,B,3) with principal scissions at a, b, c, and d. Diazomethane converted both 37 and 38 to 39 (21). MS data alone did not allow a choice between possible isomers, so Xray work was done on methylwarifteine (38) (22) and dimethylwarifteine (39) (23). The structures of these bases, and therefore of warifteine (37), are as shown. Dimethylwarifteine is identical to 0-methylcissampareine, isolated from Cissampelos pareira Linn (21). This family of alkaloids is unusual in having a benzyloxy bridge.

OMe

37 R ’ = R ~ = H

38 R’ = H . R 2 =Me 39 R ’ = R * = M e

5. Nortiliacorinine A and Nortiliacorinine B In 1969, nortiliacorinine A and nortiliacorinine B were correlated by N-methylation (CH,O/HCO,H) to tiliacorinine (40, Section II,B, 14), but the relative positions of either the NMe or the bottom-ring oxygen functions were not determined at that time (24,25). A series of NOE observations on N-acetylnortiliacorinine A (41) and the related derivative N-acetyltiliamosine (42) showed the proximity relationship of the hydrogens at positions 25, 4a, 5 , 7, and 8. Irradiation of the methoxy signal in these compounds caused an approximate


11

43 40 41 42

44 45

R'=H, R 2 = R 3 = M e R' = H, R' = Me, R' = Ac

R' = OMe. R2 = Me, R 3 = A c R'=R3=H, R2=Me R'= R' = H, R3 = Me

25% NOE enhancement of the H-13 doublet, showing that the methoxy is on ring E; therefore, by elimination, the hydroxy is on ring F (26). Feeding studies with radioactive precursors (see Section VII,A) were reported (27) to show that (S)-N-methylcoclaurine(22) and (S)-coclaurine (43) are specific precursors for the right- and left-hand halves, respectively, of an alkaloid alleged to be nortiliacorinine A. The structure given (27) for this alkaloid is inconsistent with earlier work (26,40),possibly because the identity of the alkaloid from the biosynthetic investigation was not established by comparison to an authentic sample of nortiliacorinine A (27a). The complete structures of nortiliacorinine A (44),nortiliacorinine B (45), and the related alkaloid tiliamosine (see Section II,C, 138) are, however, firmly established by instrumental studies (27a). 6. Pakistanamine Pakistanamine (46) was first characterized in 1973, and the absolute configuration was determined at C-6a, but not at C-13. In'1982, extensive proton NMR decoupling and NOE experiments (Section VI,A,2) were reported that made possible a complete stereochemical assignment of pakistanamine and, by extension, of five other (see Section II,C,6) benzylisoquinoline-proaporphine dimers. The protons of 46 were first assigned by spin decoupling; of particular interest

46

12

KEITH T. BUCK

were the 6a-, 7a-, and 7P-H. NOE measurements then showed, e.g., enhancements of 8% for 7-Ha on irradiation of 8-H, 8% for 6a-H on irradiation of 12-H, and 4% for 7-Hb on irradiation of 6a-H. As a consequence, the complete stereochemistry of 46 is as shown (28). 7. Repanduline In 1967, structure 47 (exclusive of stereochemistry) was suggested for repanduline (29). The point of fusion of the spiro rings was equivocal, and no stereochemistry was determined. Long-range NOE difference spectrometry (see Section VI,A,2,b) has now allowed assignment of all protons of repanduline (in CDC1,/20% perdeuteriobenzene), in some cases from enhancements as low as 0.1%. These results were confirmed by long-range 'H-I3C decoupling experiments. Particularly noteworthy are the interactions of H-2" with H-8', Hb with H-1 , and H-5 with the carbonyl carbon. Structure 47 was accordingly confirmed and its stereochemistry established (30).

Me

47

8. Tetrandrine The crystal structure of tetrandrine (48) has been determined by X-ray diffraction. N-2 experiences medium- to long-range steric hindrance, in parallel with the reduced reactivity in solution toward quaternization or chloroformate Ndealkylation at this site (see Sections IV,A,l and IV,A,l,a). The anticancer activity of tetrandrine may be related to these conformational effects (31).

48

1 . THE BISBENZYLISOQUINOLINE ALKALOIDS

13

49

9. Thalfine The stereochemistry of thalfine (49) was determined by reduction of the alkaloid with Zn/HCl and methylation of the product to a mixture of thalfinine (50) and its C-1’ diastereomer, epithalfinine (51). Since the stereochemistry of the left-hand half of thalfinine (S) is known (see Section II,B,lO), thalfine is therefore 49. The CD and mass spectra are recorded (32).

50 R = H--51 R = H -

10. Thalfinine

Thalfinine (50), first isolated from Thalictrum foetidum L., has been obtained from T . minus Race B , and its CD spectrum has been determined. Cleavage (Na/NH,) gave (S)-0-methylarmepavine (52), representing the left-hand portion of the molecule, as the major nonphenolic product, but a phenolic product was not isolated. Because of the co-occurrence of thalirabine (Section II,C,123) in T. minus Race B, the (S,S) configuration is suspected (32); additionally, the CD curves of thalfinine and epithalfinine (51, not a natural product) are similar to those of thalmirabine and 0-methylthalmirabine (33) (see Section II,C, 132).

52

14

KEITH T. BUCK

Me N

Z

I

T

H'

N

M

e

"H

53 R = H

54 R=Et

10a. Thalidezine The structure of thalidezine (53), exclusive of stereochemistry, was proven in 1967. In 1977, Na/NH, cleavage studies of 0-ethylthalidezine (54) afforded 55, 56, and 22 (see Section 11,A,4), the stereochemistries of which were established by CD (34).

MeHN(

zM :e

/

OMe

55 R = H 56 R=OMe

1 1 . Thalmethine Thalmethine (57) shows MS (M , 100%; M - 1 , 87%) behavior similar to that of the imino bis alkaloids thalsimine (58, Section II,B,l3) and thalsimidine (59). UV and NMR spectra are in accord with the previously proposed structure +

(35).

MeNw H'

/

o \

OH

E:? 57

MeHN'

/

OMe

o \

58 R = M e 59 R = H


15

60 R 1 = Me, R Z = H 61 R 1 = R 2 =Me 62 R ' = H, R' = Me

12. Thalmine Thalmine, first described in the 1950s, was assigned the correct structure in 1966 (36). The NMR spectra of thalictine (60) and U-methylthalictine (61) (see Section II,C, 113) have been compared with those of thalmine (62), repandine (63) U-methylrepandine (64)? and six other related compounds. On this basis, thalmine was confirmed to have (S,S) stereochemistry. U-Methylthalmine is identical to U-methylthalictine (37).

63 R = H 64 R = M e

13. Thalsimine A sample of thalsirnine (58), isolated from Thulictrum rochebruniunurn, at first appeared by NMR to be an inseparable mixture of two isomers. At room temperature in perdeuteropyridine it shows NMR resonances corresponding to 10 different methoxys and two N-methyls. However, at 95"C, thalsimine gives the expected simplified spectrum (13). Anomalous NMR behavior in CDCI, had previously been reported, without explanation, for this alkaloid (38). The unusual behavior of thalsimine is evidently due to a slow equilibration of two conformers of almost equal stability. This phenomenon has not yet been observed in other bisbenzylisoquinoline alkaloids, but suggests caution in interpreting results on apparently inseparable mixtures (13). (See also Section XI,G,l ,b.) 14. Tiliacorine and Tiliacorinine The exact structures of tiliacorine (65) and its closely related bases remained in doubt for some time after their isolation. Because the biphenyl linkage is not cleaved by NalNH,, the isolation of easily characterized monomeric degradation

16

:;-“x‘

KEITH T. BUCK

OMe %Me

OMe

8’H’,’

.,H

Me / \

OMe

.-H

, \ I

CHO

Me I

/ \

OR

\ I

OMe

OH

67

65 R = H 66 R = A C

products was not possible. However, oxidation of tiliacorine acetate (66) with KMnO, in acetone [a procedure that was shown (39,40) to degrade specifically that portion of the molecule with an unsubstituted C-8 (or 8’) position] gave, after hydrolysis, the aldehydolactam 67. The UV spectrum of 67 shows a large bathochromic shift on addition of hydroxide, indicating a puru-hydroxybenzaldehyde moiety (40). The stereochemistry of tiliacorine and that of its diastereomer tiliacorinine were determined by feeding the enantiomers of specifically radioactively labeled N-methylcoclaurine to Tiliucoru rucemosu and degrading the resulting alkaloids (Section VI1,A) (41,42).Accordingly, tiliacorine has structure 65, and tiliacorinine is represented by 40.

15. Tiliageine and Funiferine The gross structure of tiliageine (68) was determined in 1974 (43,44),but stereochemistry could not be assigned at that time. Later feeding studies (Section VII,A) with radioactively labeled materials showed that both (R)- and (S)-Nmethylcoclaurines (69 and 22, respectively) are incorporated, and that 69 is the precursor for the right-hand portion of the molecule (45).The stereochemistry of tiliageine is therefore as indicated. Previous work had shown that methylation of tiliageine gives O-methylfuniferine (70); therefore funiferine is now positively identified as 71. Confirmation for this assignment was provided by study of the aldehydolactam (72) from

68 R ’ = R * = H 70 71

R ’ = R * =Me R’ =Me. RZ = H


17

HO

69

controlled oxidation of funiferine with KMnO, in acetone (46), in the same manner as for tiliacorine acetate (Section II,B,l4; also see Section II,C,33). 16. Tubocurarine, Tubocurine, and Curine An anomalous X-ray scattering study of (+)-tubocurarine dibromide (73 . 4MeOH) confirmed the structure and absolute configuration earlier assigned. The N-N distance is 10.66 A (47,48). A purified sample of (+)-tubocurarine chloride (73a), prepared by selective quaternization of (+)-tubocurine (74) (Section V,B,l), gave the anomalous MS behavior previously ascribed to thermal disproportionation or the presence of impurities. In particular, the MS has mle 594 [17%, (M - 15)+, loss of Me] but also 608 (3.7%) and 622 (0.5%).The higher peaks seem to be due to a thermal Hofmann elimination followed by recombination with methyl radicals. Similar behavior is observed with the tertiary bases (-)curine (75) and (+)-tubocurine (74), and may be general for alkaloids of this skeletal type (49).

73 R' =Me, R Z = H . 2 B r 73a R'=Me. RZ = H .2CI74 R'. R2 = no substituent

18

KEITH T. BUCK

75

C. NEWALKALOIDS: OCCURRENCE AND STRUCTURE 1. Apateline

Daphnandra upatela Schodde (Monimiaceae) affored apateline (76),mp 197200°C (dec.) (MeOH), [aID +270". It showed strong similarities to its diastereoisomer, micranthine (77), including formation of a blue-green coloration with H,SO,-HNO,, indicative of a dibenzo-p-dioxin alkaloid. It evidences an NMR singlet at 6 5.22, exchangeable with D,O, for the lone nitrogen proton, and shows a typical UV bathochromic shift with base. Diazomethane methylation gave 78, which was identical to telobine (also isolated from this plant), thus establishing the N-methylation pattern. The mass spectrum shows mle 335, representing the top half of the apateline molecule (cleavage at a) and showing that the phenolic function is in the bottom portion (50).

76 R ~ = H - , R ~ = H 77 R1 = H---, RZ = H 78 R' =.HI Rz = Me

2. Baluchistine The basic fraction of Berberis baluchistanica Ahrendt yielded (+)-baluchistine (79), C,6H,,N,06, mp 222-224°C (MeOH), [a]L6+333" (c = 0.075, MeOH). The UV spectrum,,,,A 283 nm (EtOH), showed a shift to 290 nm, typical of a phenolic alkaloid, on addition of base. Reaction of 79 with di-


19

azomethane gave (+)-obaberine (80). Comparison of NMR shift data for 79 and other derivatives belonging to the oxyacanthine series suggested that the two 0methyls are located at C-7 (6 3.23) and C-6' (6 3.60). Confirming this assignment, the MS shows fragments at mle 382 (loss of the bottom portion of the molecule at a-b), 207 (the top fragment from cleavage at a-c), and 174 (the top left-hand portion remaining after fragmentation at b-c). Baluchistine is the first bisbenzylisoquinoline alkaloid of its basic skeletal type that has a C-6 hydroxy (50.

3. Beccapoline and Beccapolinium

Beccapoline and beccapolinium are the first bis aporphine alkaloids, and were isolated in low yield from Polyalthia beccarii Kimf. (Annonaceae) (52). Beccapoline (81), amorphous, mp >280°C (dec.), C,,H,,N,O, [by high-resolution mass spectrometry (HRMS)], shows a long-wavelength carbonyl (1650 cm- l ) and a highly conjugated UV spectrum, with a bathochromic shift in acid. The NMR resembles a superposition of the two monomeric units (with, of course, elimination of two protons), except that the N-methyl (6 2.34) and one of the methoxys (6 2.95) are strongly shielded by the adjacent oxoaporphine ring, indicating the point of attachment. The 13C NMR of 81 shows singlets for C-4 and C-7'. Zinc/HCl reduction of 81 gave 82, which still retains the benzenoid protons of 81, in accord with this assignment. Beccapolinium (83), mp 250°C (dec.), C,,H,,N,O, (as the hydroxide), shows a NMR similar to that of 81 but with an additional methyl at 6 4.92. Reduction of

81 R = no substituent

83 R=Met OH-

82 R = H 84 R=Me

20

KEITH T. BUCK

83 with Zn/HC1 gave 84, identical to material obtained by CH,O/NaBH, methylation of 82.

4. Berbacolorflammine The orange base berbacolorflammine (85), [ C X ] ~+~ 1OOO" (c 0.004), MS m / e 605, was isolated from a CHCI, extract of Pycnarrhenu longifoliu. The structure proof of this alkaloid paralleled that for the isomeric colorflammine (Section II,C,l4). Notably, reduction with NaBH, gave the known alkaloid limacine (86), and with NaBD, gave trideuteriolimacine, showing the presence of a quaternary isoquinoline ring. Comparison of the NMR spectra of 85 and 86 showed that the higher field (6 2.57) NMe of 85 is at N-2', so the 6 3.53 quaternary NMe is in ring A. This conclusion was c o n f iie d from comparison of the I3C-NMR signals of the A rings in 85 and 86 (53).

86

5. Berbibuxine The same report that clarified the structures of the calafatine N-oxides (Section II,C, 10) also described berbibuxine (87), C,,H,,N,O,, amorphous, [6]D -228" (c 0.19, CHC1,). Diazomethane converted the alkaloid to calafatine (88, Section II,C,9). The location of the phenolic function was revealed by an NOE difference spectrometry (NOEDS) study (54, see Section VI,A,2,b).

87 R = H 88 R = M e

1. THE

BlSBENZYLISOQUlNOLlNE ALKALOXDS

21

89

6. Berbivaldine Berberis valdiviana Phil. (Berberidaceae) yielded berbivaldine (89), C,,H,,N,O,, amorphous, [ti]&? +140" (c 0.4, MeOH), NMR 6 3.83 (2-OMe), 3.31 (7'-OMe), 6.03 (d, J = 2.5 Hz, 8-H), 6.35 (d,J = 9.7 Hz, 11-H), 7.00 (dd,J = 9.7 and 2.5 Hz, 12-H). The alkaloid formed an 0,O-diacetate. In dilute HC1, berbivaldine rearranged to the new alkaloid porveniramine (90, Section II,C,95). Diazomethane converted 90 to 91, a known derivative of pakistanine (92).The 0acetates of berbivaldine and the related proaporphine-benzylisoquinolinedimers pakistanamine (Section II,B,6), valdivianine (Section II,C, 143), valdiberine (Section II,C,142), and patagonine (Section II,C,91) show similar CD curves, indicating identical configurations at the two asymmetric centers. Since the stereochemistry and absolute configuration of pakistanamine are known (Section 11,B,6), the structure of berbivaldine is as indicated (28).

7. Bursanine

NKFl

Bursanine, C,,H,,N,O,, MS mle 698 (0.1%), 192 (base), was assigned structure 93 from spectral considerations and comparison with similar alkaloids.

M eH'

11'

,OMe 12'

OR'

Me0

\

0

93 R' = H, R2 = OMe 94

R' = Me, R2 = H

22

KEITH T. BUCK

In particular, it shows a 5% NOE enhancement of H-11' on irradiation of H-8 and a 3% NOE of the C-12' methoxy from irradiation of H-1 l ' , confirming the location of the diphenyl ether bridge. The CD curve is characteristic of an alkaloid of the (+)-thalicarpine (94) type (55). 8. Calafatimine mp 180- 182°C (benzene-cyclohexane), Calafatimine ( 9 9 , C,,H,oN,O,, [a]$0- 141" (CHCl,), MS rnle 636 (base), was obtained from roots of Berberis buxifoliu Lam. (56). The NMR shows five methoxys and one N-methyl(6 2.40). The MS peaks at mle 381 (85%) and m/2e 190.5 (38%), representing the top portion of the molecule following cleavage at a, showed that two of the methoxys are on the bottom rings. Reduction (NaBH,) and methylation of the resulting tetrahydro base with NaBH,-CH,O gave calafatine (88, Section 11,C,9), shown to have the (R,S) configuration (57), and its diastereomer. By analogy to other alkaloids, notably thalsimine (Section II,B, 13) and thalibrunimine (Section 11,A,4), the N-methyl is most likely in ring A (as shown), but the isomeric D ring tertiary base cannot be excluded at present.

95

9. Calafatine Calafatine (88), mp 135- 137°C (benzene-cyclohexane), is the major nonquaternary base from the roots of Berberis buxifolia Lam. (58). The UV shows ,,,A (MeOH) 281 nm (log E 3.82) and 258 nm (3.32), indicative of only nonconjugated benzenoid rings, and no base shift was observed. The MS shows a base peak at rnle 198, corresponding to the top doubly charged portion of the molecule (cleavage at a). The NMR spectrum is consistent with structure 88. In particular, it shows a high-field C-7 methoxy at F 3.27 and a shielded C-8' aromatic singlet at 6 5.38, in accord with the points of attachment of the top ether bridge, as well as a doublet of doublets for the ortho hydrogens of ring E. Other suggestive evidence was provided by the MS, which shows fragmentation typical of a berbamine skeleton. When first performed, NalNH, cleavage gave only one isolated nonphenolic product, 96, of undertermined chirality, identified solely by NMR (58). Cal-

1.

THE BISBENZYLISOQUINOLINE ALKALOIDS

Me0

23

'OMe 96

afatine has [a]g -154" (c 0.28, CHCl,) [originally erroneously reported as positive (SS)],and a reinvestigation of the Na/NH, cleavage products identified (S)-( +)-96 and (R)-(-)-N-methylcoclaurine (69) (57). An NMR NOEDS study of 88 assigned all resonances, particularly the NMe signals (2-NMe 6 2.35, 2'NMe 6 2.59) (54). 10. Calafatine 2'cY-N-Oxide and Calafatine 2'P-N-Oxide

The title compounds, isolated from Berberis buxifolia Lam. (Berberidaceae), are the most recently reported of the eight known bisbenzylisoquinoline N-oxide alkaloids. They are noteworthy in being the first N-oxides of this group to have their complete stereochemistry assigned by NMR NOEDS studies (see Section VI,A,2,b). Unfortunately, the first report (59) was based on an incorrect assignment due to overlap of the NMe and aliphatic signals of calafatine (88, Section II,C,9) (54). Calafatine 2'a-N-oxide (correct structure 97), C,,H,,N,O,, has - 19" (c 0.14, MeOH), MS mle 668 (M+, 2%), 667 (I), 652 (44, M - 16), 396 (28), 395 (80), and 198 (base, doubly charged) (cleavage at a with loss of 0).The 2'P-N-oxide (correct structure 98), has -48" (c 0.17, MeOH) and mass, UV, and CD spectra similar to those of 97. The two N-oxides differ strikingly in TLC behavior: on silica gel with CHC1,-MeOH-NH,OH (90 : 10 : I), the aoxide has R , 0.17 and the P-oxide R , 0.26 (59, with correction of structure assignments). The NMR spectra of the N-oxides resemble that of calafatine but show lower field N-oxide methyls and downfield shifts of several of the protons on rings A' and B'. Complete NOEDS studies established the interconnection of 6-OMe-5-H-4-CH2, and, similarly, of 6'-OMe-5 ' -H-4'-CH2. Irradiation of

24

KEITH T. BUCK

the 2’-NMe of 97 gave an 11% enhancement of lf-H; however, similar irradiation of 98 showed 10% enhancement of 3’-Ha, but no effect on lf-H. From these observations it is apparent that the 1’-H and 2’-NMe are on the same side of the ring in 97 but are transoid in 98, as shown (54). 11. Chenabine along with its 7’-O-demethyl analog, jheluChenabine (99), C,,H,,N,O,, mine (100, Section II,C,49), was isolated from Berberis lycium Royle (Berberidaceae). Chenabine shows [a]$5+40° (c 0.18, MeOH), IR 1680 cm-I (aromatic aldehyde), NMR (CDC1,) 6 3.25 (7’-OMe), 5.23 (s, H-8), MS mle 624 ( M + , 0.2%), 397 (base), and 227 (4, both from cleavage at a). The UV spectrum shows a bathochromic shift as well as a hyperchromic effect with base, typical of a p-hydroxybenzaldehyde.

99 R = M e 100 R = H

NOE experiments confirmed the substitution pattern of chenabine, and the MS of 0-acetylchenabine, which shows the same mle 397 base peak as the alkaloid, provided further evidence for placement of the phenolic group. The CD spectrum indicates the (S) configuration. It is not known whether 99 and 100 are in vivo degradation products of a bisbenzylisoquinoline precursor or are primary products of biosynthetic coupling (60). 12. Chillanamine was obtained from Berberis buxijolia Lam. Chillanamine ( l O l ) , C,,H,,N,O,, (Berberidaceae) (57). It shows MS mle 626 (M’) and 192 (base), representing the two isoquinoline fragments from cleavage at a. The NMR shows considerable symmetry and the diagnostic doublets for the ortho protons of ring C (6 6.58 and 6.69, J = 8.5 Hz). The 13-H gives a 6.8% NOE enhancement on irradiation of the C-12 methoxy, indicative of the bridge location. Comparison of the CD curve of 101 with those of other alkaloids from the same plant suggested the stereochemistry indicated, but insufficient material was available for confirmatory cleavage experiments.


25

13. Chitraline The roots of Berberis orrhoborrys Bienert ex Aitch. (Berberidaceae) gave chitraline (102), C,,H,,N,06, [a]$5+ 136" (c 0.172, MeOH)(61,63). The MS shows major fragmentation at a, suggesting that one OH is on the isoquinoline ring. The UV and NMR spectra of 102 show strong resemblances to those of pakistanine (92). Acetylation of 102 to 103 caused a downfield shift of the H-8' singlet (from 6 6.37 to 6.53) and an upfield shift of H-11 (from 6 8.12 to 7.69), the latter effect comparable to that observed for 92. The CD curves of 102 and 92 are similar, showing that these alkaloids belong to the same stereochemical series. Since chitraline gave a green coloration on a TLC plate with iodoplatinate reagent (a specific reaction of C-1 phenolic aporphines), it may be assigned the indicated structure (61).

102 R ' = R * = H 103 R ' = R 2 = A c

Chitraline is obtained from B . baluchisranica under neutral conditions, so it is an actual alkaloid and not an artifact from acid-catalyzed dienone-phenol rearrangement of a proaporphine-benzylisoquinoline dimer (61). Chitraline has also been isolated from B . zebiliuna Schneider (62), and B . calliobotrys (62). A possible biosynthetic scheme relating chitraline with co-occumng alkaloids has been proposed (62, see Section VI1,C). 14. Colorflammine A chloroform extract of Pycnurrhena longifolia provided the orange alkaloid colorflammine (104), [a]L0+1050" ( c 0.06), FDMS mle 605. Its NMR spectrum shows a 3H singlet at 6 2.45, indicative of a quaternary nitrogen. Boro-

26

KEITH T. BUCK

104

NL-T

MeH-'

Meomhe HO

/

\

'OMe

106

0'

105

hydride reduction gave limacusine (105, confirmed by 'H and 13CNMR), showing both the gross skeleton of 104 and its degree of unsaturation. A sample of 105 prepared by NaBD, reduction of 104 showed no signal for H-i', previously identified in the nondeuterated 105 by NOE difference spectrometry (see Section VI,A,2,b) and homonuclear decoupling. Thus the quaternary nitrogen is in ring D. Colorflammine, like the simple dihydroisoquinolinium alkaloid pycnarrhine (106), showed no UV base shift but in acid gave a colorless solution and a changed UV spectrum (53). 15. Coyhaiquine Coyhaiquine (107), C,6H,,N0,, from Berberis empetrifolia Lam. (Berberidaceae), although not formally a bis alkaloid, appears to be derived by in vivo degradation of a proaporphine-benzylisoquinoline. NMR spin decoupling experiments assigned the chemical shifts of the 6a, 7 a , and 76 hydrogens. NOE experiments then showed a 3% enhancement of the 7a-H on irradiation of the 8H, establishing the indicated syn stereochemistry (64).

107

Comparison of NMR data for coyhaiquine and other dienone alkaloids showed that the relative stereochemistries can be assigned easily. In coyhaiquine the chemical shifts of H-11 and H-12 (6 6.37 and 7.06, respectively) differ by 0.69 ppm; a similar difference (0.70 ppm) is observed for pakistanamine (46). How-

27


ever, the differences in the anti series of alkaloids, e.g., epivaldiberine (108, 0.43 ppm) and orientalinone (109, 0.45 ppm), are uniformly smaller. Since the stereochemistry of the dienone-phenol rearrangement of proaporphine-benzylisoquinoline to aporphine-benzylisoquinoline alkaloids is known (28) (see Section IV,A,6), this method provides an easy correlation of the stereochemistries of these co-occurring dimers.

OMe

108

109

16. Curacautine

-5" (c = 0.18, MeOH), was isolated Curacautine (110), C,,H,,N,O,, from Berberis buxifoliu Lam. (Berberidaceae). It shows carbonyl bands at 1640 and 1690 cm-', a small MS parent ion at mle 682, and a base peak of 411 (cleavage at a). The CD curve indicates (S) configuration. Oxidation of the cooccurring calafatine (88, Section II,C,9) with KMnO, in acetone gave 110, thus establishing the substitution pattern and confirming the stereochemistry of curacautine (57).

110

17. Cycleanine N-Oxide

Cycleanine N-oxide (lll),[a]k5-7.6" (c 0.38, MeOH), is apparently not an artifact since it occurs [with cycleanine (112)] even in fresh extracts of Synclisiu scubridu Miers (Menispennaceae). The electron impact mass spectrum (EI-MS) is similar to that of cycleanine (rnle 622), but the field desorption mass spectrum (FD-MS) shows principal mle 638. The 'H NMR is comparable to that of 112, except for an N-methyl shifted to 6 3.32. Reduction of 111 with H,SO, gave 112; also, 111 was the less polar product of reaction of cycleanine with H,O, (65). Because of symmetry, only two monoxides are possible, but the steremhemistry of the oxidized nitrogen of 111 was not determined.

28

KElTH T. BUCK

Me0 " H

I

'OMe

111 x = o 112 X = no substituent

18. Daphnine The orange-yellow alkaloid daphnine (113) was isolated from Daphnandra repandula (66). The structure was proven by NOEDS studies (see Section VI,A,2,b) of its dihydro diacetate in CD,CO,D. These measurements showed the connectivity relationships of 2'-Me-3'-H-4'-H-5 '-H-6'-OMe and 5-H-6OMe, which served to eliminate other isomeric structures, notably a 7-6' etherlinked dimer (67). The structure of daphnine was confirmed by an X-ray analysis of the dihydroiodide. It was postulated that daphnine, the only bisbenzylisoquinoline alkaloid with a 7-7' ether linkage, arises by rearrangement of (-)nortenuipine (114) or its enantiomer, which also occur in Duphnandra species (66).

"12

MeN, tg

/

\

'0

1

0

OJ

113

MeH,' N

'

:T

\

k

'0

'0

/

6-f

Me

114

19. Daurisoline Menispermum dauricum (Menispermaceae) yielded daurisoline (115), - 129" (c 0.65, MeOH), C37H42N206, mp 96-102°C (cyclohexane),

1.


29

,,,A

(MeOH) 284 nm (log E 4.01), MS rnle 610 ( M + , 0.25%), 206 (92.5%, cleavage at a), 192 (base, cleavage at b), 177 (5.35%, loss of Me from base), NMR (CDCl,, 100 MHz) 6 2.50, 2.44 (two NMe), 3.60, 3.75, 3.82 (three OMe), -5.0 (2H, phenolic, D,O exchangeable), 6.10-7.14 (1 1 aromatic H). Complete methylation (Mel, base) of daurisoline gave an 0,0-dimethyl dimethiodide identical to that obtained from dauricine (116). In dauricine, the MS rnle 192, representing loss of a Me from a head fragment, is only a minor (1.9%) peak; therefore daurisoline must have a hydroxy on one of the isoquinoline rings. Since the NMR spectrum shows only one peak (6 3.60) in the range for a 7- (or 7'-) OMe, there was at this point in the structure proof a choice between two possible isomeric structures for daurisoline.

M H.1. -b e

N

x

'OH 115 116 118 119 120

3 a. H'

0

Me

R'=R2=Me. R 3 = H R'=R2=R3=Me R'=R3=Me.R2=H R'=H, R 2 = R 3 = M e R ' = R2 = H, R' = M e

The structure was firmly established as 115 by an unusual strategem. The N,Ndimethyl quaternary salt of 115 was alkylated with p-chlorobenzyl chloride, and the product was subjected to Hofmann degradation, giving 117. (The styrene rather than stilbene pathway for the degradation was ruled out by the absence in the MS of 117 of significant head fragments, rnle 220.) This material cannot undergo the doubly benzylic MS cleavage shown by the parent alkaloid, and gives instead major fragments from scissions at a and b of the diphenyl ether linkage. The ions at mle 561, 563, and 565 (intensity ratios 9 : 6 : 1, M - a + 1) have the isotope ratios expected for a fragment containing two C1.

117

30

KEITH T. BUCK

The large specific rotation of daurisoline places it in the (R,R) group, along with dauricine, daurinoline (118), dauricinoline (119), and dauricoline (120), other alkaloids of the dauricine subgroup that are known from M . dauricum (68). Daurisoline has also been isolated from Polyulthia nitidissima Benth. (Annonaceae) (69). 20. 1,2-Dehydroapateline 1,2-Dehydroapateline (121) from Daphnandru upatela Schodde (50)and Doryphoru aromatica (F. M. Bailey) (70) has reported mp 196-198°C (dec.) (70) and 192-198°C (dec.) (50), +137", and IR 1615 cm-l. The NMR shows one N-methyl (6 2.54). 1,2-Dehydroapateline gave a positive test for a dibenzodioxin alkaloid with H,SO,-HNO, (blue-green coloration) (70), and the UV spectrum revealed a typical base shift. Sodium borohydride reduction gave material identical to apateline (76, Section II,C,l) in all respects, including specific rotation, thereby firmly establishing structure 121 (50).

(QT +A _ _ -..---

_ _ __------

Me

121 R = H 122 enantiomer of 121 123 R = M e

21. 1,2-Dehydromicranthine A new Daphnundra sp. (Monimiaceae) yielded 1,2-dehydromicranthine (122), mp 188-194°C (dec.), [a]gO - 150" (CHCI,), UV A,, 335 nm (log E 3.4, aromatic imine). Sodium borohydride reduction gave micranthine (77) (71). Dehydromicranthine and dehydroapateline (Section II,C,20) are enantiomers. 22. Dehydrotelobine was obtained from the bark of DaphDehydrotelobine (123), C,,H,,N,O,, nandra upatela Schodde (Monimiaceae). The NMR spectrum shows great similarity to that of telobine (78), but the UV spectrum (A, 336 nm) indicates a more conjugated system. The alkaloid also has only a weak MS mle 335 (corresponding to cleavage at a, a major fragmentation mode in reduced alkaloids such as


31

telobine). Reduction (H,/Pd-MeOH, CHCl,), and methylation (CH,O/NaBH,) of 123 gave the N-methyl dihydro derivative, identical to that obtained on methylation of O-methylapateline (78, Section II,C, 1). The reduction was stereospecific, and only the one series of possible diastereomers was produced. Since 0-methylapateline is identical to telobine (by comparison of N-acetyl derivatives), the stereochemistry is established. Dehydrotelobine appears to be a biological product rather than an isolation artifact as it was not produced in significant quantity even after prolonged exposure of telobine to light and air (50). Dehydrotelobine has also been isolated from Albertisia pupuanu Becc. (Menispermaceae) (72). 23. 7-0-Demethylisothalicberine 7-0-Demethylisothalicberine (124), C,,H,,N,O,, mp 245-247°C (CHC1,cyclohexane), [a]hO-230" (c 0.2, CHCl,), was isolated, along with the closely related new base isothalicberine (125) (see Section II,C,45a) and the known 0methylisothalicberine (126), from Berberis chilensis Gillies ex Hook (Berberidaceae). The NMR spectrum of 124 shows only two methoxys but is otherwise similar to that of 126. Diazomethane converted 124 to 126. The MS m / e 382 and 381 (cleavage at a) of 124 confirmed that one of the phenolic functions lies in the bottom portion of the molecule. Deuterium exchange (D,O-NaODDMF, prolonged heating) replaced only one hydrogen (at 5"), showing that the OH in the top portion has no free ortho position (73).

M H,: .a i

\

N

'ORZ 5"

w

YL /

3..

.'H

0 '

124 R ' = R * = H 125 R ' = M e . R Z = H 126 R' = R Z = Me

24. 7-0-Demethylpeinamine 7-0-Demethylpeinamine (127), C,,H,,N,O,,

from Abutu grisebachii Triana

& Planchon (Prance) (Menispermaceae) formed crystals (CHC1,-EtOAc), mp 205-206"C, [a]hO-86" (c 1, MeOH). The MS shows cleavages a-e. Successive

methylation of 127 with CH,N, and CH,O/HCO,H gave the completely methylated 128, which was proven by NMR and ORD to be the enantiomer of isotetrandrine. Comparison of NMR data showed that ring A of 127 contains the secondary N, and the MS fragments established that C-6' is methoxylated and

32

KEITH T. BUCK

127 R = H 128 R = M e

that ring E contains a free OH. The remaining OH was proven to be at C-7 because the extremely high-field (6 3.11) signal of the C-7 methoxy of 128 is absent in 127 (74).

25. N-Desmethylcycleanine Stephania glabra (Roxb.) Miers (Menispermaceae) yielded N-desmethylcymp 102-103"C, - 165" ( c = 0.29, CHC1,). cleanine (129), C,,H,oN,O,, It shows one N-methyl (6 2.51) and IR absorption for NH at 3350 cm-l. Reaction of 129 with CH,O/HCO,H gave cycleanine (112). The 'H- and 13CNMR spectra of 129 and 112 show considerable symmetry, with the greatest differences between these alkaloids in the C-1 and C-1' resonances (75). Since cycleanine has an axis of symmetry, there is no question of deciding which N of 129 is methylated.

129

R=H

26. N-Desmethylthalidasine Thalictrumfuberi Ulbr. afforded, in addition to the known alkaloid thalidasine (130), N-desmethylthalidasine (131), C,,H,,N,O,, amorphous mp 137- 139"C, [a], -86.9' ( c 0.4141, MeOH). N-Methylation (CH,O-NaBH,) of 131 gave thalidasine (identical by ORD to material of known absolute configuration), and Na/NH, cleavage of the alkaloid gave 132, showing the location of the secondary N (76).

c 3 Meoy 33


Me(HN

'H R .

/

\

/

OMe

/

0'

HO

130 R = M e 131 R = H

k .a RN H
0

89

.c

326 R’ = R’ = Me, Rz = H 326a R’ = RZ =Me, R’ = H 327 R’ = R’ = Me, Rz = Et 330 R’ = ti, R2 = R’ = Me

(4.30). The mass spectrum shows major fragmentations at a, b, and c (147). Thalirevoline gave a positive phosphomolybdic acid test for a phenol but gave a negative Gibbs’ test, indicating that the OH is para substituted. Diazomethane converted the alkaloid to thalirevolutine (276, Section II,C, 126), also isolated from T . revohturn. Cleavage (Na/NH,) of O-ethylthalirevoline (327) yielded 328 and 329. The mass spectrum of 329, mle 387 (2%, M+) , 206 (base, cleavage at a), and 181 (2%, cleavage at a), showed that the OH lies on the benzyl ring portion. Additionally, the NMR spectrum (90 MHz, CDC1,) of 329 shows the ortho benzyl protons as an AB quartet at 6 6.21, 6.51 (J = 8.3 Hz). Since the final evidence for the structure of thalirevoline rests on the Gibbs’ test, the validity of which has been questioned (152), the choice of structure 326 over the alternative 326a for thalirevoline should be considered provisional (147).

Meop

M He Nf .ag z \ : :

HO

/

/

OR

OMe

Me0

Me

‘ 328

329 R = E t 331 R = M e

126. Thalirevolutine Thalictrum revolutum D. C. also yielded thalirevolutine (276), C, ,H,,N,O,, crystals (ether), mp 105-108°C. The UV spectrum of 276 was unaffected by acid or base, as expected for a ditertiary nonphenolic alkaloid. O-Methylation (CH,N,) of both thalirevoline (326, Section II,C,125) and fetidine (330) gave thalirevolutine, establishing structure 276. The mass and NMR spectra confirmed this conclusion, as did Na/NH, cleavage of 276, which afforded 328 and 331. Due to intramolecular hydrogen-bonding between the nitrogen and the phenol, 331 shows an anomalous CD curve [resembling that of an (R)-benzyliso-

90

KElTH T. BUCK

quinoline], but on addition of acid, or after 0-methylation, the expected CD behavior was observed (147,153). 127. Thalirugidine Thalictrum rugosum Ait. (T. glaucum Desf.) was the source of thalirugidine (332), C39H46N208, amorphous, [a]&o+112" ( c 0.19, MeOH), MS m / e 670 (1.4%, M+), 222 (base, cleavage at a). Thalirugidine gave an 0,O-dimethyl derivative with CH,N, and an 0,O-diethyl derivative (333) with diazoethane. Sodium/ammonia cleavage of the latter afforded 56 and 55, both previously identified as products of the known alkaloid thalidezine (53, Section II,B, lOa), as well as crystalline 31 1, also obtained from degradation of 0-ethylthaligosine (310). Additionally, KMnO,/Me,CO oxidation of 333 gave 334 and 227 (146).

. R20 . O b N M e 0

334

R' = OEt.

R2 = M e

128. Thalirugine Thalirugine (312), C,,H,,N,O,, [a]L0 +92" ( c 0.25, MeOH), an amorphous alkaloid from Thalictrum rugosum (T. glaucum) shows only a weak MS parent ion, m / e 640 (0.01%), and fragments at mle 222 (base, cleavage at a), 207 (35%, 222 - Me), and 192 (83, cleavage at b), behavior typical of a tail-to-tail linked dimer with dissimilar head units. Thalirugine formed with CH,N, an 0,O-dimethyl derivative (335), the mass spectrum of which shows m/e 668 (0.3%,M+), 236 (base, cleavage at a), and 206 (91, cleavage at b), proving that the two phenol functions of 312 are divided between the head units. Sodium/ ammonia cleavage of 0,O-diethylthalirugine (336) gave 231 and 311; the latter was also obtained by degradation of 0-ethylthaligosine (Section II,C, 118). Ox-


91

0 R'

Me N H f .b

'OMe 312 335 336 337

R1=R2=H

R' = R ~ = M ~ R1= R2 = Et R'= H, RZ = M e

idation of 336 with Kh4n041Me,C0 gave 4,334, and 227. A positive Gibbs' test obtained for thalirugine is additional evidence for a 5'-OH in the alkaloid (146). 129. Thaliruginine amorphous, [a]fP+ 104" (c 0.16, MeOH), Thaliruginine (337), C,,H,,N,O,, was obtained from Thalictrum rugosum (T. glaucum). It has IR (CHC1,) 3520 cm-' (OH), UV,,,A 281 nm (log E 3.90), shifted in 0.01 N NaOH to 281 (3.97), 309 sh (3.09), MS mle 654 (0.8%, M+), 222 (68, cleavage at a), 206 (base, cleavage at b). Thaliruginine gave an 0-methyl derivative, 335, identical to 0,O-dimethylthalirugine (Section II,C, 128). Cleavage (Na/NH,) of O-ethylthaliruginine produced (S)-0-methylarmepavine (52) and 311, completing the structure proof (146). 130. Thalistine One of the alkaloids reported from Thalictrum minus L. Race B is thalistine (338), C39H44N208,[a]&0+104" (c 0.35, MeOH), IR 3520 cm-' (OH), MS mle 668 ( 5 % , M +), 222 (base, cleavage at a), 220 (91, cleavage at b). The NMR spectrum shows a 2H coincident singlet for H-8 and H-8' at 6 5.76, four OMe, a methylenedioxy at 6 5.88, and a D,O-exchangeable broad singlet at 6 5.8 (OH). Thalistine gave a positive phenol test with phosphomolybdic acid and a positive Gibbs' test for a para-unsubstituted phenol. Diazomethane converted

92

KEITH T. BUCK

thalistine to N-desmethylthalistyline (134), an alkaloid of T . longistylum D.C. (Section II,C,28), and diazoethane gave the 0-ethyl derivative, 339. Cleavage of 339 with Na/NH, gave the known compounds 55 ( 3 3 3 9 , and 322. Degradation of the methylenedioxy group and elimination of one of the oxygens of the left-hand head unit of 339 is not unexpected (32,34).The resulting products are not sufficient to locate the diphenyl ether unambiguously; however, oxidation of 339 with KMnO, in acetone gave 325, 334, and 227, ruling out other alternatives. The CD spectrum of thalistine is in accord with the (S,S) configuration (33). 131. Thalistyline HRMS mle 697.3513, was found in both the Thalistyline (319), C41H49N208+, CHC1,-soluble and quaternary fractions of Thalictrum podocarpum Humb. and T . longistylum D.C. It was isolated as the chloride, mp 150-153"C, [a]&5+ 146" ( C 0.1, MeOH), NMR (CDC1,) 6 2.48 (NMe), 3.45 (NMe,+), 5.89 (CH,O,), five methoxys, nine aromatic H, including two higher field (H-8 and H-8', 6 5.70, 5.77), and an A,B, quartet (6 6.63, 6.98, J = 8 Hz).

'-I

\

340

341 R = M e

Sodium/ammonia cleavage of thalistyline produced 340, from reductive Hoffmann elimination, and 322 (isolated as 341), from fission of the methylenedioxy group. Oxidation (KMnO, in acetone) gave 325 and 227, showing the location of the methylenedioxy and position of the ether linkage of thalistyline. The CD curves of thalistyline and its methodiiodide resemble that of thalibrine (Section II,C,ll l), of known (S,S) stereochemistry, and are similar but opposite in sign to those of dauricine (116) (R,R) and its dimethiodide, suggesting the indicated stereochemistry (77,78). 132. Thalmirabine Thalictrum minus Race B was the source of thalmirabine (342), C,,H,,N,O,, amorphous, [a]kO +116" (c 0.2, MeOH), IR 3530 cm-' (OH), MS mle 668 (37%, M + ) , 442 (4, cleavage at a and b), 222 (56, cleavage at b and c), 221 [base, cleavage at a and b (double ion), and/or b and c], 206 (18, cleavage at a


93

342 R = H 343 R = E t

and d). The NMR spectrum shows an OH (broad s, 6 5.20, D,O exchanged) and five OMe. The Gibbs' test for a para-unsubstituted phenol was negative. Cleavage (Na/NH,) of 0-ethylthalmirabine (343) gave 52, 343a, and 311. Fragments 343a and 311 clearly are derived from a 5-8' ether linkage, but the exact nature of the benzyl unit linkage was still uncertain, although it was apparent that the monooxygenated benzyl ring is part of the right-hand half of the molecule. Oxidation of thalmirabine (342) with KMnO, in acetone and CH,N, methylation of the product gave 172, thus establishing the bridging of the lefthand benzyl residue (33).

::

M e ; !

/

ORZ

343a R' = OH, RZ = Me

133. Thalpindione Thalpindione, an evidently unusual alkaloid from Thalictrum alpinum L. (Ranunculaceae), correct empirical formula C,,H,,N,O,, was isolated as a pale yellow amorphous material, [a]&1-41.5' (c 0.29, MeOH), UV,,,A 283 nm (sh, log t 3.77), 275 (3.78), unaffected by base (cryptophenol) or acid, IR 3530 cm- (OH), 1663 (C = 0).Initially, the erroneous structure 344 was assigned

344 R = H 345 R = Me

94

KEITH T. BUCK

to the alkaloid, based largely on 90-MHz NMR evidence (which did not allow assignment of individual aromatic protons due to paucity of material) and on analogy to the related co-occumng alkaloids thalidasine (130) and thalrugosidine (136). Since CH,N, converted thalpindione to thalrugosinone (Section II,C, 135), the latter was assigned the incorrect structure 345. The substitution patterns of thalpindione and thalrugosinone were deduced from NMR data, which indicated a C-7 OH [C-7 OMe for 130 6 3.27, for thalrugosinone 6 3.33 (79)l. A reinvestigation of thalrugosinone (see Section XI,A,2) allowed assignment of the correct structure to thalpindione. 134. Thalrugosaminine Thalrugosaminine (309, see Section II,C, 118), C,9H,,N,0,, [a]&s -90.4" (c 0.104, MeOH) (154), was isolated from Thalictrurn rugosum ( 1 5 3 , T. revolutum (154), T. minus Race B (32), and T. alpinum (79) as the amorphous hemihydrate, mp 90-95°C ( 1 5 3 , 103-105°C. (154). The UV spectrum shows no acid or base shift, and no phenol or imine is evident in the IR spectrum. The NMR spectrum shows two NMe, five OMe, and nine aromatic H. The mass spectrum, m / e 652 (49%, M+), 651 (33), 426 (19), 425 (59), 213 (base, doubly charged, cleavage at a) is typical of a head-to-head doubly linked dimer. Cleavage (Na/NH,) of thalrugosaminine, which was at first only partially definitive due to shortage of material (155), gave 346 and 197. Oxidation KMnO,/Me,CO) of the alkaloid produced a diacid, identified as its dimethyl ester, 172, defining the linkage of the lower rings (154). OMe

'OH 346

135. Thalrugosinone Thalrugosinone, correct empirical formula C,,H,,N,O, , was obtained from the ether-soluble nonphenolic tertiary alkaloid fraction of Thalictrum rugosum Ait. (T. glaucum Desf.) as an amorphous material, darkening in air, [a]g -46.4" (c 0.125, MeOH). The UV spectrum shows somewhat stronger higher wavelength absorptions than related alkaloids that lack carbonyl functions, and the IR spectrum has C = O absorption at 1660 cm- l . Too small a quantity of the alkaloid was available to allow degradative study. From available evidence,

I . THE BISBENZYLISOQUINOLINE ALKALOIDS

95

thalrugosinone was assigned the incorrect structure 345 (119). For the correct structure, see Section XI, A,4. 136. Tiliacorinine 2'-N-Oxide was The amorphous alkaloid tiliacorinine 2I-N-oxide (347), C,,H,,N,O,, obtained, along with the known tiliacorinine (40), from Tiliacora triandra Diels, a menispermaceous plant of Thailand (156). The alkaloid has mp 215-217°C (dec.), [a]b9+238.3" (c 1.1, CHCl,), HRMS mle 592.2563. Its NMR spectrum is very similar to that of 40, with the exception of the 2'-NMe, which is shifted to 6 2.99 (versus 2.62 for 40) (24).The mass spectrum shows mle 592 (20%, M+ ) , 591 (20), 576 (46), 575 (46), 574 (46), and is otherwise similar to that of tiliacorinine. Phosphorus trichloride deoxygenation of 347 gave 40, proving the structure except for the N-oxide stereochemistry. Tiliacorinine 2'-N-oxide is the third reported bisbenzylisoquinolineN-oxide alkaloid (see Sections II,C ,37 and II,C,107) (156). OMe

347

137. Tiliafunimine was isolated from Tiliacora funifera (T. Tiliafunimine (348), C,,H,,N,O,, warneckei) Engl. ex Diels (Menispermaceae) as colorless needles, mp 198+294.3" (c 0.52, CHCl,), IR (KBr) 1503 cm-', 1618 (sh) 200°C, (C=N), UV , ,X (MeOH) 212 nm (log E 4.77), 238 sh (4.46), 285 (3.99), 319 sh (3.85), shifted with HCl to 225 (4.74), 292 sh (3.88), 334 (4.15), MS mle 592 (96%, M+), 591 (base). The spectral evidence suggested an iminobisbenzyliso-

NK :qN OH

Me

"H

340

96

KEITH T. BUCK

349

R=H

quinoline alkaloid. Reduction of tiliafunimine with NaBH, was stereospecific, giving a single dihydrobase, which on methylation yielded the known alkaloid thalrugosine (349), also shown to be present in T. funifera. The imine function was placed in ring A on NMR grounds: the NMe (6 2.67) lies clearly in the relatively low-field region characteristic of a ring D isotetrandrine (236) substituent (157).No definite commitment was made about the configuration of the single asymmetric center of tiliafunimine (157,158);however, the stereochemistry of thalrugosine is well established, leaving almost no doubt on this matter. 138. Tiliamosine was first isolated from Tiliucoru rucemosa Tiliarnosine (350), C,,H,,N,O,, Colebr. (Menispermaceae) and characterized as its N-acetyl derivative (42), mp 276-277°C (dec.), [a]&7+530" (CHCI,), IR (KBr) 1640 cm-' (NAc) (26). Compound 42 gave a positive color reaction (25) for a dibenzo-p-dioxin and a positive test (159)for a cryptophenol. The mass spectrum (mle 634, 408, 407, 366,365,35 1, 183) is characteristic of a biphenyl-linked dibenzo-p-dioxin structure. The N-acetate also showed a phenolic OH [IR (KBr) 3360 cm-', UV bathochromic base shift] and could be converted to a 0,N-diacetate, IR 1762 (OAc) and 1642 cm-' (NAc).

350 351

R' = OMe, R2 = R' = H R' = OMe, Rz = R' = Me

The structure of tiliamosine, exclusive of stereochemistry, was deduced by NMR spin decoupling and NOE studies of 42 and the N-acetate of the related alkaloid nortiliacorinine A (44,Section II,B,5). The 100-MHz NMR spectrum of 42 very closely resembles that of 41, but 42 has an additional methoxy (6 3.88),

1. THE BISBENZYLISOQUINOLINEALKALOIDS

97

concomitant with absence of one singlet (6 6.30) aromatic H. An approximately 25% NOE of the aromatic H-27 signal at 6 6.65 occurred on irradiation of the benzylic protons of 42, but there was no effect on H-25; a similar experiment on 41 showed enhancement of both H-20 and H-27. Also, irradiation of 21-OMe (6 3.84) of 41 enhanced the (6 6.30) H-20, showing this to be the location of the additional OMe in 42. Other experiments showed the proximity of H-27 to H-4a (five-bond zigzag coupling), of H-4a to the nonequivalent C-5 methylene protons, and of this methylene to the aromatic protons of ring F. Irradiation of the methoxys of tiliamosine acetate affected the H-13 doublet, showing the presence of an OMe on ring E, and therefore of an OH on ring F (26). A degradative approach (40) to structure determination of tiliacorine alkaloids is described in Section II,B,l4, and the absolute configurations of several are known from plant feeding experiments (42)(Section VI1,A). The large positive rotation of tiliamosine N-acetate indicates that it belongs to the (S,S) series (27a,160). Tiliamosine has more recently been isolated from Pachygone ovata (Poir.) Miers ex Hook. (Menispermaceae) in the form of the amorphous free base, mp 167-170°C (CHC1,-MeOH) +267" ( c 0.48, CHCl,), NMR (600.6 MHz, CDC1,) 6 2.32 (NMe), 3.83, 3.94, 3.98 (three OMe), and eight well-resolved aromatic H. Methylation (CH,O/HCO,H) of tiliamosine gave 258, identical to N,N, 0-trimethylpachygonamine (see Section II,C, 89); N,N , 0,O-tetramethylpachygonamine proved identical to N, 0-dimethyltiliamosine (351) (114). Tiliamosine is the first dibenzo-p-dioxin bisbenzylisoquinoline alkaloid having a tetroxygenated benzene ring (26). 139. Toddalidimerine Toddalia asiatica Lamk. (Rutaceae) provided a low yield of toddalidimerine (352), the first bisbenzophenanthridine alkaloid having dissimilar subunits. It

Me0

352 R = H 353 R = M e

OMe

354

98

KEITH T. BUCK

melts at 307°C (CH,Cl,-Et,O), has [a]hO$60" (c 2, CHCl,), and shows MS mle 738.2567 (C,H3,N,0,), with major fragments 348 (base) and 391 (6%) (both from cleavage at a) and 333 (30%, 391 - Me,CO). Curiously, no m / e 405 peak, derivable from primary cleavage at b, was detected. The NMR spectrum shows one NMe (6 2.71), two doublets (6 2.92, 2.99) for the methylenes adjacent to the carbonyl, and 6 5.03 and 5.12 peaks for the two associated methine protons (coupling constants unspecified), as well as the expected aromatic, OMe, and CH,O, resonances. An attempt to convert toddalidimerine to the known alkaloid 353 by methylation with CH,O/HCO,H was unsuccessful, leading by further reaction to the cleavage product 354 in quantitative yield (161). 140. Trigilletimine (HRMS m / e 558.2131), was first obtained Trigilletimine (355), C3,H,,N,0, as an uncharacterized base (TGS- 1) from Triclisia gilletii (DeWild.) Staner and T . patens Oliv. in 1974. Trigilletimine formed colorless needles, mp 284°C (dec.), [a]$5-285.7" (c 0.7, CH,Cl,), and gave a positive dibenzo-p-dioxin color test with H,SO,-HNO,. The UV spectrum,,,,A (MeOH) 210 nm (log E 4.72), 232 (sh) (4.67), 273 (sh) (4.21), 311 (sh) (3.46), and 351 (3.09, undergoing a bathochromic shift in acid, indicates an aromatic heterocyclic system. The NMR spectrum (60 MHz, CDCl,), 6 2.40 (NMe), 3.92, 3.99 (two OMe), 7.39, 8.34 (two lH, d, J = 6 Hz), and ten unresolved ArH, is in agreement with a dibenzo-p-dioxin alkaloid with one isoquinoline head unit, as is the mass spectrum, in which the base peak is the molecular ion. OMe

OMe

0'

355

356 357

R=H R=Me

Catalytic reduction (EtOH, Pd/C) of trigilletimine gave a single tetrahydro isomer (356), which on N-methylation (CH,O/NaBH,) yielded 357. Compound 357 is enantiomeric to the N-methyl derivative (204)of the known alkaloid telobine (Section II,C, 1). However, 356 is neither enantiomeric nor identical to telobine, and therefore the NMe and NH functions are reversed. Accordingly, trigilletimine is 355 (162). Trigilletimine is the first dibenzo-p-dioxin alkaloid that incorporates an aromatized isoquinoline ring (162,163).

1. THE BISBENZYLISOQUWOLINE ALKALOIDS

99

141. Uskudaramine Thalictrum minus L. var. microphyllum (Ranunculaceae) was the source of the amorphous base (+)-uskudaramine (358), C,,H,N,08, [a]&s+84" ( c 0.15, MeOH). The structure proof of uskudaramine was simplified by comparison of its properties with those of the isomeric (+)-istanbulamine (173, Section II,C,47), isolated from the same source. Notably, the NMR spectrum of 358 lacks the H-8' (6 6.84) singlet of 173, and its UV spectrum shows not only a bathochromic base shift but also a hyperchromic effect, characteristic of a 3- or 9-hydroxyaporphine. OMe

358

W

Uskudaramine yielded an 0,0,O-triacetate, causing a downfield shift (from 6 7.99 to 8.11) of H- 11. Hence the alkaloid has three OH, one in the D ring of the aporphine moiety. An NMR NOE difference study (see Section VI,A,2,b) of the alkaloid showed, among other things, that only one aromatic H (H-1 1) is located on the aporphine portion and that it is adjacent to a OMe. A 1% NOE enhancement of the H-8' signal by irradiation of H-10' shows their proximity in the preferred solution conformation of uskudaramine. Uskudaramine is the first aporphine-benzylisoquinoline dimer joined by a biphenyl linkage and is thought to be derived by direct oxidative coupling of aporphine and benzylisoquinoline precursors (164). 142. Valdiberine amorphous, [a]&5+91" (c 0.4, MeOH), was Valdiberine (149), C,,H,,N,O,, isolated, along with its diastereomer, epivaldiberine (108, Section II,C,34), from Berberis valdiviana Phil. The NMR spectrum shows two OMe (6 3.80, coinci-

MeNT;2M 'H

/'

/

359

RI

= H, RZ = Me

100

KEITH T. BUCK

dent peaks) and lacks the higher field signals characteristic of a 1- or 7'-OMe. Acid-catalyzed rearrangement of valdiberine gave (+)-chitdine (102, Section II,C,l3), proving its structure (28). Prior to its isolation, valdiberine was suggested as a likely biosynthetic intermediate between berbamunine (182) and alkaloids of the khyberine (150, Section II,C,54) and chitraline series (62). 143. Valdivianine Another benzylisoquinoline-aporphine dimer from Berberis valdiviana and B. empetrifolia is valdivianine (359), amorphous, C,,H,$J,O,, [ c Y ] ~+ ~ 120" (c 0.2, MeOH), CD (MeOH) A E (nm) -0.7 (300), +8.0 (278), +3.8 (235), +17 (21 1). Its NMR spectrum indicates three OMe, 6 3.83 (6H, 2- and 6'-OMe) and 3.54 (7'-OMe). Other features of the NMR spectrum closely resemble those of pakistanamine (46,Section II,B ,6). Acid-catalyzed dienone-phenol rearrangement of 359 produced (+)-pakistanine (92), a known alkaloid which also occurs in B . valdiviana, thus proving the structure (28). 144. Vanuatine

+ 138" (c 0.12, MeOH), was ob(+)-Vanuatine (360), C39H,6N,0,, tained from bark of Hernandia peltata Meissner (Hernandiaceae). The MS base peak, mle 192 (cleavage at a), suggested a tail-to-tail singly bridged dimer with head units of equal mass. An NOE difference study (see Section VI,A,2,b) showed an enhancement of 5% of H-lo', and, more interestingly, of 1.5% of H-1 1, on irradiation of H-8', showing their conformational proximity. The NMR spectrum shows only lower field (6 3.72-3.88) OMe, indicative of OH at C-7 and C-7'. Methylation (CH,N,) of vanuatine and cleavage (Na/NH3) of the product gave (+)-0-methylarmepavine (52) and compound 201, which was characterized by MS, NMR, JJV, and CD. These data were sufficient to assign structure 360 to vanuatine (110). M H fe-.a N

'' '

W

:

?

OMe

1o.a.

...H Me

/

l?'

Me0

'

R2

360 R' = H, R2 = OMe 361 R ' = O H . R Z = H

145. Vateamine In addition to malekulatine (Section II,C,59) and vanuatine (360, Section II,C, 144), Hernandia peltata also yielded a third bisreticuline alkaloid, vat-


101

MeoX3JHMe

Me0

RO Me0

362 R = H 363 R=Me

eamine (361), C3,H4,N,0,, [cx]g5 +204" ( c 0.14, MeOH). Vateamine, like vanuatine, shows only a small MS parent ion and a large mle 192 base peak. All protons of 361 were assigned by NOE difference study of the NMR spectrum; unlike 360, the C ring of vateamine shows two ortho protons, J , = 8.5 Hz. Vateamine gave with CH,N, an O,O,O-trimethyl derivative, which was cleaved (Na/NH3) to 362 and 363. It is noteworthy that both vateamine and vanuatine show, by NMR, solution conformations different from those of their O-permethylated derivatives; the C-8 protons of 361 and 360 are shifted on methylation from 6 5.15 and 5.48 to 6 6.05 and 6.13, respectively (110).

111. Known Alkaloids from New Sources New plant species from which known alkaloids have been isolated during the period 1975-1984 are listed, alphabetically, in Table I. See Table V (Section X1,D) for a list of new sources for thegeriod 1984-1986. TABLE I Known Bisbenzylisoquinoline Alkaloids from New Sources, 1975- 1984 Plant

Abuta grisebachii A . splendida Albertisia papuana

Andrachne cordifolia Archangelisia Java Berberis spp. (22 studied) Berberis spp. (24 studied) Berberis spp. (25 studied) Berberis spp. (22 studied) Berberis spp. B. calliobotrys

Alkaloid(s) Magnoline (= grisabutine) Aromoline, homoaromoline Aromoline, cocsoline, cocsuline, daphnoline, homoaromoline, isotrilobine, lindoldhamine, obaberine, oxyacanthine Cocsuline, penduline Homoaromoline, limacine Berbamine, isotetrandrine Berbamine, oxyacanthine Berbamine, oxyacanthine Berbamine Several Berberis alkaloids Chitraline, kalashine, 1-0-methylpakistanine, pakktanamine, pakistanine

Reference 97 106 72

165 I66 167,168 167 I69 I70 171,I72 173 62

(continued)

102

KEITH T. BUCK

TABLE I (Continued) Plant

B. chilensis B . coriaria B. empetrifolia B. integerrimu B. jaeschkeana B . julianae B. lycium

B . oblongata

B . orthobotrys B . thunbergii (fruits) B. valdiviana B. zebiliana Cissampelos pareira

Cocculus hirsutus

C. leaebe ( C . pendulus) Colubrina furalaotra ssp. faralaotra C. faralaotra ssp. sinuata Cyclea barbata C. hainanensis C. hypoglauca C . tonkinensis Daphnandra apatela D. dielsii D. johnsonii Daphnandra sp Dehassia triandra Doryphora aromatica Guatteria megalophylla Heracleum wallichii Hernandia ovigera

Alkaloid(s)

Reference

Berbamine, isothalicberine, 0-methylisothalicberine Penduline Isotetrandrine, pakistanine Oxyacan thine Berbamine Berbamine, oxyacanthine, pakistanamine Aromoline, baluchistanamine, berbamine, berbarnunine, isotetrandrine, oxyacanthine Berbamine, berbamunine, oxyacanthine Aromoline, berbamine, oxyacanthine, pakistanamine, pakistanine Isotetrandrine, berbamine Pakistanamine Berbamine Chondocurine, cycleanine, hayatidine, insularine, isochondodendrine Isotrilobine, trilobine Cocsoline, cocsuline, penduline Limacine Limacine Chondocurine, isochondodendrine (+ ,+)-4”-O-Methylcurine, dl-curine I-Curine, cycleanine I-Curine, cycleanine Telobine Repanduline O-Methylrepandine, nortenuipine, repandine, repandinine 0,N-Dimethylmicranthine, micranthine, (+ )-tenuipine Obaberine Daphnandrine, homoaromoline, isotetrandrine (R,R)-Isochondodendrine Cycleanine, isochondodendrine Dehydrothalicarpine

I 74 73 I75 176 176,177 I77u 178 I 79 180 181

124 125 125,I24 63 63,61 I82 28 183 139 184,185 I 84 185

139,185 I86 18 7 ,I87a 89,188 90 139 189,190 191

193 I92 50 71 I03 71 194 70 82 I95 130

103


TABLE I (Continued) Plant

Isolona hexaloba I . pilosa Isopyrum thalictroides Limaciopsis loangensis Mahonia repens Momordicu foetidu Ocoteu venenosu Pachygone ovatu Pycnurrhenu longijolia

P. novoguineensis Sciudotenia toxiferu Stephania elegans

S. epigeae S. erecta S. glubra S. japonica S.japonica var. austrulis Synclisia scabridu Thalictrum dasycarpum (achenes) T. dioicum

T. faberi T. foliolosum

T. kuhistanicum T. lucidum

T. minus T. minus (Bulgarian chemotype)

T. minus var. microphyllum T. minus Race B

Alkaloid(s) Isochondodendrine Curine, isochondodendrine 0-Methylrepandine, (R,S)-tetrandrine, (S,S)-tetrandrine, (*)-tetrandrine Berbamine, cycleanine, isotetrandrine, thalrugosamine, thalrugosine Obaberine, obamegine, oxyacanthine, thalrugosine Fetidine Rodiasine Trilobine Aromoline, daphnoline, homoaromoline, limacine, obaberine Berbamine, isofangchinoline, limacine, phaeanthine, pycnamine Isochondodendrine Cycleanine, isochondodendrine, isotetrandrine Cepharanthine, curine, cycleanine Cepharanthine, homoaromoline Cycleanine Stebisimine Thalrugosine Cocsoline, cocsuline, norcycleanine, cycleanine Thalicarpine Pennsylvanine, thalicarpine Thalidasine Thalicarpine, thalidasine thalisopine (= thaligosine) thalrugidine, thalrugosaminine, thalrugosidine Thalmidine, thalmine Obamegine Annoline, oxyacanthine, thalicberine Homoarmoline, obaberine, O-methylthalicberine, thalidasine, thalrugosine Aromoline 0-Methylthalicberine, 0-methylthalmethine, thalicberine, thalmethine Adiantifoline, 0-methylthalicberine, obaberine, thaliadenine, thaligosine, thalmelatidine, thalrugosine (= thaligine) Ohaberine, thalidasine, thalrugosine

Reference

196 196 197 121 198

,198a 199 113 107 200 134 201 202 203 75 204 205 65 65,206 207,208 209 209u 76 210 211 210,211 212 213,214 213 214 142 215 143

32 33 ~~

(continued)

104

KEITH T. BUCK

TABLE I (Continued) ~~

~~

Plant

T . podocarpum T. revolutum

T. revolutum (tops) T . revolurum (fruit) T. sachalinense T. sultanabadense Tiliacora dinklagei T. funifera T. triandra Triclisia dictyophylla T. gillettii T . patens

T . subcordata Uvaria ovata

Alkaloid(s) Hernandezine, thalidezine 0-Methylthalicberine, thalicarpine, thalidasine, thalrugosaminine, pennsylvanine, thalictrogamine Thalicarpine, thalmelatine 0-Methylthalicberine, thalmelatine Thalrugosine Hernandezine (= thalicsimine), thalidezine Funiferine, nortiliacorinine A, tiliacorinine Isotetrandrine, thalrugosine Nortiliacorinine A, tiliacorine, tiliacorinine Cocsuline, trigilletimine N,N-dimethylphaeanthine,phaeanthine Obamegine Aromoline , N,N-dimethylphaeanthine,phaeanthine Tetrandrine Chondrofoline

Reference

34 I54 154,132 132 216 118 217 140,100 43 I57 I56 218 219 102,220 221 322 22 1 222

IV. Reactions This section includes representative examples of the major types of reactions that are encountered in bisbenzylisoquinoline alkaloid research. Some of this material is not otherwise covered in this work. Diagnostic procedures, such as solubility tests and color reactions, are not considered.

A. CHEMICAL METHODS 1. Alkylation

Methylation of alkaloids containing either phenolic hydroxy groups or secondary amine functions is the most common procedure for converting such alkaloids to known derivatives; many examples are given in Section I1,C. Diazomethane is the reagent of choice for 0-methylation, and diazoethane for 0-ethylation. It is possible to effect 0-alkylation in the presence of secondary amine functions, as in the conversion of peinamine to its trideuteriomethyl ether (Section II,C,92) and of N-desmethylthalrugosidine to the 0-ethyl ether (Section II,C,29). Another 0-alkylation method, exemplified by the preparation of 0-methyl, 0-ethyl, and 0-isopropyl ethers of berbamine (364), consisted of heating the alkaloid in

1. THE

BISBENZYLISOQUINOLINE ALKALOIDS

105

364

toluene with sodium and the corresponding oxalate ester; 75% conversion to the methyl ether was obtained (223). N-Methylation of secondary amines is usually accomplished either with CH,O/HCO,H (Leuckart/Clarke-Eschweiler reaction) or with CH,O followed by NaBH, reduction. Methyl iodide treatment of secondary or tertiary bisbenzylisoquinoline alkaloids leads ultimately to the bis quaternary salts, and, in the presence of base, phenolic alkaloids are also 0-alkylated. For example, lindoldhamine (165) on treatment with ethyl bromide in 0.5 N ethanolic KOH gave the N,N,O,O,O-pentaethyl derivative (108, Section II,C,56); daurisoline was similarly permethylated with Me1 and base (68, Section II,C,19). Partial N-methylation can also be accomplished with MeI. For example, tetrandrine (48) gave on treatment with 1 equiv Me1 a 4 : 1 mixture of the monoquaternary salts 365 and 33. The pure minor isomer could be obtained by sequential quaternization of tetrandrine with 1 equiv benzyl bromide, then 1 equiv MeI, conversion of the bisquaternary salt to the dichloride form with anion-exchange resin, and cleavage of the benzyl group by catalytic reduction (H,/Pd-EtOH) (20). Partial 0-methylation of alkaloids containing more than one OH can be accomplished with CH,N, either by prior partial protection of the phenols as 0-acetates (148) or by use of less than a stoichiometric amount of CH,N, (132) (see, e.g., Section II,C,122). M H(e N L\ : : y H &

/

OMe

/

0'

365

la. N-Dealkylation It has been shown that chloroformate N-dealkylation of bisbenzylisoquinoline alkaloids is not as specific as formerly thought. Tetrandrine (48) was N-demethylated by excess methyl chloroformate in DME at room temperature to a mixture of N-Znortetrandrine, N-2'-nortetrandrine, and N,N'-bisnortetrandrine. In contrast, microbial degradation (Section IV,B) was selective (224). The dequaternization of alkaloids of the tubocurarine family is described in Section V,B ,2.

106

KElTH T.BUCK

2. Acylation Acylation (specifically, acetylation) of secondary nitrogens has occasionally been used to separate or characterize bisbenzyltetrahydroisoquinolinealkaloids, as in the case of tiliamosine (Section II,C,138). O-Acetylation has been used principally as an adjunct to NMR studies of phenolic alkaloids. For example, comparison of thalictrogamine and its 0,O-diacetate enabled assignment of the hydroxys (209, Section Vl,A,2,a). 3. Ether Cleavage

The selective O-demethylation by HBr of tetrandrine (48) was studied under different conditions; among the products were penduline (366), fangchinoline (367), atherospermoline (368), and, ultimately, the completely demethylated 369 (225).Cycleanine (112) was demethylated by HBr primarily to 370 and 371,

366 R 1 = R 2 = R 3 = M e , R 4 = H 367 R’=R’=R‘=Me, R 2 = H 368 R’ = R 4 = Me, R2 = R3 = H 369 R‘ = R2 = R 3 = R 4 = H

showing the importance of electronic factors (226). The same selectivity was shown in the demethylation of cycleanine with pyridine hydrochloride; the ultimate product was the completely O-demethylated 372, and the intermediates showed initial loss of 7- and 7’-OMe (227). Thermolysis of cycleanine hydrochloride (190-225°C) resulted in sequential O-demethylation (228).

NKfl


MeH ‘

107

Me

OR’

Me0

‘ 0

OMe

373 R’ = Me, RZ = H 374 R’= RZ = H

Sodium benzylselenoate, easily prepared in situ, in refluxing DMF showed a high selectivity of ether cleavage, bringing about demethylation of thalicarpine (94) to thalictropine (373) in 51% yield, accompanied by 22% 374. This procedure thus makes quantities of the rare 373 available (229). A Japanese patent claims the preparation of demethylenecepharanthine (375) by selective cleavage of the methylenedioxy group of cepharanthine (288) by sequential treatment with BClJCHCl, and MeOH (230).

t

375

The principal type of ether cleavage classically employed in bisbenzylisoquinoline alkaloid research is reductive reaction with Na/NH,, which cleaves diphenyl ether linkages, providing characterizable fragments. Numerous examples are to be found in Section I1,C. A drawback is that methylenedioxy (e.g., see Section II,C, 131) and certain alkoxy (e.g., see Section II,C, 130) functions are also attacked, leading occasionally to ambiguous results; quaternary alkaloids also suffer Hofmanmelimination (e.g., see Section II,C,l31). 4. Oxidation Oxidation of iminobisbenzylisoquinolines results first in a benzoylimino compound, and, under stronger conditions, dehydrogenation to a benzoylisoquinoline. An example is the conversion of thalibrunimine (27, Section II,A,4) to oxothalibrunimine (254, Section II,C,86) by refluxing a benzene solution in air, and to thalictrinine (143) by heating with Pd/C in p-cymene (81) (Section II,C,ll4). For an example of dehydrogenation in absence of 0, see Section V,B,3. In contrast, reaction of tertiary bisbenzylisoquinolineswith common oxidants leads first to an enamine (not necessarily isolable), which is easily cleaved to an

KElTH T.BUCK

108

aldehydo isoquinolone, as in the preparation of baluchistanamine (376) from oxyacanthine (247) (39,231).This procedure was particularly useful in establishing the structures of the biphenyl-linked alkaloids, as in the oxidation of funiferine with KMnO, in acetone (46, Section II,B, 15); the structure of rodiasine (377) was similarly determined (39). In another example, reaction of obaberine (80) with Kh4n0, in Ac,O led specifically to 378 in 35% yield, and in three other cases oxidation also proceeded (but in 5 4 % yield) to products from cleavage of the benzylisoquinoline unit having an unsubstituted C-8 (or C-8') (39,231).The oxidation can be carried out on the 0-acetates of phenolic alkaloids with KMnO,/Me,CO (209).In the case of aporphine-benzylisoquinoline dimers, the benzylisoquinoline moiety is preferentially attacked. Thus, KMnO,/Me,CO converted thaliadanine first to thaliadine, and, on longer reaction, to dehydrothaliadine (2) (Sections II,C,109 and II,C,llO)

Z M e

MeN H'

H '

'OMe

HO

377

378

Model studies of papaverinium salts showed that cleavage products are formed in good yield with singlet oxygen or CuC1/02 (232,233). Other examples of oxidative degradation are cited in Section VI1,A. A variation of this degradation employed mercuric acetate in refluxing 10%HOAc, which converted cycleanine (112) slowly to 379. In the presence of EDTA, the mercurated derivative 380 was obtained. The concommitant cleavage and aromatization appear to proceed via a 2,3-dehydro intermediate (234) and are a consequence of the unusual solution conformation of the molecule (235).


109

M e 0e o w N h e

(I CHZ R

379 R = O H 380 R = H g l

Ceric ammonium nitrate appears to be a valuable reagent for dehydrogenation of bisbenzylisoquinoline alkaloids. For example, oxidation of tetrandrine (48) with 8 mol of this reagent in buffered HOAc, followed by NaBH, reduction of the intermediate imine 381, gave a 95% yield of diamine 382, as well as the crystalline diol 383. Similarly successful results were obtained with hernandezine (24a) and 0-methylmicranthine (384), the latter demonstrating that this procedure is compatible with secondary amino groups. Berbamine (364),

tc:mt

MeN,

OMe

/

/NMe

381

Me Nc

:

m

N

Me

382

M H,' e

N\ k

'

0

0

1

;

Me

?

0'

385

110

KEITH T.BUCK

thalibrunine (23),and tenuipine (385)gave good yields of diamines, but the bottom portions of these molecules formed complex mixtures, apparently due to attack on the OH and methylenedioxy functions. This method is supplementary to Na/NH, cleavage and probably superior in many cases to photooxidative degradation (of which no recent examples have appeared). However, photooxidation is applicable to phenolic alkaloids [e.g., berbamine (364), although the phenolic fragment was not isolable] (236). Even during NaBH, reduction of hernandaline (256),dehydrogenation to 386 was a problem unless a very large excess of reducing agent was employed (237). Thalicarpine (94),when subjected to electrochemical oxidation or reaction with VOF, , yielded the diastereomeric spirodienones 387; after reduction (NaBH,), one set of the resulting epimers underwent dienol-benzene rearrangement to the bis aporphine 388 (238,239). Milder oxidative conditions (Iz, NaOAc, dioxane) converted thalicarpine to its dehydro analog (255a) in 45% yield (240);a more convenient procedure giving a 55% yield consisted of refluxing 94 with Pd/C in CH,CN (241). Dehydrogenation of cancentrine (28) with Pd/C in refluxing naphthalene gave low yields of 389 and 390, identified only by TLC comparison with isolated materials (242).

&p CHzOH

'

Me0

Me0

OMe

Me

M

e

'

:

'

:

$

(

t

Me0

0

OMe

0

386

:

K

y

Me

' 0

387

e M H'

,OMe

E

p

M

Me0

'

e

0

388

Conversion of tertiary alkaloids to N-oxides can be brought about in vivo, in the laboratory (243), or during storage of plant materials, leading to artifacts and a lowered yield of isolated tertiary bases. [The yield of tertiary bases can be increased by reduction (e.g., with H,SO,) during the isolation process (244).]In the laboratory, oxidation is usually carried out with H,Oz or organic peracids and gives a mixture of positional and stereoisomers, as in the conversion of funiferine to funiferine N-oxide (Section II,C,37). In the bisbenzylisoquinoline series, some N-oxides appear to be enzymatic products because of the specificity of the


111

Me0

Me0

389

390

oxidation site or because they are detected even in carefully worked up fresh material [e.g., tetrandrine N-2’-monoxide (Section II,C,lO7)]. In the case of head-to-head alkaloids that carry a substituent at C-8 (or C-8’), but in which the corresponding position on the other moiety is unsubstituted, N-oxidation of the less substituted ring occurs preferentially. Similar specificity in enzymatic benzyl cleavage of these alkaloids is also observed (54).

5. Reduction Reduction is commonly employed to convert imino and 0x0 bisbenzylisoquinoline alkaloids to identifiable derivatives, or to other alkaloids. Thus thalsimine (58) gave, with either Zn/H,SO, or NaBH,, a mixture of norhernandezine (234) and its epimer (391) (81). Sodium borohydride reduction of thalictrinine (Section II,C, 114) gave specifically dihydrothalictrinine (Section II,C,31), from attack at the less hindered side of the carbonyl (81). OMe

234 R = H - - 391 R = H -

Polarography of thalsimine (58), leading to reduction of the imine, was used as an assay method for the alkaloid, in tandem with TLC separation of crude extracts of Thalictrum simplex (245). Polarographic reduction of thalfine (49), thalsimine (58), thalsimidine (59), tetrandrine (48), and hernandezine (24a) was used to determine relative basicities (246). A combination of chromatography and polarography was used for quantitative assay of fetidine (330) (247).N-Oxides are easily converted to the corresponding tertiary bases, as in the reduction of funiferine N-oxide to funiferine with H,SO, (93) (Section II,C,37).

112

KEITH T. BUCK

6. Rearrangement Rearrangement of dimeric benzylisoquinoline alkaloids is most commonly encountered among those compounds containing a proaporphine unit. Under acidic conditions, the proaporphine moiety rearranges to a phenolic aporphine; prior reduction (e.g., with NaBH,) gives a dienol, which rearranges with elimination of the OH. These rearrangements have been studied in detail; in both types of reaction, aryl migration occurs in a manner that relieves steric compression between the C-1 oxygen substituent and C-8, governed by the stereochemistry of C-6a, and (in the case of dienols) is independent of the stereochemistry of the leaving group. Examples are the stereospecific conversion of valdiberine to chitraline (Section II,C, 142), of epivaldiberine to khyberine (Section II,C,34), and of mixed pakistaniminols (392) to 393 (28). M H' e

N

T

'

0

z T F

4 z

392

M H'e N g z J

0'

Me

R '

393 R = H 394 R = O H

In contrast to acid-catalyzed rearrangement, which gave 394, pakistanamine (46)underwent photochemical rearrangement by sunlight in EtOH, under nitrogen, to 395; in the presence of oxygen, 396 was obtained. This facile process may account for some unusually substituted alkaloids (248). Cancentrine (28) methiodide rearranged in boiling Ac,O/NaOAc to 396a and 396b (249).


113

Me0 Me0

396a R = H 396b R = CHZCHZNIMdAc

7. H-Exchange Deuterium exchange of active hydrogens has often been employed to elucidate the structures of bisbenzylisoquinoline alkaloids. A typical application of Dexchange was provided by the structure proof of cocsuline (Section II,B, la); this alkaloid exchanged 3”-H (ortho to OH) in strong base, and 5-Hwith DCl/CH,OD (19). Sciadoline (Section II,C, 102) and isochondodendrine(212) (82),which lack free hydrogens ortho or para to the phenolic functions, resisted D-exchange in base. The presence of unhindered OH and NH (19) functions may be verified by their exchange with D,O under mild conditions (e.g., isothalidezine, Section II,C,46). Cryptophenolic hydrogens resist exchange; for example, the OH NMR signal of (R,R)-12’-O-methylcurine was not affected by addition of D,O (Section II,C,64). A preparation of tritium-labeled berbamine by gas-liquid exchange in dioxane has been reported (250). 8. Elimination

Hofmann elimination has been used as a tool in structure proof (see daurisoline, Section II,C, 19, and 2’-N-methylberbamine, Section II,C,62). Unintentional Hofmann elimination of quaternary bases can be brought about by excess djazomethane (251). The reported process for dequaternization of tubocurarine

397

R=Me

114

KElTH T.BUCK

chloride (73a) by refluxing in ethanolamine has been shown to give mainly Hofmann elimination products; 0,O-dimethyl-( +)-chondocurarine chloride (397) also gave Hofmann elimination. However, it proved possible to N-dealkylate the quaternary nitrogens of both compounds with sodium thiophenoxide (252) (see Section V,B,2). B . BIOCHEMICAL TRANSFORMATION This section considers in vivo transformations other than those involved in biosynthesis, which forms the subject of Section VII. At present, tetrandrine (48) and thalicarpine (94) are the only bisbenzylisoquinoline alkaloids whose microbial transformations have been studied. In work that is apparently the first such investigation of any benzylisoquinoline-derivedalkaloids, likely organisms were selected by their ability to metabolize monomeric benzylisoquinoline alkaloids (253,254) and then by test culturing with d-tetrandrine (224,255)or thalicarpine (237,255). In contrast to (R,S)-laudanosine (398), which suffered primarily O-dealkylation by several microorganisms, d-tetrandrine was converted specifically to Ndealkylated products by species of Streptomyces, Penicillium, Mucor, and Cunninghamella (254,256,257).CunninghamelZa blakesleeana gave a 20% yield of N-nor-d-tetrandrine (399) (224,254),while S. griseus gave the "-nor base, the rare alkaloid cycleanorine (399a) in 50% yield, making the latter more readily available (257). Several other microorganisms gave either 399 or 399a in culture with tetrandrine, and minor unidentified products were also present (224).

Ly /

Me0

' OMe 398

Me

R1;E:T /

\

'

OMe

399

'0 R1 = H, R2 = Me

399a R' = Me, R2 = H

Streptomyces punipalus converted thaicarpine (94) to hernandalinol (400), whose structure was proven by synthesis by reduction (H,/Pt-HOAc or excess NaBH,) of the alkaloid hemandaline (256). It was also shown that 256 is converted to 400 by S. punipalus, and therefore inferred that 256 is an intermediate in the overall transformation of 94. Of 22 microorganisms that were screened, 5 were shown to give metabolites from thalicarpine, but only S. punipalus was investigated in detail (237). The above microbial transformations have been reviewed (258). In one of the few animal studies of the metabolic products of bisbenzyliso-

1,


115

400 R = CHzOH

quinoline alkaloids, the fate of tetrandrine in rats was investigated. After intsagastric administration of the alkaloid (200 mg/kg), liver, feces, and urine were examined. Fangchinoline (367) and tetrandrine N-2'-monoxide (294, Section II,C,107) were identified (259,260). When given orally to humans or intragastrically to rats, tetrandrine was recovered largely unchanged, along with its metabolites, 294, isotetrandrine N-2'-oxide (400a), and cycleanorine (399a) (262). Apparently the mammalian metabolism can deactivate tetrandrine by either demethylation or oxidation (259,260). Metabolites of thalicarpine excreted in urine are hernandaline (256), hernandalinol (400), and dehydrothalicarpine (255a) (262).

400a

V. Synthesis This section consists primarily of total synthesis work. Most partial syntheses are to be found in Sections I1 and IV, and only those not previously discussed or those of particular interest are considered here. The last decade has produced relatively few new total syntheses of bisbenzylisoquinoline alkaloids, evidently because commercial applications that could not be filled with isolated or semisynthetic materials have not developed, and because instrumental methods have made structure proof by interrelation of new alkaloids with known materials increasingly easy. A. TOTALSYNTHESIS 1. Syntheses Employing the Ullmann Reaction

The total synthesis of diphenyl ether-linked bisbenzylisoquinoline alkaloids must involve at some point the formation of the ether linkage(s). This pivotal

116

KEITH T. BUCK

step has been accomplished in a limited number of ways, the most common and traditional of which is the Ullmann reaction (displacement of an aryl halide by a phenoxide under catalysis by a copper species). In order to obtain the proper isomer and preserve stereochemicalintegrity, it is desirable to perform this coupling as a final step, using optically resolved monomers. Until 1975, reported yields for such couplings were generally quite low (e.g., 2% for tetramethylmagnolamine (402) from (Qarmepavine (161) and (R)-6'-bromolaudanosine (401), using Cu-Cu(OAc), as catalyst, without solvent (263).Use of pentafluorophenylcopperin pyridine raised the yield of 402 to 53%; syntheses of several other dimers, none of them natural products, were also described (264,265). Even with the traditional catalyst CuO, the yield of the Ullmann reaction was improved with pyridine as solvent (266).

OMe

161

401

M% e!t H,,'

P

\

'OMe

M

e

o \

OMe

402

A total synthesis of magnolamine (6) has been reported. The optically resolved compounds 403 and 404 were coupled by refluxing for 24 hr with CuO and K,CO, in dry pyridine under nitrogen. The resulting compound 405 (3.6% yield) was debenzylated in 58.3% yield with ethanolic concentrated HCl to magnolm i n e (6) (6). The formation of diphenyl ether linkages may be accomplished at intermediate points in the reaction sequence, as in the total syntheses of obaberine (80) and the related triply bridged alkaloids trilobine (220) and isotrilobine (30). A key feature of this work was the judicious use of protecting groups. The common intermediate 405a was converted to a mixture of the diastereomers 406 and 407 (5 :2 crude isomer ratio). The (S,R) isomer yielded obaberine (go), and the (S,S) isomer was transformed to trilobine (220). Since trilobine had already been N-

1.


M H' e

\ N

~

~

+

PhCz:yl ~

~

'

OMe OCHzPh

/P

HO

117

h

\

404

403

M H'

e

K: y H h l e

N

\

'OMe

0'

OR

405 R CHZPh

N

K

q

/

H CO Ph

\

'OMe

o \ 405a

Me N R

Y

a

-..HN CO Ph

406 R = H 407 R = H - - -

methylated to isotrilobine (30), this work constitutes a formal synthesis of three alkaloids (267,268). In order to circumvent the problem of low yields in the usual Ullmann reaction, most syntheses of bisbenzylisoquinolinealkaloids have formed the diphenyl ether linkages at an early stage and confronted the problem of isomer separation later. In the case of phaeantharine (18) (Section II,A,3), which has no asymmetric carbons, this approach was clearly preferred. This synthesis exemplifies the use of Reissert alkylation as a key step (9,269). Several analogs of bisbenzylisoquinoline alkaloids were prepared in an analogous manner (270,271). One

118

KEITH T. BUCK

406

(1) AIH,

407

80

f21H2, Pd, HOAC (3lCH2o -NaBH,

Br

*

Me0 M e o m N C O P h

+

/\CN

H

NaH

DMF

PhCON NC

(21 Me1 \

’OMe synthetic approach took advantage of nitro group activation for both the ether formation and attachment of the isoquinoline unit. The intermediate 408 was elaborated to (*)-hernandaline (256) and thalicarpine (94) (128).

408

119


S

l(llPocI, l2)Mel 13) NaBH, I

17

The Willgerodt-Kindler reaction has been used to synthesize O-methyldauricine (17). The product was evidently a mixture of diastereomers (272-274). A similar approach provided stebisimine (409), obaberine (go), and isotetrandrine (236)(275). In a variation, enamine thioether 410 reacted with 411 to generate bis amide intermediates for the synthesis of 80, 236, and 409 (276). S Me

OMe

410

409

411

2. Oxidative and Reductive Coupling The synthesis of a number of bisbenzylisoquinoline alkaloids by direct dimerization of a phenolic benzylisoquinoline monomer is an extremely attractive

120

KEITH T.BUCK

goal, both because of its simplicity and because it would mimic the biogenesis of these alkaloids (see Section VII). Unfortunately, high-yielding laboratory syntheses of this type have so far been elusive. In addition to problems of regio- and stereospecificity, dimerization of simple monomers often fails because intramolecular reaction is generally preferred to intermolecular coupling (277,277~). For example, a recent study of the oxidation of 412 and 413 with lead tetraacetate yielded 414 and 415, respectively, rather than dimeric products (278).

OH

412 R = H 413 R = CHO

Me0 m

N

e

O

M

u

e

‘Me0 ‘ O W N

CHO

OH

Me0O

414

~

O

415

Even those cases of chemical oxidation that gave oxygen-bridgeddimers often did so with disappointing yields and afforded undesired isomers. A typical example was the oxidation of 416 with FeC1, to a mixture of 417 (1.1%) and 417a (1.6%) (279). Somewhat more encouraging results were obtained with anodic oxidation of N-carbethoxy-N-norarmepavine(418), which gave primarily C-C dimerization (45%), but also 8% of a C - 0 dimer having the dauricine (116)

H

N

HO

F

’

F H \

417a

OH

Meoy

121

1. THE BISBENZYLJSOQUINOLINEALKALOIDS

Coon

Me0

HO

M e N T r *

/

\

418

/

HO

OR

Me

\

419 R = H 420 R = Me IR.R)

skeleton (280, 281). Oxidation of N-methylcoclaurine(16) with H202 catalyzed by homogenized potato peels gave head-to-tail C-0 coupling to the dimer 419 (isolated as the triacetate) in 0.39% yield; some trimer was also obtained. This reaction serves as a model for neferine (420) biosynthesis (282). Oxidation has been used to convert one type of dimeric skeleton to another. Thus, a mixture (421) of racemic berbamunine and magnoline, prepared via the bis diazoketone 422, was oxidized with buffered K,Fe(CN), to 423, which was methylated to a mixture of pakistanamine (46) isomers (283). Electroreduction COCHNr

Q ,fJCOCHN

2.

\

M

e

t

!

! OCHZPh

\

422

' 0

OH

421

Me N%

:

'2

M

e

/

/

423

has been claimed as a means of alkylating simple 3,4-dihydroisoquinolinesto bisbenzylisoquinoline types with bis halomethyl diphenyl ethers (284,285).A model for the synthesis of cancentrine (28) alkaloids via condensation of 424 with 1,2-cyclohexanedioneand rearrangement of the product to 425 (62% yield) has been reported (286). M Me0 e

Me0

O

' OMe 424

y

:p Me0

' OMe

425

122

KEITH T. BUCK

B. PARTIALSYNTHESIS 1. Alkylation

Selective quaternization of (+)-tubocurine (74) with 0.5 equiv Me1 under the usual conditions gave primarily (+)-isotubocurarine chloride (426) (287).However, when 74 was treated first with 0.5 equiv HC1, then MeI, and neutralized, (+)-tubocurarine chloride (73a) was a major product (49).The selective monoquaternization of tetrandrine to cycleahomine and its isomer is discussed in Section IV,A, 1 .

426 427

R' = R 2 = R 3 = H , R 4 = M e , X = C I R' 2 R 3 = Me, RZ = R' = X = no substituent

2. Dealkylation Cepharanthine (288) was demethylenated with BCl,/CH,Cl, to the diol375. Treatment of 375 with CsF/DMF and I4CH,Br, gave specifically labeled cepharanthine for biochemical studies. The ethylenedioxy analog was also prepared (80,288,289).The selective N-dealkylation of tubocurarine chloride (73a) and 0,O-dimethylchondocurarine (397), leading, respectively, to (+)-tubomine (74) and O,O-dimethyl-( +)-tubocurine (427), was accomplished with sodium thiophenoxide (252) (see Section IV,A,8). 3. Dehydrogenation

The imino base sciadoferine (Section II,C, 101) was converted to sciadoline (Section II,C, 102) by dehydrogenation with Pd in aqueous maleic acid (134). 4. Rearrangement As a technique for partial synthesis, rearrangement of bisbenzylisoquinoline alkaloids has most often been used on spirodienones, as in the conversion of valdiberine to chitraline (Section II,C,142), and is of value mainly in structure proof.


123

5. Hydroxylation Tetrandrine (48) was converted to the related alkaloids thalidezine (53) and hernandezine (24a). The key initial step, bromination, was highly specific (290); the resulting 5-bromotetrandrine (428) was reacted with butyllithium and then with nitrobenzene to give 53. Methylation (CH,N,) provided 24a (290).

428

R=Br

VI. Methods and Techniques A. SPECTROMETRY 1. Mass Spectrometry Mass spectrometry (MS) continues to have great importance for structure determination of bisbenzylisoquinoline alkaloids, as the many cases cited in Section I1 demonstrate. MS has been particularly useful in cases of dimers with unusual structural features (such as the warifteines, which contain a p-xylyl moiety (21) (Section 11,B,4). High abundances of doubly charged fragment ions are often observed in headto-head coupled alkaloids. Studies on model compounds suggested that these ions may arise by a stepwise process: (1) generation of a singly charged radical cation, (2) loss of a benzyl radical, and (3) expulsion of a benzyl anion from the intermediate cation. Such a process would require lower energy than the simultaneous expulsion of two benzyl radicals (291,292). Chemical ionization (C1)-MS can be used to study alkaloids that are not amenable to examination by electron impact (E1)-MS. For example, the quaternary alkaloid thalirabine (Section II,C,123), undergoes fragmentation under the conditions of ELMS and does not show a parent ion, however, the CI-MS shows a double Hofmann elimination product which retains the skeletal atoms (32). Field desorption (FD)-MS has similar utility, as in the case of cycleanine N-oxide (Section II,C,l7j for which FD-MS shows the parent ion not detectable by EI-MS (65). Desorption/CIMS (DKIMS) was used on dihydrosecocepharanthine (Sec. II,C,30) and related bases (8 0 ,2 9 2 ~ ) . The anomalous MS behavior of (+)-tubocurine and (+)-tubocurarine chloride

124

KEITH T. BUCK

has been discussed in Section II,B,l6. These alkaloids give, in addition to (M 15)+ peaks due to loss of Me, peaks due to recapture of Me radicals by the presumed Hofmann degradation product (49). MS has been used as a method of quantitative assay (relative error 15%)of the thalicarpine content of Thalictrum minus L. (293).

2. Nuclear Magnetic Resonance a. Conventional lH NMR. Nuclear magnetic resonance (NMR) has long been important in bisbenzylisoquinoline alkaloid research. As one recent example, NMR provided the final structure proof for a sample of newly isolated obamegine (428a), neatly ruling out possible isomers; inaccuracies in the reported NMR data were corrected (198). The value of NMR has been greatly extended by the use of fairly new techniques. Of fundamental importance is Fourier transform (FT) NMR, which almost eliminates the problem of attaining adequate resolution, even when working with very small samples (for a general discussion, see Ref. 294).

428a

An 'H-NMR study of thalsimine (Section LI,B,13) showed that the alkaloid exists at room temperature as a mixture of two conformers. The spectrum in perdeuteriopyridine shows 10 OMe and 2 NMe peaks, but on heating the sample to 95°C the spectrum collapses to the expected pattern (13). The NMR spectra of bisbenzylisoquinolines are often very sensitive to temperature or variations in acidity or basicity, making exact comparisons of spectra with literature values difficult (53). The 'H-NMR spectra of isochondodendrine (212) and cycleanine (112) show equivalence, due to symmetry, of pairs of benzyl ring aromatic protons (e.g., H-10 and H-10'). However, because of restricted rotation of the benzyl rings, all four protons within either ring are nonequivalent (82). Acetylation of phenolic functions produces predictable effects on adjacent aromatic protons. For example, the assignment of the OH groups of thalictrogamine (429) to C-1 and C-7' was based on an upfield shift of H-11 and a downfield shift of H-8' in the diacetate (209). The NMR shifts of the C-8 hydrogen in several bisbenzylisoquinoline-aporphine dimers have been summarized (295). 'H-NMR spectra of some bisbenzylisoquinolineand related dimeric alkaloids have been tabulated (296,297).


M‘H

e\

N

K

p

11 /

/

OMe

OMe

Me0

I L3

Me

‘ 0

429

The solution conformation of cycleanine (112) was deduced by 300-MHz ‘HNMR and double resonance studies (206) and was confirmed by 13C NMR (206). Similar conclusions were reached by a temperature study of cycleanine in CDCI, and in CF,CO,H, and by study of its methiodide. In the preferred “tub” conformation, the 7- and 7’-OMe are twisted out of conjugation with the aromatic rings. This finding is in accord with the observed ease of demethylation of these groups. Additionally, cycleanine is resistant to oxidative dehydrogenation; instead, the methylene groups are attacked (235).

b. Nuclear Overhauser Enhancement (NOE) and NOE Difference Spectrometry (NOEDS). NOE is a well-known NMR technique, which has been extensively reviewed (294,299). However, only relatively recently have extremely stable and sensitive measurements been possible with the aid of Fourier transform equipment with superconducting magnets. NOE measures the dipoledipole interaction between protons during spin-spin lattice relaxation, which typically alters the amplitude and width of the affected signal(s). Since this effect is a function of the geometry of the interacting protons, and varies as the negative sixth power of the distance, small conformational differences can be expected to cause significant changes in the NOE. A series of NOE observations can be used to establish a chain of connectivities, thereby elucidating the complete structure of a complex molecule. The recently developed NOEDS technique has made it possible to assess these often small effects accurately. With NOEDS, the spectrum is scanned alternately by FT before and at a short interval (typically about 1 sec) after irradiation of the target proton(s). The difference between the unperturbed spectrum and the NOE spectrum is then accumulated as the NOEDS. The magnitude and sign of the NOE are solvent dependent. Use of a D-exchangeable deuterated solvent can simplify the spectrum by eliminating exchangeable proton signals (67).Enhancements as small as 0.18% are measurable (30,67,137,294). NOEDS was first applied to bisbenzylisoquinoline alkaloid research in 1976, with the determination of the structure, exclusive of stereochemistry, of tiliamosine (350, Section II,C,138). All protons except the methylenes of rings A and D were assigned. The position of bridging of the top rings of dihydrodaphnine diacetate, and therefore of daphnine (Section ILC, 181, was shown by NOEDS. NOEDS also established the complete connectivity relationships of the two calafatine N-2‘-oxides (Section II,C, lo), and also of calafatine (Section II,C,9),

126

KEITH T. BUCK

osornine (Section II,C,83), and berbibuxine (Section II,C,5). The relative stereochemistry, and therefore (by CD) the absolute configurations of pakistanamine and related alkaloids were determined from NOE data (Section II,B,6). For an example of conformational information deduced from NOEDS , see vanuatine (Section I1,C, 144). The case of temuconine (Section II,C,106) demonstrates the value of complete decoupling of all protons before assigning NOEDS. In the original study the methine protons were not identified, and an error in interpretation of the NOE effect between the bottom and top aromatic rings led to the proposal of an incorrect structure (137,138). However, when sufficient NMR data are collected by 'H decoupling and NOEDS, the structures of bisbenzylisoquinolinealkaloids can be determined using very small amounts of material, making a purely instrumental approach superior to the classical Na/NH3 cleavage procedure (137). The complete structure, exclusive of absolute configuration, of repanduline (Section II,B,7) was deduced by long-range (-4.5 A) NOEDS; the 32,000 observations required 60 hr to acquire (30). The first elucidation of the nitrogen stereochemistryof a bisbenzylisoquinoline N-oxide alkaloid (see calafatine N-oxides, Section II,C, 10) was made possible by NOEDS. A procedure was developed that systematically interconnects all protons, allowing complete structure determination (54).A previous attempt to prove the stereochemistry of the epimeric calafatine N-oxides had given an erroneous result due to inadequate decoupling data (59). c. 13C NMR. In what appears to be the first 13C-NMR study of a bisbenzylisoquinoline alkaloid, the 13C-NMR spectra of isochondodendrine, its dimethyl ether, and diacetate were reported in 1978 (301,300).As with the 'H-NMR work just discussed, the 13C spectra showed nonequivalence of protons of individual benzyl rings due to restricted rotation. The same laboratory has also produced l3C studies of the berbamine-type alkaloids phaeanthine, tenuipine, nortenuipine, berbamine, and the 0-acetates of the last two (302); of bebeerine and related derivatives (303); of daphnoline and derivatives; and of repandine and its 0-methyl ether (304). These studies showed that I3CNMR provides usefuJ data on the conformation and configuration of bisbenzylisoquinoline alkaloids. The 13C-NMR spectra of the following alkaloids have also been assigned: cycleanine (206), isochondodendrine (= sciadenine), thalicarpine, tetrandrine, limacine, hernandezine, thalibrunine, thalibrunimine, epistephanine, hypoepistephanine, and panurensine (305). The above I3C-NMR studies have been reviewed (306). Reduction (NaBH,) of berbacolorflammine (Section II,C,4) to limacine had almost no effect on the 13C signals at C-4' and C-1 ' but did introduce new signals for the saturated carbons of ring A in limacine, confirming the locations of unsaturation. Similar reduction with NaBD, produced a trideuterio derivative


127

lacking the 13C signals for the aliphatic carbons of ring A. Analogous results were observed on reduction of colorflammine (Section II,C, 14) to limacusine (53). The 13C-NMR spectra of cancentrine and related compounds were measured and compared to determine the structure of the new alkaloid 10-oxocancentrine (Section II,C,85) (127). The 13C-NMR spectra of bisbenzylisoquinoline and related alkaloids have been tabulated (301). 3. Optical Activity Measurements In cases where large specific rotations are observed, it is possible to assign the stereochemistry from a single measurement at the Na D line. Circular dichroism (CD) curves, when available, provide much more definitive information (307), but several correlations of specific rotation with general stereochemistry have been noted (95). For example, the absolute configuration of tiliamosine (Section II,C,138) was assigned from these data, and the stereochemistries of pakistanamine and other proaporphine-benzylisoquinoline dimers were similarly correlated (28). In the case of certain phenolic alkaloids (e.g., thalibrunine, Section 11,A,4), internal hydrogen-bonding may produce an anomalous rotation (160). In addition to examples quoted in Section II,C, the CD spectra of the following compounds have been recorded: hernandezine, isotetrandrine, thalsimine, thalsimidine, U-methylthalicberine, thalisopine, thalisopidine, thalmine, thalfine, three related derivatives, and two unidentified bases isomeric to thalbadensine. Spectra were measured in neutral MeOH, as well as after addition of HC1. Several general principles of structural-spectral correlation were deduced (141). 4. UV Spectrophotometry Ultraviolet (UV) spectrophotometryhas been a valuable tool in bisbenzylisoquinoline alkaloid research. One example is its use in the identification of a newly isolated sample of pennsylvanine (317). In order to rule out the isomer, thalidoxine (429a), the alkaloid was oxidized (as its 0-acetate) and the resulting 430 was examined by UV spectrophotometryunder neutral and basic conditions. The data unequivocally confirmed structure 430, and hence 317 for the alkaloid (209). M H'

e

N

'OR* OR'

K

f

Me0

l

' 0

429a R' = Me, R Z = H

Me

128

KElTH T.BUCK

430

In addition to its obvious routine importance, UV spectrophotometryhas been used as an assay method; the berbamine content of crude ethanolic extracts of 22 Berberis species was determined, with standard deviation 3.83%, by measuring the absorption at 282 nm (171). Thalicarpine was similarly assayed at 280 nm and also by TLC densitometry and titrimetry or potentiometry (308). Tetrandrine was determined in drug preparations by UV spectrophotometry of a dilute HCl solution at 280 nm (standard deviation 0.40%) (309). The bisbenzylisoquinolines typically exhibit UV A,, at approximately 283 nm (E 7300-9800); dauricine (116) has a noticeably higher extinction (E 11,800). These coefficients are only somewhat larger than the range for monomeric benzylisoquinolines (310).

5. Phosphorescence and Flourescence Phosphorescence and fluorescence of a bisbenzylisoquinoline alkaloid were observed, apparently for the f i s t time, in tubocurarine chloride and O,O,Ntrimethyltubocurarine (311). The phenomenon has also been studied in several alkaloids of the oxyacanthine and berbamine subgroups, and it has importance as an assay method (311) and as a tool for structure determination. The emission characteristics are a function of the gross structure, the stereochemistry, and the degree of 0-alkylation (310,311). 6. X-Ray Diffraction

X-Ray crystallography is occasionally employed in bisbenzylisoquinoline alkaloid research [see daphnine (Section II,C, 18) and methyl- and dimethylwarifteine (Section II,B,4)] and may become a more common technique.

B . ANALYTICAL METHODS This section briefly covers only material not adequately exemplified in previous sections.

1. THE BISBENZYLISOQUINOLINEALKALOIDS

129

1. Titration

Nonaqueous titration of berbamine in acetone or Ac,O-HOAc has been reported (312). The acid-base behavior of thalicarpine has been studied, and a quantitative determination by titration in ethylene glycol has been devised (313).

2. Extraction The extraction of fetidine under various conditions has been reported (314318). Isolation procedures for thalsimine (319), berbamine (320,321), oxyacanthine (321), and dauricine (322) have been described. An assay method for tubocurarine in cadaver liver by extraction with Bromothymol Blue/CHCl, has been reported (322a).

C. SEPARATION TECHNIQUES 1. Thin-Layer Chromatography

Thin-layer chromatography (TLC) has proven to be a highly sensitive and selective method for the isolation and purification of alkaloids. A striking case in point is the work on khyberine (Section II,C,54); a total of 1 mg (1 ppm of plant material) was isolated by three consecutive TLC runs (62). A TLC study of the alkaloids of Berberis vulgaris reported separation of oxyacanthine and berbamine (323).Berbamine was detected as a contaminant of berberine preparations (324).The chromatographic behavior of berbamine, oxyacanthine, and penduline was described (175). A quick method for serial determination of thalicarpine in Thalictrum species has appeared (325). Crude extracts and pure alkaloids of Thalictrum species have been examined in several TLC systems (326). The separation and semiquantitation of d-chondrocurarine chloride as a Contaminantof d-tubocurarine chloride has been described (327); an improved TLC procedure for tubocurarine and commercial curare has appeared more recently (328). The behavior of tubocurarine on TLC plates of anionexchange resin and fillers has been reported (329). Fangchinoline has been detected as a contaminant of tetrandrine by TLC (330). TLC separation and densitometric determinations of alkaloids of Cyclea densiflora, Stephania herbacea, S . brachandra, and S.tetrandra have been described; the bis bases isolated were isochondodendrine, curine, berbamine, cycleanine, cepharanthine, curarine, fangchinoline, homoaromoline, isotetrandrine (= isosinomenine A), and tetrandrine (= sinomenine A) ( 3 3 0 ~ )A. TLC-densitometric method for assay of dauricine from biological specimens has been reported (331). Tubocurarine served as a test case for pseudophase liquid chromatogra-

130

KElTH T.BUCK

phy, a technique employing cationic micelles of cetyltrimethylammoniumchloride (332). TLC procedures for some of the bisbenzylisoquinolinealkaloids have been reviewed (333,334). 2. High-Performance Liquid Chromatography A high-performance liquid chromatographic (HPLC) method has enabled the determination of thalicarpine and its metabolites hernandaline, hernandalinol, and dehydrothalicarpine, in urine (262). Thalmelatine, thalipine, and thalicarpine were quantitated in Thalictrum minus (335).HPLC methods for quantitation of tubocurarine in curare ( 3 3 5 ~and ) in human plasma (335b,335c) have been described. 3. Gas Chromatography

An automated determination of fetidine in urine involving extraction and gas chromatography (GC) on OV- 1/Chromosorb G with helium carrier gas has been developed (336).

D. BIOLOGICAL ASSAY Biological assays are, of course, necessary in the final stages of evaluation of alkaloid isolates as drugs. Many examples may be found in Section VIII (see Table II). The most economical approach to the screening of large numbers of crude extracts is probably to use in virro assay on cell cultures (e.g., KB carcinoma), followed by in vivo evduatim, d, fmdy, isolanbn of compounds from active fractions (208).

E. CLASSIFICATION During the last decade, as the number of bisbenzylisoquinolinealkaloids continued to increase rapidly, a systematic classification system became highly desirable, and no doubt many workers were using informal systems. In 1976, a formal line notation was developed that designates the skeleton and location of substituents (337); it is suitable for computer retrieval and has found use in review articles (see Section IX). A more extended system that allows specification of substituents and is adaptable to unusual structural types [e.g., repanduline (Section II,B,7)] has also been described (338). The chirality of asymmetric centers may also be designated (160).

1.


131

VII. Biosynthesis This section considers proven biochemical pathways within alkaloid-producing plants, as well as the stronger circumstantial evidence based on structural features (e.g., optical rotation, substitution patterns) and biosynthetic speculations not included in the material of Section 11. The biochemical reaction products of alkaloids after administration to non-alkaloid-producing species are discussed in Section IV,B. Biological activity is discussed in Section VIII. A. ISOTOPELABELING STUDIES The majority of recent biosynthetic studies on bisbenzylisoquinoline alkaloids has been done by Bhakuni and co-workers, using feeding of isotopically labeled precursors to alkaloid-producingplants; this work has been reviewed (339,340). In this manner, several of these alkaloids were shown to be derived by coupling of coclaurine or N-methylcoclaurine units; the thalicarpine family of alkaloids, however, is formed from two (5')-reticuline (430a) units (148,339). .n

Me0

HOQa:OOH

OH 430a

Feeding experiments on Cocculus laurifolius D.C. with a combination of 14Cand 3H-labeled N-methylcoclaurine (22 and enantiomer) and related compounds substantiated the biosynthetic scheme shown for cocsuline (29) (Scheme 1). Tyrosine (431) was shown to be an efficient precursor of cocsuline (29), and the intermediacy of (5')-norcoclaurine (432), (S)-coclaurine (43), and (S)-N-methylcoclaurine (22) was demonstrated by the following observations. Tritiumlabeled (R,S)-0-methylmepavine (433) was not incorporated, nor was 14Clabeled (R,S)-N-methylnorcoclaurine(434). Feeding the racemic 435 resulted in appearance of only half of the total radioactivity in the isolated cocsuline, showing that only one enantiomer is utilized, and feeding of the enantiomers of N-methylcoclaurine, labeled with either l-3H or N-14C, proved that it is the (S) form. This result is corroborated by the reported isolation of (S)-N-methylcoclaurine from the undoped plant. The proton of the asymmetric carbon of 22 is retained during biosynthesis, since the ratio 14C :3H in 436, as determined by degradation, does not change during its incorporation. However, as expected,

132

KEITH T. BUCK

22

Nw2l

Me

-Me"'

\

'0

HO

'

SCHEME 1

HoyRz

R'O

Me

T /

HO

Me0

' T

432 R ' = R 2 = H

433 RO

Me0

434 R = H 435 R=Me

436

*M:12


/

HO

133

Me

' 437

the doubly labeled 437 eliminated one OMe during dimerization. The principal degradative experiments are shown in Scheme 2 (341). A similar approach was used to establish the biosynthetic pathway in Cocculus Zuurifolius of cocsulinine (31), the first triply bridged dimer to be so studied. (S)-N-Methylcoclaurine proved to be the precursor for both halves of the alkaloid. 0-Demethylation was shown to be the final step in the biogenesis by the demonstration of efficient incorporation of tritiated 0-methylcocsulinine (preOMe

1) CHzNz

29

2) Me1 3) KOH

I

Me0

,

YMe \

Me0

y?

OMe

Me0 +

Me0 SCHEME 2

134

KElTH T. BUCK

N

MeH'

R

/ \

,0

/

OH

q

F

/

'0

T

438 R=Me 438a R = H

sumably 438), prepared by exchange of 0-methylcocsulinine with T,O/DMF in a sealed tube at 100°C for 110 hr,-into labeled cocsulinine (presuGably 438a) (342). The biosynthesis of the diastereomeric biphenyl-linked alkaloids tiliacorine (65) and tiliacorinine (40) in Tifiacoraracemosa Colebr. was studied by isotopic labeling. In this case, the technique proved particularly valuable since these alkaloids are not cleaved into monomers by Na/NH,. Labeled racemic norcoclaurine, coclaurine, and N-methylcoclaurine were readily incorporated into both alkaloids. Tiliacorine from feeding of 439 was degraded by conversion to the 0-methyl dimethiodide and oxidation of the latter with alkaline KMnO,; after CH,N, methylation, the resulting compounds 440 and 441 had, respectively, two-thirds and one-third of the radioactivity of the labeled tiliacorine (65* * *); the isolated labeled tiliacorinine (40* * *) from the same feeding experiments gave similar results (Scheme 3). OMe

OMe

MeOOC@,QCooMe MeOOC

COOMe T

+w T

COOMe

COOMe

OMe

OMe T

440

441

SCHEME 3

135


The configurations of the asymmetric centers of tiliacorine and tiliacorinine were shown by separately feeding only one labeled enantiomer of N-methylcoclaurine. (S)-and (R)-N-methylcoclaurine were incorporated equally into tiliacorine, but the labeled (S)form (22*) was converted 70 times more readily than the other enantiomer into tiliacorinine. Alkaline permanganate oxidation of the dimethiodides of tiliacorine derived separately from labeled antipodes deOMe

T

22*

OMe

MeOOC

COOMe

i

OMe

Me0

T

MeT@

69 "

OH 65"

bMe

/

OMe

+

MeOOC MeOOC

6 COOMe

T

COOMe

OMe

SCHEME 4

136

KEITH T.BUCK

graded the phenolic rings as well as the benzylic linkages, giving (after methylation) the products shown in Scheme 4. Analogous results were obtained for tiliacorinine. Molar activity determinations then proved that the C-1 and C-1' centers of tiliacorine and tiliacorinine are as indicated (41,42). An approach simih to that used on tiliacorine and tiliacorinine was used to establish the stereochemistry of an alkaloid alleged to be nortiliacorinine A (correct structure 44),and therefore of the isomeric alkaloid nortiliacorinine B ( 4 9 , both of which give tiliacorinine (40) on N-methylation (CH,O/HCO,H). The stereocbem~calconclusions of this work are correct (see Section II,B,5) (27,27a). The data indicated the biosynthetic sequence: tyrosine to norcoclaurine to (8-coclaurine to nortiliacorinine A (27). The absolute configuration of tiliageine (68), and therefore of the interrelated funiferine (71), was demonstrated by feeding [3' ,5',8-3H]N-methylcoclaurine to Tiliacora racemosa Colebr. Tiliageine from feeding labeled (S)-N-methylcoclaurine (22*) gave, on oxidation (KMnO,, pH 6) and methylation, radioinactive 442,while that from the ( R ) precursor gave 442* having half the radioactivity of

HO

"HNMe

\

N p:T

T /

HO

H.

MeH'

\

'

/

T

/

OH

Me0

T

'

I

I

22"

COOMe

MeOOC OMe

442

Me

M

e

;\ P

:

P

/ M

T /

HO

'

/

OH

Me0

' T

T

69 COOMe

MeOOC OMe

442

SCHEME 5

~

e

Me

1. THE


137

the labeled tiliageine (443) (see Scheme 5). Since this oxidation degrades the phenolic ring of the biphenyl system, and since it had already been shown that the two phenolic groups of tiliageine are in the same benzylisoquinoline moiety (see Section II,B,15), tiliageine has structure 68 (45). Labeling studies are simplified in the case of oxygen-bridged bisbenzylisoquinoline alkaloids by the ability to use Na/NH, cleavage. It was shown that Cocculus laurifolius elaborates oxyacanthine (247) (343) and isotetrandrine (236) (344) from (R,S)-N-methylcoclaurine,and tetrandrine (48) (345) from (S)-N-methylcoclaurine (22). Stephania glabra (Roxb.) was shown to produce cycleanine (112) and Ndesmethylcycleanine (129) via dimerization of both (R)-N-methylcoclaurine (69) and (R)-coclaurine (although the racemic form of the latter was used in these experiments). The plant was proven to utilize L-tyrosine to biosynthesize the intermediate N-methylcoclaurine. The exact sequence of dimerization-N-methylationlN-demethylation has not yet been determined (346). Thalicarpine (94) is unusual in that both halves of the molecule are derived from a reticuline-typeprecursor (298,347-349). This mode of biogenesis is found only in the aporphine-benzylisoquinoline dimers, with the exception of the recently discovered alkaloids malekulatine(Section II,C,59), vanuatine (Section II,C, 144) and vateamine (Section II,C, 145) (110).Feeding (R,S)-[l-14C]-reticuline(444)to Thalictrum minus var. datum resulted in incorporationin both portions of thalicarpine, as shown by Na/NH, cleavage and study of the fragments (348). Further investigation revealed that labeled norreticuline (445) is also an efficient precursor, and, most significantly, that (S)-( +)-[8-3H]isoboldine (446) is readily incorporated. Both reticuline and isoboldine were detected as intermediates in T . minus by isotopic dilution, although they do not occur at levels suitable for isolation by conventional procedures. The high level of isoboldine incorporation indicates that formation of the aporphine moiety precedes dimer formation. Thus the preferred biosynthetic pathway for thalicqine (94) in this species appears to be as shown in Scheme 6. Thalictrum minus is also able to utilize orientaline (447) and protosinomenine ( W ) ,presumably via intramolecular oxidative coupling to dienones and rearrangement of these to isoboldine, but with greatly reduced efficiency (349).

OH

OH

444

R=Me

445

R=H

446

0 R'

447 R' = Me, RZ = H 448

R' = H, R' = M e

138

KEITH T.BUCK

Me0

, Me

Me0

-

i Me0

94 \

OH

SCHEME 6

In another study of thalicarpine biosynthesis, feeding experiments were done on Cocculus laurifolius D.C. (Menispermaceae). In this plant, reticuline was readily incorporated into thalicarpine; however, as shown by tritium labeling, only the (S) isomer (which has also been isolated directly from C . luurifolius) is an efficient precursor. Norreticuline was also easily incorporated into thalicarpine. The definitive experiment involved feeding doubly labeled norreticuline (448a) and degrading (Na/NH, cleavage) the resulting labeled thalicarpine (448b) (Scheme 7). Comparison of 14C: 3H ratios showed that half of the 4'-0methyl groups of norreticuline are eliminated during the biosynthesis ( 3 4 3 ,

M:y /

f

Me0

M

e\

;

K /

'OMe

' OH

OMe

448a

448b

Me0

'OMe OMe

SCHEMEI

Me

\

0

I I

M' 1e N q \ : ?

F

+

MeoF /

Me0

'

1 Me

1.

139

THE BISBENZYLISOQUINOLINEALKALOIDS

/

\

OMe OH

Me0

\

0

OH

448a

I Me

Me /

M T,’

e\ /

OH

N OMe

k/

HO

F Me

448b

\

0

SCHEME 8

supporting the theory that the primary coupling is between two reticulines, followed by intramolecularcyclization and rearrangement via a dienone (Scheme 8). This work is supplementary to that (349) just discussed and indicates that both C. luurifolius and T . minus elaborate thalicarpine from (S)-reticulinebut via different intermediates (110,347).

B . OTHERBIOCHEMICAL STUDIES Cultures of callus tissue of Stephunia cepharantha were shown to produce berbamine (364), also found in the whole plant, and aromoline (449),not re-

449

140

KEITH T. BUCK

ported in the intact plant. The principal alkaloids of S. cepharanrha, cepharanthine (288) and isotetrandrine (236), were not found in the callus, apparently because of a lack of enzymes responsible for the final conversion of 449 to 288 and of 364 to 236. The effect of auxins on alkaloid production was also studied (350). The cycleanine (112) content of Stephuniu glubra tubers was increased by addition of boron and molybdenum to the soil (351). The thalicarpine (94) yield of various cultivars of Thulictrum minus was determined in order to select the best plants for commercial production (352). C. CIRCUMSTANTIAL EVIDENCE

Several biosynthetic proposals have been advanced, based on patterns of occurrence, known in vitro reactivity of bisbenzylisoquinoline alkaloids, and mechanistic analogy. Although unconfirmed (e.g., by isotopic labeling), these theories point the way toward further research. The chemosystematics of Thalictrum species (Ranunculaceae) has been reviewed. The principal conclusions were as follows: (1) all aporphine-benzylisoquinoline alkaloids found in T. minus have the same location of the diphenyl ether linkage; (2) the alkaloids produced are correlated with the chromosome number, the predominant types progressing from bisbenzylisoquinoline to aporphine-benzylisoquinoline with increasing ploidy ; (3) simple benzylisoquinoline and aporphine alkaloids are present in small amounts, and then only if oxidative coupling is blocked by substitution (353,354). As in the case of the biscoclaurines, singly bridged bisreticuline alkaloids have tail-to-tail or head-totail coupling, but not head-to-head (110). All bisbenzylisoquinoline alkaloids from Berberidaceae have either ( lR, 1'S) or (lS,1'R)configurations. The extra oxygen function of the C ring of thalibrunine (Section II,A,4), calafatine (Section II,C,9), and related alkaloids apparently arises from secondary oxidation ortho or para to the diphenyl ether linkage (57). A scheme for the biosynthesis of pakistanine (see Section II,C,52), kalashine (Section II,C,52), and related alkaloids from either a pakistanamine (Section II,B,6) or valdiberine (Section II,C, 142) precursor has been suggested (62) (see Section II,C,52). An intriguing proposal has been advanced that imine and enamine intermediates may be involved in the biogenesis of micranthine (77), cissampaeine (450), and related alkaloids (Schemes 9 and 10) (355). Biosynthetic routes have been suggested for the formation of the methyleneoxy bridges of cissampareine (450), repanduline (47), and insularine (451), via oxidative coupling of 0-methyls (355a).

On the basis of in vitro oxidation of simple benzylisoquinolinequaternary salts with O,/Cu , it was proposed that secobisbenzylisoquinolinealkaloids could be derived by singlet oxygen oxidation of bisbenzylisoquinolines, specifically, bal+

1.


141

H-'

Me

77 122

SCHEME 9

Me0

451 OMe

Me0

Me0

452

Me0

453

142

KEITH T.BUCK

&

Me N OMe

OMe OMe

450

SCHEME 10

uchistanamine (376) from oxyacanthine (247) (233). A possible relationship between lignan and alkaloid biosynthesis in Berberis chilensis has been suggested. The alkaloid berbamine (384) and the co-occumng lignans 453 and 452 could accordingly all be derived from oxidation, by the same enzyme system, of phenolic precursors at different stages in their elaboration (1 74).

VIII. Pharmacology This section outlines pharmacological research on bisbenzylisoquinoline alkaloids for the period under review. The only member of this group that has been widely employed in medicine is tubocurarine (Monograph Number 9608, The Merck Index, Tenth Ed.); because of the sheer volume of clinical work involving its use as a muscle relaxant, material relating only to tubocurarine is omitted (356). Work on nonnaturally occumng alkaloid derivatives (e.g., quaternary salts) and synthetic analogs is not included. The pharmacology of tetrandrine has also been discussed in Vol. 25 (1985) of this treatise. Table I1 gives an alphabetical listing of alkaloids and their pharmacological activities. See Table VI (Section XIJ) for a similar tabulation for the period 1984-1986.

TABLE I1 Pharmacological Activity of BisbenzylisoquinolineAlkaloids Alkaloid Adiantifoline Berbamine

Berbamunine Bisnorthalphenine Cepharanoline Cepharanthine

Pharmacological activity Hypotensive in rabbits No observed antimicrobial activity In patented drug for treating hepatobiliary disease; antibiotic Cytotoxic, but not antiviral in animals Increased leukocyte level in leukopenia patients Strongly toxic to mice, inactive against HeLa, Ehrlich ascites, S180 cells, and Staphylococcus aureus Inhibitor of collagen- or ADP-induced human platelet aggregation Not antiarthritic in mice or rats Hypotensive; not antiinflammatory, analgesic, or analeptic Inhibited hypotonic hemolysis of human erythrocytes by membrane incorporation Investigated as lipid peroxidation inhibitor Hypotensive in cat, dog, and rabbit by direct CNS effect and blood vessel dilation Tuberculostatic potential assayed Corrected low white cell count (rats, dogs); counteracted H37Rv (mice); anticoagulant, increased liver protein (rat); in humans, raised white cell counts in most cases, also treated cancer, migraine, insomnia, fatigue Increased leukocyte levels in humans Spasmolytic (rabbit intestine); not adrenolytic, not antiinflammatory (rats) Antibacterial (Mycobacterium smegmutis, S. aureus, Candida albicans) Inactive against HeLa cells in vitro Active against HeLa cells in vitro. Ehrlich ascites and S180 cells in vivo (mice); LD50 (mice) determined; antibacterial, particularly toward Sarcinu lutea; did not cause hemolysis of rabbit red blood cells. Inhibited bilirubin-induced K + release by maternal and umbilical cord erythrocytes Inhibited Fe2+ -catalyzed lipid peroxidation in rat liver mitochondria and human erythrocyte ghosts Did not protect rat liver against radiation-induced lipid peroxidation Decreased membrane fluidity, inhibiting K + re-

Reference

2,357 L

358 359 167 360

361,362 363 364 365 366 367 368 173

369 370 132 360 360

3 71 3 72 3 73 374,375,376 (continued)

144

KElTH T.BUCK

TABLE I1 (Continued) Alkaloid

Pharmacological activity lease from several cell types induced by various agents Restored antibody-forming capacity of irradiated mice by affecting lymphocytes Imunosupressant in rat peritoneal mast cells by reducing membrane fluidity Reduced leukopenia during cancer therapy (mice) Inhibited HgCI2-induced rabbit erythrocyte membrane damage Antineoplastic activity in animals Radioprotective against induced leukocytopenia Clinical use to control hypotension during anesthesia; long-term animal tests showed no significant liver or kidney impairment Inhibited collagen- or thrombin-induced human platelet aggregation; specific inhibitor of arachidonic acid release Enhanced antitumor effect of rat gamma globulin Inhibited gastric movement (dogs) by suppressing histamine release Prolonged survival of mice with transplanted Ehrlich tumor No effect on granuloma or thymus weight in rats implanted with HCHO-soaked filter paper Small doses decreased rejection of spleen cell grafts in mice; larger doses increased it At 0.1-0.8 mM, induced invagination of human erythrocytes Prevented Fez+ -induced deterioration of mitochondrial function; inhibited radiation-induced peroxidation of soybean liposomes Intravenous injection in rabbits caused brief vasodilation and slight vasomotion Antihistamine, nasal antiallergen (humans) Protective against lung radiation damage (rabbit) Protective and curative for X-ray and chemically induced leukocytopenia Inhibited T-cell transformation of human lymphocytes; inhibited helper T cells, enhanced suppressor T-cell function Enhanced antibody formation in irradiated mice In mice bearing transplanted tumors, tumor growth was retarded Prevented CCL-induced liver damage in rats Inhibited K + release from red blood cells induced by various agents; also protected mitochondria

Reference

377 378 379 380 381 202 382

383,384

385 386,387,388 389 390 391 392 393,394

395 396 397 202 398

3 77 399 400 401,402

(continued)

145


TABLE I1 (Continued) ~

Alkaloid

Cocsulinine Curine

Cyclanoline Cycleanine

Dauricine

Pharmacological activity Protected mice against hemopoiesis induced by mitomycin C Inhibited platelet aggregation induced by ADP or collagen Inhibited lysolecithin-induced K + efflux from erythrocytes Suppressed radiation-induced lipid peroxidation and loss of membrane integrity of liposomes Decreased formation of irreversibly sickled cells in vifro In mouse spleen, enhanced antibody-dependent cellular cytotoxicity response Hair tonic adjuvant I n vitro antisickling activity Induced invagination and increased resistance of human erythrocytes to hemolysis Lessened suppression of hemopoiesis in mouse spleen after administration of mitomycin C Caused membrane shape change without altering K + efflux in human erythrocytes Stabilized Ehrlich ascites tumor cell membranes Effective in therapy of rheumatoid arthritis, especially in conjunction with corticosteroid Inhibited Fez+ -induced lipid peroxidation of rat liver microsomal and mitochondria1 membranes and soybean liposomes Increased leukocyte levels in humans Active in vitro on human carcinoma 9KB Muscle relaxant Therapeutic index as muscle relaxant determined Clinical trial as muscle relaxant Muscle relaxant Active against HeLa cells in vitro Not tuberculostatic CNS depressant, sedative, uterolytic (rat) Bactericidal and virucidal activity assayed Toxic to HeLa-S3 cells in vitro; no in vivo antitumor activity Inhibitor of human platelet aggregation; weak inhibitor of lysolecithin-induced K + efflux from erythrocytes Inhibition of biological membrane lipid peroxidation evaluated Antihypertensive in cats, rats, and rabbits Inhibited aortic strip contraction by Ca2+ antagonism

Reference

403 361,362 361 404 405,406 407 408 409 365 403 410 411 412 366

369 19 202 413 414 415 360 368 416 417 360 361.362

366 418 419

(confinued)

146

KEITH T. BUCK

TABLE I1 (Continued) ~~

Alkaloid

N-Demethylthalphenine N-Desmethylthalidasine N-Desmethylthalidezine N-Desmethylthalistyline Epistephanine

Fangchinoline

Fetidine

Hemandezine

Pharmacological activity

Reference

Hypotensive in cats and rats Absorption, distribution, and excretion studied in rats after oral dose; tritium labeling also used Pharmacokinetics studied in rabbits, using TLC and densitometry Action in cat myocardium papillary muscle, possibly by CaZ+ antagonism; also antagonized isoprenaline Local anesthetic (guinea pig), antiarrhythmic, hypotensive (cat) Antibiotic (M. smegmatis, S. aureus, C . albicans)

420 421,422

Anticancer activity in animals Hypotensive in dogs and rabbits Hypotensive in dogs and rabbits

76 34 34

Antibacterial (M. smegmatis, S. aureus) Hypotensive in dogs and rabbits Weakly active in vitro against HeLa cells; not active in vivo (mouse) against Ehrlich ascites cells Blocked sympathetic nerve response, did not affect adrenaline response Active against HeLa cells in v i m , not active toward Ehrlich ascites cells in mouse Inhibitor of collagen-induced human platelet aggregation Induced invagination and increased resistance of human erythrocytes to hypotonic hemolysis Inhibited Fez+-induced lipid peroxidation of biological membranes Lowered blood glucose levels of fasting rats; effect antagonized by alloxan Antiinflammatory by i.p. injection against CHzOinduced edema in rats Hypotensive Antianythmic in animal models Antiinflammatory (rat); hypothermic (rabbit) Caused dyspnea, drowsiness in mice ( L D s determined); CNS depressant in rabbits; short-term reduction of arterial blood pressure in dogs and cats; respiratory depressant (cat) Kptensive (dog,mbbit); antibacterial (X aureus, M . smegmatis, C . albicans) Weak anticancer activity (rats, mice)

331 423,424

425 132

78 34 360

426 360 361,362 365 366 198a

427 428 429 430 431

34

432 (continued)

147


TABLE I1 (Continued) Alkaloid Homoamnoline

Huangshanine Hypoepistephanine Isochondodendrine lsoliensinine Isotetrandrine

Isotrilobine

Limacine Macoline

Magno1amine Magnoline

Methothalistyline

0-Methyldauricine

Pharmacological activity Antibacterial ( M . smegmatis, C. albicans); hypotensive (dog) Inhibited collagen- and ADP-induced human platelet aggregation; inhibited lysolecithin-induced K + efflux from erythrocytes Membrane stabilizer Cytotoxic to Walker 256 carcinoma cells Active against HeLa cells in vitro Analgesic Analgesic dosage determined in mice Active against HeLa in vitro Effect on osmotic resistance of human erythrocyte membrane Antiinflammatory, analgesic, hypothermic in rats; reduced blood uric acid levels; antagonized induced ileum contractions; not anticonwlsant Weakly antibiotic; effective against Ehrlich ascites and S180 tumors in mice only at dose close to LD50 Antiinflammatory in rats Antiarthritic Weakly spasmolytic; not active against KB cells in vitro or L1218 leukemia cells in vivo Evaluated as potential tuberculostat Membrane stabilizer; radioprotective Inhibitor of induced platelet aggregation No effect on lysolecithin-induced K + efflux from erythrocytes Antiinflammatory, antiarthritic in mice Toxic to HeLa-S3 cells in vitro, Ehrlich ascites and S 180 cells in vivo; antibacterial; hemolytic Potential therapy of amoebic meningoencephalitis Curarizing activity evaluated by studies of competitive binding of cholinergic receptor with labeled a-bungmtoxin Antineoplastic Evaluated as potential tuberculostat Inhibited feeding of bark beetle (Scolytus multistriatus) Evaluated as potential tuberculostat Hypotensive in dogs and rabbits Active against M . smegmatis and S . aureus Evaluated as potential tuberculostat Antineoplastic in animals Cytotoxic to HeLa cells in v i m ; no significant antibacterial activity

Reference

214 361,362

366 I01 360 190 433 360 365 434

360 435 436 121 412 366 361,362 361 436 360 437 438

381 368 439 368 34,78 78 368 381 360 ~~

(continued)

148

KElTH T.BUCK



Reference

Methylisochondodendrine

Effect on Fez+ -induced lipid peroxidation of biological membranes Evaluated as potential tuberculostat Evaluated as potential tuberculostat Active against M. smegmatis and C . albicans Hypotensive in dogs; slightly bacteriostatic Active against HeLa-S3 cells in vitro; ineffective in vivo toward Ehrlich ascites cells in mice Antiarrhythmic effect determined in animals Active against M . smegmatis but not against several other microbes Effect on Fez+ -induced lipid peroxidation of biological membranes Weak spasmolytic effect (rabbit intestine); antiinflammatory (rat); not adrenolytic Hypotensive in rabbits Hypotensive (dogs); very weakly antibacterial Tuberculostatic action evaluated Hypotensive in dogs; antibacterial toward several species No curarelike activity; antagonized phenylephrineinduced rabbit aorta contraction; transient blood pressure reduction in dogs Active against HeLa-S3 cells in vitro; high toxicity (mice); not hemolytic; not significantly antibacterial Tuberculostatic potential assayed Component of drug for hepatobiliary diseases Very weakly antibacterial Hypotensive; not antiinflammatory, analgesic or analeptic Hypotensive Active against M . smegmaris but not against several other bacteria Mosquito larvicide; paralytic in mammals and quail; moderate activity against gram-positive bacteria (Bacillus subtilis, S. aureus) Muscle relaxant effect assayed by screen grip test on rats and mice Toxicity and cross-resistance study on Chinese hamster ovary cells Evaluated as potential tuberculostat Active against HeLa cells in v i m Clinically effective oral antihypertensive drug Increased myocardial blood flow; Ca antagonist

366

0-Methylrepandine 0-Methylthalibrine 0-Methylthalicberine

0-Methylthalmetbine Norcycleanine Obaberine

Obamegine

Oxyacanthine

Penduline Pennsylvanine Phaeantharine

Phaeanthine

Repandine Stebisimine Tetrandrine

368 368 33 214 360 429 154 366 370 357 214 368 214 440

360

368 358 214 364

19 154 8

219 441 368 360 442 443 (continued)

149



Pharmacological activity Weak analgesic; antiinflammatory (rat) i.m. but not orally; minor effect on urinary uric acid output; no CNS activity Active against HeLa and HeLa-S3 cells in vitro, against Ehrlich ascites and S180 cells in viwo (mice); antibacterial toward gram-positive species Antisilicotic in rats Protective in experimental myocardial infarction (dogs) In isolated rabbit left atria, did not antagonize increase of CAMP and force of contraction caused by isoprenaline Effects on guinea pig atrium studied Inhibited contraction of isolated rat uterus induced by oxytocin; effect reversed by Ca2 + Prevented or amelliorated induced arrhythmias in rats, guinea pigs Reduced blood pressure by dilating blood vessels (dogs) Antiarrhythmic (swine heart), partially antagonized by Ca2+ Blocker of slow channel action potential and contraction of isolated guinea pig papillary muscle Partial inhibitor of human esophageal carcinoma ECa 109 and ECa 109-G3 in vitro Evaluated as potential tuberculostat Antineoplastic activity studied in animals Theories of carcinogenesis related to structure of promoters and inhibitors, including tetrandrine Phase I1 clinical anticancer studies Membrane stabilizing activity investigated Incorporated dose-dependently into human erythrocyte membranes, providing resistance to hypotonic hemolysis Ineffective in inhibiting mitochondria1 respiration of Ehrlich ascites cell suspensions Antineoplastic (mouse, S 180 tumor); antihypertensive Antiinflammatory (rats, rabbits); LD50 (mice) determined Hypotensive (i.v., rats); mechanism of action investigated Inhibited ADP- and collagen-induced human platelet aggregation; inhibited lysolecithin-induced K + efflux from erythrocytes

Reference 435

360

444,445 446,447 448

449 450 451 452 453 454 455 368 381 456 45 7 366 365

458 459 460 461 361,362

(continued)

KEITH T.BUCK


Pharmacological activity Glycosaminoglycan content of rats with/without tetrandrine treatment Inhibited thymidine and uridine uptake by HeLa cells; some other parameters affected Long-term clinical use in silicosis therapy Toxicity and accumulation in dogs was dose dependent Ca2+ antagonist in isolated cat papillary muscle Caused diminution of silicosis nodules in rabbits Ca2+ antagonist (isolated pig coronary artery) Induced dose-dependent hypotension and bradycardia; fatal at high doses (rhesus monkeys) Possible relationship between biochemical reactions and antisilicotic activity Relaxation effect on rabbit and rat aortic strips, apparently due to Ca2 antagonism Antisilicosis effect related to amino acid composition of lung collagen Toxicology in beagle dogs and rhesus monkeys Antiarrhythmic in cat papillary muscle Ca2+ antagonist in heart Effects on isoprenaline- and Ca2+ -mediated positive chronotropic action in isolated rabbit atria Inhibited biosynthesis of DNA, RNA, and protein by mouse sarcoma (S180) cells in vitro; mechanism studied High i.v. doses caused acute hypotension and toxicity in dogs and rhesus monkeys; at lower doses imtation and bone marrow changes resulted; no tolerance developed Decreased toxicity of cardiac glycosides in guinea pigs; Ca2+ antagonized this action Antiarrhythmic effect of tetrandrine on induced arrhythmias in guinea pig heart nullified by tetrandrine Relaxed ouabain-induced contraction of pig coronary artery strips; effect antagonized by Ca2+ Calcium antagonist; prolonged peak effect of divasid and ouabain and reduced their toxicity Counteracted ventricular fibrillation induced in rats. cats, and guinea pigs; effectiveness compared to that of several other drugs Activity against KB carcinoma Evaluated as potential tuberculostat

Reference

445 462,463 464,465 466 467 468 469 470 259,260 4 71

+

Thalfetidine

472 4 73 474 4 75 4 76

477

4 78

4 79 480

481 482 483,484

208 368 (continued)

1.

151

THE BISBENZYLISOQUINOLINEALKALOIDS TABLE I1 (Conrinued)

Alkaloid Thalfine Thalfinine

Thaliadanine Thdiadine Thalibrine Thalicarpine

Pharmacological activity Antibacterial (M. smegmatis) No effect on rabbit blood pressure Antibacterial (M. smegmatis) Transient drop in blood pressure (i.v., rabbit) Hypotensive Antibacterial ( M . smegmaris) Hypotensive (rabbits) Hypotensive (rabbits) Inactive toward M . smegmatis Antibacterial ( S . aureus, M. smegmatis, C . albicans) Strongly active against HeLa cells in vitro Liposome-entrapped thalicarpine effective against Walker tumor cells in vitro,though free drug ineffective (by WmTc labeling) Did not affect various tumor types in rats, not toxic to organs At 100 mg/kg/day i.p. in mice inhibited Lewis lung carcinoma but caused isolated necroses Intraperitoneally in mice and rats, caused decrease, then increase of leukocytes and lymphocytes, but did not affect hemoglobin or erythrocytes Inhibitor of biosynthesis of DNA, RNA, and protein in mouse sarcoma (S180) cells; inhibitor of acetate incorporation into lipids; mechanism investigated Plasma decay and urinary excretion of 3H-labeled thalicarpine studied in carcinoma patients In vitro inhibition of rat liver microsomal aniline hydroxylase by methylcholanthrene; effect on microsomal cytochromes P-4.50 and bs, and NADPH cytochrome c reductase studied Hypothesized mechanism of antitumor activity Assay method for preliminary screening for anticancer activity Incorporation in liposomes greatly enhanced toxicity to Walker S and TLX-5 cells in vitro Toxicity in rat and mouse determined; rapid, but not slow, administration caused toxicity; marked activity against Sa9 and HEF cell cultures Dosages determined that produced almost no toxicity in pregnant rats and offspring Hypotensive in rabbits; antibacterial (M.smegmatis) Enhanced effect of cyclophosphamide against Lewis lung carcinoma and L1210 leukemia (mice) Immunosuppressive in mice

Reference

32,357 32 32,357 32 151 2,357 2,357 78

360 485

486 487 488

477

489 490

456 491 492 493,494

495 154 496 497,498 (continued)

152

KEITH T. BUCK


Pharmacological activity Toxicity and distribution studies in mice, rats, hamsters, and dogs Single-dose toxicity in rhesus monkeys Toxicity in dogs and monkeys Toxicity in rats and rhesus monkeys Phase I clinical trials (human, dog, monkey, rodent) Activity against KB carcinoma Phase I1 cancer therapy trials Antianythmic activity tested in animals Structure-activity relationship deduced by crossresistance study on Chinese hamster ovary cells In cultured mouse leukemia cells L1210, inhibited DNA, RNA, and protein synthesis Reversibly bound calf thymus DNA, but not human serum albumin in v i m ; bound unidentified component of human serum in vivo Weakly mutagenic in human embryonal lung cell cultures; inhibited DNA synthesis Weak antitussive (dogs) Abbreviated phase I1 clinical trial in advanced cancer patients; several adverse effects, but no hematologic, hepatic, or renal toxicity Clinical pharmacology, including metabolic studies Inhibition of thymidine and uridine uptake by HeLa cells in v i m Effective on Walker carcinosarcoma, Yoshida sarcoma, and Jensen sarcoma in vivo; some action on lymphoma NKILy, no effect in sarcoma 37, reduction of survival time for Guer sarcoma; some weight loss; doses to 150 mg/kg not lethal Not effective on Lewis lung carcinoma, but potenti1ated action of 1,2-bis(2,6-dioxopiperizinyl)propane Did not inhibit mitochondria1 respiration of Ehrlich ascites cell suspensions at reasonable concentrations Low chronic human toxicity, but no significant tumor response in Phase I trials Hematotoxic (mice) when in combination with cyclophosphamide or likurim Moderately active on sarcoma 37; potentiated cyclophosphamide Suppressed growth of Ehrlich ascites tumor, Walker carcinosarcoma, sarcoma 37, Lewis carcinoma, sarcoma 180 in rats; intermittent dosage (Walker

Reference 499 500 501 502 503

208 457 429 441

504,505 506

507,508 509 510

51 1

462 512

513

458

514 515

516 51 7

(continued)

1.

153

THE BISBENZYLISOQUINOLINE ALKALOIDS TABLE I1 (Continued)

Alkaloid

Thalicberine Thalicsimine Thalidasine

Thalidezine Thalifakrine Thalirabine Thaliacebine Thalirevoline Thalirevolutine Thalisopine (= thaligosine) Thalistine Thalistyline

Pharmacological activity carcinosarcoma) preferred to continuous administration Toxicology, including LD50, determined in rats, mice Cumulative toxicology (i.v., mice) Single dosage i.p. more effective than multiple doses in mice with Ehrlich ascites or NK/Ly Toxicity and decreased organ weight in mice Review of lethality and toxicity to mice Review of clinical pharmacology of thalicqine as antitumor agent Phase I1 clinical cancer chemotherapy studies Prolonged the action of sodium hexobarbital Depressed intestinal motility in rats Active against HeLa and Ehrlich ascites cells in vitro, low toxicity Antiinflammatory (rats, rabbits); LD50 determined (i.p., mice) Thalidasine liposome complexes were more effective antitumor agents in mice than thalidasine alone Liposome complex preparation; LD50 (mice); toxicity tests (rabbits) Antimicrobial, particularly against M. smegmatis Hypotensive (rabbits) Body weight and blood indices remained normal in rabbits during therapy; suppressed Lewis lung and ascites tumors in mice (LD50 determined) Inhibited Ehrlich ascites, S180, Lewis lung tumors in mice; no effect on hepatoma or uterine tumors; i.p. and i.v. LDs0s determined Anticancer activity in animals Antitumor and antimicrobial action Hypotensive (dogs, rabbits) Hypotensive (dogs, rabbits) Cytotoxic to Walker 256 carcinoma cells Antibacterial (M.srnegmatis); induced pressor effect in rabbits; hypotensive in dogs Hypotensive Hypotensive (rabbits); antibacterial (M. smegmatis) Hypotensive (rabbits); antibacterial ( M . srnegrnatis) Hypotensive (rabbits) Antiarrhythmic (dogs, cats, rats) Active against M . smegmatis and S. aureus Hypotensive (dogs, rabbits)

Reference

518 519 520 521 522 523 457 524 525 360 460 526,527

528 32,214 357 529

530

76 151 34 34 101 32,357 151 32,357 147 147 429,531 33 34.78 (continued)

154

KEITH T. BUCK

TABLE I1 (Continued) ~~~

Alkaloid

Thalmelatine Thalmine

Thalrnirabine Thalpine Thalrugosaminine

Thalrugosine Thalsimine

Trilobine

d-Tubocurine

Warifteine

Pharmacological activity Antibacterial (S. aureus, M. smegmatis) Curare-like activity, lowered blood pressure (dogs); antagonized phenylephrine-induced contractions of isolated rabbit aorta; blocked neuromuscular transmission in rat hemidiaphragm preparation Active against M. smegmaris but not against five other microorganisms Antiarrhythmic effect tested in animals Antiblastic effect on ascites lymphoma NK/Ly in rats and mice Active against M. smegmaris Active against M. smegmatis Active against M . smegmaris but not against five other bacteria Hypotensive (rabbits) Hypotensive (dogs); antimicrobial (six bacteria) Antiinflammatory (rats); reduced vascular permeability and lowered body temperature of rabbits Weak anticancer activity (rats, mice) Raised pain threshold in mice; did not induce or relieve morphine withdrawal symptoms in rats or monkeys and hence is nonaddicting Antiinflammatory , antiarthritic (mice) Strongly active against HeLa-S3 in vitro Sodium nitroprusside potentiated blocking produced by d-tubocurine in frog gastrocnemius muscle Dopaminergic antagonist in perfused rabbit ear artery Inhibited indirectly stimulated twitch response of tibialis anterior and gastrocnemius muscles in anesthetized cats and isolated rat diaphragm; effect antagonized by neostigmine methosulfate; anesthetic

Reference

78 440

154 429 432 33 132 154,155 154,357 214 532

432 533

436 360 534 535 536

IX. Reviews of Bisbenzylisoquinoline Alkaloids Following is a list of major reviews that have appeared during the period of coverage, with a brief appraisal of their content. Several reviews are available that cover brief periods (e.g., The Specialist Periodical Reports of the Chemical Society) or are more general in nature, and are not included here. Reviews of specific areas (e.g., I3C NMR) are mentioned in the appropriate sections of this chapter.

1. THE


155

1. 0. N. Tolkachev, E. P. Nakova, and R. P. Evstigneeva, Usp. Khim. 49, 1617 (1980) (Chem. Abstr. 94, 15922). Synthesis of bisbenzylisoquinolinealkaloids. A general review in Russian, citing mainly older literature; only five of 153 citations are more recent than 1969. 2. 0. N. Tolkachev, E. P. Nakova, and R. P. Evstigneeva, Khim. Prir. Soedin., 451 (1977); English translation, Chern. Nu?. Compd., 382 (1977) (Chem. Abstr. 87,201829). A more up-to-date treatment than the first review cited; over one-third of 191 references cited are post-1969. Discusses representative bis alkaloids of various types. Includes sections on chemical reactions and spectral methods (UV, IR, ORD, CD, NMR, MS) and a brief treatment of biological activity. 3. T. Kametani, “The Chemistry of the Isoquinoline Alkaloids,” Vol. 2, Chapt. 7. Sendai Institute of Heterocyclic Chemistry, Sendai, 1974. A listing of 95 bisbenzylisoquinoline alkaloids arranged by structural types, with structures, molecular formulas, and references to papers citing physical properties, sources, structure proof, and synthesis. A comprehensive summary with 111 references. 4. H. Guinaudeau, M. Leboeuf, and A. Cav6, J. Nut. Prod. 42, 133 (1979). Dimeric aporphinebenzylisoquinoline and aporphine-pavine alkaloids. Tabulates physical properties, sources, and references to synthesis of 28 alkaloids. 5. K. P. Guha, B. Mukherjee, and R. Mukherjee, J . Nut. Prod. 42, 1 (1979). Bisbenzylsioquinoline alkaloids. Tabular discussion of 186 alkaloids, arranged by structural type, giving detailed physical data, sources, and synopses of structure proofs. Includes a section on chemical methods of structure proof. Covers literature to 1977; 277 references. 6. P. L. Schiff, Jr., J. Nut. Prod. 46, 1 (1983). Bisbenzylisoquinolinealkaloids. Comprehensive tabulation of literature for 1978- 1981 (Chemical Abstracts Volumes 88-95), with 164 references. Covers structure revisions, additional (mainly spectral) data on known alkaloids, new sources of known alkaloids, structures, properties, summarized confirmatory reactions of new alkaloids, and biosynthetic evidence. Alkaloids are tabulated by botanical sources and pbarmacological activity. A section on methods (CD, luminescence spectra, specific rotation, TLC) is included. 7. P. L. Schiff, Jr., in “The Chemistry and Biology of Isoquinoline Alkaloids” (J. D. Phillipson, M. F. Roberts, and M. H. Zenk, eds.), pp. 126-141. Springer-Verlag, Berlin, 1985. Continues the previous review by Schiff, but in more condensed form (physical data not listed). Thirty-one alkaloids of new or revised structure are cited from the period 1981-1983, with 49 references. Methods of degradation are discussed.

X. Tabulation of Bisbenzylisoquinoline Alkaloids A. ALPHABETICAL LIST

Table 111lists all known bisbenzylisoquinolinealkaloids, their synonyms, and Chemical Abstracts registry numbers (when assigned), along with a reference in which their chemistry is discussed. To preserve continuity, the same reference letters are used here as in the table in Volume 16 of this treatise (cited herein).

B. TABULATION BY MOLECULAR WEIGHT Table IV is intended primarily for reference in conjunction with mass spectrometry studies. It has not been possible to evaluate all older literature critically; therefore some inaccuracies may not have been eliminated.

156

KEITH T. BUCK

TABLE 111 Alphabetical List of Bisbenzylisoquinoline Alkaloids Alkaloid Adiantifoline Apareline Aromoline Atherospermoline Aztequine Baluchistanamine Baluchistine Base A (Chondrodendron limaciifoliurn) Base L (Colubrinafaraluotru spp. furuluotru) Beccapoline Beccapolinium Belarine Berbacolorflammine Berbamine Berbamunine Berbibuxine Berbivaldine Bis( 1 1-hydroche1erythrine)acetone Bisjatrorrhizine N.N’-Bisnoraromoline Bursanine Calafatimine Calafatine Calafatine 2’a-N-oxide Calafatine 2‘P-N-oxide Cancentrine Cepharanoline Cepharanthine Chelidimerine Chenabine Chillanamine Chitraline Chondrocurarine Chondrocurine Chondrofoline Cissampareine

Synonym(s)

0-12’-Demethyltelobine Thalicrine, N-methyldaphnoline Aztechin 0-6-Demethyloxyacanthine

Berbenine

0-1,0-6-DidemethyIpakistanamine Bijatrorrhizine 2,2’ -Didemethylaromoline

0-Methylcepharanoline

N,N’-Dimethylchondrocurine,Nmethyltubocurarine 2’-Demethyltubocurarine, tubocurine, chondocurine 0-7-Methylcurine, (R,R)-7-0methylbebeerine 0-Methylwarifteine

CA Registry No.

Ref.a

20823-96-5 68779-85-1 519-53-9 21008-67y3 57608-18-1 55085-44-4 72154-62-2 -

b

-

U

85643-65-8 85643-68-1 35471-06-8 80550-38-5 478-61-5 485-18-7 84423-04-1

x

23006-09-9 35470-49-6 38962-93-5 82958-13-2 77793-42-1 73168-72-6 91126-80-6 91126-81-7 29417-90-5 27686-34-6 48 1-49-2 39110-99-1 85588-86-9 89412-84-0 77754-91-7 6880-94-0

a a a x x

477-58-7

a

31944-91-5

a

32728-54-4

x

x c,f b

b,w a x

d

x a x b b X

x

x x

x x a b a x

x x a

(continued)

157


TABLE I11 (Continued) CA Registry

Alkaloid Coclobine Cocsoline Cocsuline Cocsulinine Colorflammine Coyhaiquine Curacautine Curine Cuspidaline Cycleacurine Cycleadrine Cycleahomine Cycleanine

Cycleanine N-oxide Cycleanorine Cycleapeltine Daphnandrine Daphnine Daphnoline Dauricine Dauricinoline Dauricoline Daurinoline Daurisoline 1,2-Dehydroapateline Dehydromicranthine 1,2-Dehydrotelobine Dehydrothalicarpine Dehydrothalmelatine Demerarine 7-0-Demethylisothalicberine 7-0-Demethylpeinamine De-N-methyltenuipine 0-Desmethyladiantifoline N-Desmethylcycleanine N-Desmethyldauricine N-Desmethylthalidasine N-Desmethylthalidezine

S ynonym(s)

2‘-Demethylcocsuline Efirine, trigilletine, N-methyl- 12’-O-desmethyltrilobine

d-Chond(r)odendrine, d-bebeerine, aristolochine ((236 alkaloid) 1-Epigrisabine

Methylisochondodendrine (erroneous), 0.0-Dimethylisochondrodendrine 2’-Nortetrandrine, 2’4-demethyltetrandrine Faralaotrine 0-12’-Methyldaphnoline Trilobamine

0-7-Demethyldauricine I ’,2‘-Didehydroapateline 1’,2’-Didehydrotelobine

Thalictrucarpine

2’-Demethyldauricine N-Demethylthalidasine N-Demethylthalidezine

No.

Ref.u

24306-65-8 54352-70-4 26279-88-9

b X X

54370-90-0 80550-39-6 85643-88-5 89412-86-2 436-05-5

X

10410-53-4 38849-84-2 38769-07-2 41222-80-4 5 18-94-5

b

85805-55-6 38769-08-3

X

38849-80-8 1183-76-2 8053 1-83-5 479-36-1 524-17-4 34159-93-8 29550-42-3 2831-75-6 70553-76-3 68711-77-3 58207-93-5 68711-78-4 7224-94-4 16624-99-0 15353-21-6 7371 1-14-5 66254-50-0 3 1199-54-9 83730-51-2 34302-34-6 78432-93-6 65230-06-0

a

X X

X X

a a a b

a

C

X C

b

a a b X X

X

X X

b b X X

d a X

a X X

(continued)

158

KEITH T. BUCK

TABLE 111 (Conrinued) CA Registry

Alkaloid N-Desmethylthalistyline N-Desmethylthalrugosidine

12'-0-Desmethyltrilobine Dihydromethylwarifteine Dihydrosecocepharanthine Dihydrothalictrinine Dihydrowarifteine (R,R)-0.0-Dimethylcurine DimethyWhydrowarifteine 0,N-Dimethy lmicranthine Dimethylwarifteine Dinklacorine Dinklageine Dirosine Dryadine Dryadodaphnine Epistephanine ( -)-Epistephanine Epivaldiberine Espinidine Espinine Fangchinoline Faralaotrine Fetidine Funiferine

Synonym(s) N-Demethyithalisty line N-Demethylthalrugosidine Base B (Stephanin sasakii)

(R,R)-0,O-Dimethylbebeerine ( -)-Isotrilobine

0-Methylcissampareine 0-12-Demethyl-0-12'-methyltiliacorine

( +)-Limacine Cycleapeltine

0-12-Demethyl-0-12'-

No.

Ref. a

62251-51-8 74683-04-8 39986-72-6 31 114-26-8 89503-79-7 72187-02-1 30996-85-1 1812-55-1 30994-04-8 36296-04-5 7678-91-3 60579-86-4

X

11076-61-2 1356-72-5 22559-05-3 22559-06-4 549-08-6 40039-47-2 84472-22-0 26 137-41-7 26137-40-6 436-77-1 38849-80-8 7072-86-8 1394-44-1

f b b

X

a X

x X

X X X

a X X

b

b a X

a a b X X3Y

X

methylrodiasine Funiferine dimetho salt Funiferine N-oxide Gilgitine Gilletine Grisabine Guattegaumerine

0-12-Demethyl-0-12'-methylrodiasine 2-oxide

1-Epicuspidaline

N,N-Dimethyllindoldhamine,1'p-

1394-46-3 61912-73-0

X

X

84435-37-0 52038-20-7 62057-36-7 2 1446-35-5

X

16543-77-4 26057-51-2 6879-67-0

b b b

10210-99-8 6681-13-6

-

X X X

H-berbamunine , 1a-H-magnoline Hayatidine Hayatine Hayatinine

Hemandaline Hemandezine

(&)-Curine, (+)-bebeerhe 0-Methylbebeerine, 0-4"-methylcurine, O-methylchondrodendnne Thalicsimine, hemandesine

b

(continued)

159


TABLE Ill (Continued) CA Registry

Alkaloid Hernandezine N-oxide Himanthine Homoaromoline Homothalicrine Huangshanine Hypoepistephanine Insulanoline Insularine Isochondrocurarine Isochondrodendrine

Isodaurisoline Isogilletine N-oxide Isoliensinine Isotenuipine Isotetrandrine Isothalicberine Isothalidezine lsotrilobine Istanbulamine Iznikine Jhelumine Johnsonine Jolantinine Kalashine Karakoramine Khyberine Krukovine Lauberine Liensinine Limacine Limacusine Lindoldhamine Macolidine Macolie Magnolamine Magnoline Malekulatine Melanthioidine Menisidine

Synonym(s)

0-7,0-7'-Didemethylcycleanine, isobebeerine , isochondodendrine

(R ,S)-Tetrandrine , O-methylberbamine, isosinomenine A

Hornotrilobine, N,O-dimethylcocsaline

Iolantinine

Grisabutine

Ref.a

No.

78414-48-9 17132-74-0 6870-15-1 88313-35-3 33116-41-5 478-62-6 549-07-5 1357-94-4 477-62-3

X

f C

f X C C

C

f b

88524-56-5 77431-57-3 6817-41-0 35306-97-9 477-57-6

X

25514-42-5 64924-28-3 26195-62-0

X

82953-24-0 82958-14-3 85588-85-8 69064-34-2 64986-29-4 76372-24-2 85588-84-7 77795-10-9 57377-42-1 19879-48-2 2586-96-1 10172-02-8 10172-03-9 69342-37-2 66288-77-5 66216-59-9 573-73-9 6859-66-1 87183-76-4 4085-28-3 -

X

X

b a b

X C

X X

X X X X X

X

b b b b X X X X

b X

b d

(continued)

160

KEITH T. BUCK

TABLE 111 (Continued) CA Registry

Alkaloid Menisine Methothalistyline Methylapateline 2’-N-Methylberbamine 0-Methylcocsoline (R,R)-12‘-0-Methylcurine 0-Methyldauricine N-Methyl-7 -0-demethy lpeinamine 0-Methyldeoxopunjabine Methyldihydrowarifteine 0-Methylisothalicberine 7-0-Methyllindddhmine

7’-0-Methyllindoldhamine 0-Methylmicranthine N-Methylnorapateline N-Methylpachygonamine 1-0-Methylpakistanine 0-Methylpunjabine 0-Methylrepandine 0-Methylthalibrine 0-Methylthalibrunimine 0-Methylthalicberine 0-Methylthalmethine Methylwarifteine Micranthine Monomethyltetrandrinium Neferine Nemuarine Neochondrocurarine Neoprotocuridine Neothalibrine No name (Stephania hernandifoliff,C35H3&06) N-2’-Noradiantifoline 2-N-Norberbamine Norcyclemine 2’-Norisotetrandrine Normenisarine 2-N-Norobamegine Norpmurensine Norrodiasine

Synonym(s)

Thalistyline metho salt 1’-Epicocsuline, (+)-N-methylapateline

4”’-O-Methylbebeerine 0,O-Dimethyldauricinoline

Dihydrocissampareine 0-Methyl-1-isothalicberine N,N‘-Didemethylisodaunsoline N,N’-Didemethyldaurisoline N-Methyl-0-norapateline

N-Methyldihydrococlobine B

Thalmidine Cissampareine

2-Norberbamine

2’-Dernethylisotetrandnne

No.

Ref.0

65853-13-6 68779-86-2

X

68231-29-8 54352-71-5 59685-16-4 2202-17-7 66254-51-1 89503-80-0 3 1114-26-8 19879-44-8 88524-58-7 88524-57-6 40225-93-2 69088-72-8 87686-94-0 36418-13-0 59 194-22-2 4021-17-4 59654-05-6 75956-50-2 5096-71-9 5979-99-7 32728-54-4 36104-64-0 53935-72-1 2292-16-2 38739-62-7 1359-89-3 568-56-9 73609-03-7 11076-57-6 83348-50-9 39028-61-0 478-63-7 70191-82- 1 -

2-Norobamegine

38962-94-6 55702-00-6 1360-14-1

d X X X

b,x a X

X X

X X X

a X X X

X

d X

X

b b X

a a b,h a f d X

f X

a C

X

d a X

g

(continued)

1. THE

161



Alkaloid Nortenuipine 2-Nortetrandrine

Northalibrine 2’-Northalibrunine Northalicarpine Nortiliacorine A Nortiliacorinine A Nortiliacorinine B Obaberine Obamegine Oblongamine Ocodemerine Ocotine Ocotosine Osomine Otocamine Oxandrine 10-Oxocancentrine Oxoepistephanine Oxothalibrunimine Oxothalicarpine Oxyacanthine 2’-N-Oxyisotetrandrine Pachygonamine Pakistanamine Pakistanine Panurensine Patagonine Peinamine Pendine Penduline Pendulinine Pennsylpavine Pennsylpavoline Pennsylvanamine Pennsylvanine

Synonym@)

No.

Ref.O

0-Nortenuipine, N-demethyltenuipine (erroneous) 2-N-Demethyltetrandrine, 2-demethyltetrandrine, 2-nor-(+)tetrandrine

36067-01-3

gh

19196-54-4

g

59614-33-4 59553-88-7 5602 1-86-4 27577-49-7 26426-60-8 26771-94-6 1263-80-5

X

479-37-8 6351 1-70-6 11004-85-6 18529-55-0

C

18529-51-6 89412-88-4 11004-99-2 68798-36-7 72187-00-9 64234-41-9 548-40-3

g,h

70191-83-2 87686-93-9 36506-66-8 36506-69-1 5570 1-99-0 84423-06-3 64625-88-3 591 14-65-7 26137-45-1 591 14-69-1 53416-82-3 53416-83-4 53466-31-2 53416-85-6

X

N-2’-Demethylthalibrunine Isotiliarine Pseudotiliarine 0-Methyloxyacanthine, N-methyldihydrococlobine A Stepholine

Dihydroocotosine, 2’-Demethylrodiasine

N-Methylocoteamine, Nmethylsepeerine Isotetrandrine N-2‘-oxide

Paquistanine 0-7 ’-Demethylpakistanamine (-)-2-Demethylberbamine

X X

a X X

b

X

b gh

X

b X X

a X

z

b

X X

a X X X X

a X

a a a a

(continued)

162

KEITH T. BUCK

TABLE 111 (Continued) Alkaloid Phaeantharine Phaeanthine Phlebicine Porveniramine Protochondrocurarine Protocuridine Pseudorepanduline Pseudoxandrine Punjabine Pycnamine Pycnarrhenamine Pycnarrhenine Repandine Repandinine Repanduline Revolutinone Revolutopine Rodiasine Sanguidimerine Sciadenine Sciadoferine Sciadoline Secocepharanthine Sepeerine Sindamine Stebisimine Stepinonine Talcamine Telobine Temuconine Tenuipine Tetradehydrolimacine Tetradehydrolimacusine Tetrandrine

Synonym(s) Pheanthine, (-)-tetrandrine, 0 , O dimethylkrukovine

CA Registry

No.

Ref.

27670-80-0 1263-79-2 52674-06-3 84423-08-5 1360-60-7 1392-96-7 57821-67-7

b a X

f d X

-

X

84435-36-9 569-16-4 -

X

-

N-Methyldemerarine ( f)-Tenuipine

X

5 18-92-3

6883-11-0 20398-02-1 74046-19-8 62724-07-6 6391-64-6 0-6'-Methylphlebicine 41758-45-6 59043-23-1 0-7-Demeth y lc ycleanine 68676-59-5 2.3-Dihydrosciadoline 1,2,3,4-Tetradehydro-2-demethyl- 62404-95-9 sciadenine 89503-78-6 6787-93-5 Ocoteamine 84435-34-7 5692-04-6 1,2-Didehydronorepistephanine 38835-79-9 89412-85-1 41758-42-3 18210-69-0 0-7-Methylberbamunine 1263-91-4 -

b b b b d X

X X

a a X

X X X C

X

b a X

a X C 2 2

D-Tetrandrine, (+)-tetrandrine, (S,S)-tetrandrine, sinomenine A

518-34-3

(R,S)-Tetrandrine

1-Isotetrandrine, isosinomenine A,

4 77-57-6

g g

Tetrandrine N-2'-monoxide

0-methylberbamine, 0,O'-Dimethylobamegine, 0 , O ' Dimethylstepholine Tetrandrine 2'-oxide

62828-25-5

X

-

( ?)-Tetrandrine

X

(continued)

1.

163

THE BISBENZYLISOQUINOUM ALKALOIDS TABLE 111 (Continued)

Alkaloid Thalbadenzine Thaldimerine Thalfetidine Thalfine Thalfinine Thaliadanine Thaliadine Thalibrine Thalibrunimine Thalibrunine Thalicarpine Thalicberine Thalictine Thalictrinine Thalictrogamine Thalictropine Thalidasine Thalidezine Thalidoxine Thalifabenne Thalifabine Thaligosidine Thaligosine Thaligosinine Thalilutidine Thalilutine Thalipine Thalirabine Thaliracebine Thalirevoline Thalirevolutine

Thalirugidine Thalirugine Thaliruginine Thalisamine Thalisopidine Thalisopine Thalistine

Synonym(s)

Thalfoetidine Thalphine Thalphinine 0-Demethyladiantifoline 3-Demethoxyhemandaline

Didehydro-2’-northalibrunine 2’-Hydroxyhemandezine Thaliblastine, taliblastine

0-1-Demethylthalicarpine 0-Methy lthalfetidine, thalidazine Thalidesine

Thalisopine, talysopine, thalisopidine methyl ether

0-5-Demethylthalistyline 0-7-Methylrevolutopine 0-Methylfetidine, O-methylfoetidine, 0,O-dimethylrevolutopine

0-7 ’-Methylthalimgine Dihydrothalsimine A, (+)-N’norhemandezine Thalisopidine methyl ether, talysopine, thaligosine

CA Registry No.

66834-86-4 11051-30-2 16687-93-7 27764-05-2 27164-06-3 31199-54-9 675 10-96-7 59614-34-5 59553-87-6 11021-81-1 5373-42-2 602-83-5 58092-24-3 72187-01-0 41928-76-1 39032-60-5 16623-56-6 18251-36-0 50802-24-9 88313-32-0 88313-34-2 64252-82-0 22226-72-8 64235-38-7 66408-23-9 66408-21-7 62724-08-1 67624-63-9 67591-63-3 65853-12-5 6275 1-64-8

Ref.a X

b a X X

X X X X

X

b b X X

a a b X

a X X X

X X X X X X

x X X

64215-95-8 64235-41-2 64215-93-6 26326-54-5

g

26989-49-1 22226-72-8

a b .h

75352-25-9

x

X X X

(continued)

KElTH T. BUCK

164


Alkaloid Thalistyline Thalistyline metho salt Thalmelatidine Thalmelatine Thalmethine Thalmine Thalmineline Thalmirabine Thalpindione Thalrugosamine Thalrugosaminine Thalrugosidine Thalrugosine Thahgosinone Thalsimidine Thalsimine Tiliacoridine Tiliacorine Tiliacorinine Tiliacorinine 2'-N-oxide Tiliafunimine Tiliageine Tiliamosine Tiliandrine Tiliarine Toddalidirnerine Tomentocurine Toxicoferine Tricordatine Trigilletimine Trilobine Tubocurarine (as chloride hydrochloride)

S ynonym(s)

Methothalistyline

Thalmetine

0-7-Demethy lthahgosinone

0-Methylthalisopine 0-7-Demethylthalidasine Thaligine, isofangchinoline Thalcimidine Thalcimine

0-7 ,0-12-Didemethyl-O-12'methylrodiasine

D-Tubocurarine, (+)-tubocurarine Amerizol, Amelizol, Tubarine, D-pancurarine chloride, Tubadil, Intocostrine C, Delacurarine, dextrotubocurarine chloride

( -)-Tubocurarine

Tubocurine Uskudaramine Valdiberine

Chondrocurine, D-tubocurine, 2'demethyltubocur&ne

No.

Ref.a

62251-53-0 65853-13-6 3 1199-55-0 5308-77-0 3729-83-7 7682-65-7 28328-00-9 75352-27-1 74690-97-4 39027-78-6 22226-73-9 33954-34-6 33889-68-8 73609-02-6 22223-14-9 5525-36-0 11076-69-0 21013-12-9 27073-73-0 80161-67-7 65995-41-7 53755-51-4 62592-71-6 11051-31-3 7221-73-0 81421-65-0 1361-62-2 12578-01-7 51076-20-1 52038-21-8 6138-73-4 57-95-4 57-94-3

-

X X

a C

X

X

a X

v,x a X

a a v,x b X

g X

X X X

X,Y X

g c,g X

d a a X

a X

g

477-58-7

X

83983-89-5 84472-23-1

X

X

(continued)

165

1. THE BISBENZYLISOQUMOLINE ALKALOIDS

TABLE I11 (Continued)

Alkaloid

Synonym(s)

0-1-Demethylpakistanamine

Valdivianine Vanuatine Vateamine Warifteine

CA Registry No.

Ref. a

84423-01-8 87183-74-2 87183-75-3 30996-86-2

x x x x

References to Table 111: a. M. P. Cava, K. T. Buck, and K. L. Stuart, in “The Alkaloids” (R. H. F. Manske, ed.), Vol. 14, Chap. 5 . Academic Press, New York, 1977. b. M. Curcumelli-Rodostomo, in “The Alkaloids” (R. H. F. Manske, ed.), Vol. 13, Chap. 7. Academic Press, New York, 1971. C. M. Curcumelli-Rodostamoand M. Kulka, in “The Alkaloids” (R. H. F. Manske, ed.), Vol. 9, Chap. 4. Academic Press, New York, 1967. d. M. Kulka in “The Alkaloids” (R. H. F. Manske, ed.), Vol. 7, Chap. 21. Academic Press, New York, 1960. f. T. Kametani, “The Chemistry of the Isoquinoline Alkaloids,” Chap. 6. Elsevier, Amsterdam, 1969. g. K. P. Guha, B. Mukherjee, and R. Mukherjee, J . Nut. Prod. 42, 1 (1979). h. T. Kametani, “The Chemistry of the Isoquinoline Alkaloids,” Vol. 2, Chap. 7. Sendai Institute of Heterocyclic Chemistry, Sendai, 1974. U Incompletely characterized; see Ref. 89. V Revised structure; see Section XI,A. W Structure and reported Occurrence questionable; see Ref. 537. X This chapter. Y The structures and molecular formulas of fetidine and tiliageine were given incorrectly in Vol. 16 (1977) of this treatise. 2. See Section IX, Review 6.

TABLE IV Tabulation of BisbenzylisoquinolineAlkaloids by Molecular Weight

Mol. wt.

Formula

42 1 433 505 535 546

C25H27N05 C26H27N05 C29H3IN07 C30H33N08 C34H3f1205

548

C34H32N205

Alkaloid Karakoramine Coyhaiquine Hernandaline Thaliadine 1,2-Dehydroapateline 1,2-Dehydromicranthine Apateline COcsoline 12’-0-Desmethyltrilobine N-Methylnorapateline (continued)

166

KEITH T. BUCK

TABLE IV (Continued) Mol. wt.

550 558 560 562

Formula

C34H34NZ05 C35H30N205 C35H32NZ05

C35H34NZ05

564

566 568

576 576

578

Alkaloid Micranthine Tricordatine Tiliandrine Trigilletimine 1,2-DehydroteIobine Cocsuline N-Methylapateline 0-Methylcocsoline 0-Methylmicranthine Nortiliacorine A Nortiliacorinine A Nortiliacorinine B Telobine Tiliarine Trilobine Pachygonamine N,N-Bisnoraromoline Lindoldhamine Nonnenisarine 0,N-Dimethylmicranthine Dinklacorine Isotrilobine Tiliacorine Tiliacorinine No name (Stephania hernandifolia) Cocsulinine Gilletine

580

588

C36H32N206

590

C36H34N206

592 592

C35H32N207 C36H36N206

N-Methy lpachygonamine Pendine Pendulinine Cycleacurine Daphnoline 7-0-Demethylpeinamine 7-0-Methyllindoldhamine 7'-0-Methyllindoldhamine 2-N-Norobamegine Tiliacorinine 2'4-oxide Menisarine Sciadoline Stebisimine Punjabine Cepharanoline Hypoepistephanine (continued)

167



Formula

Alkaloid 0-Methyldeoxopunjabine Sciadoferine Thalmethine Tiliafunimine Tiliamosine Warifteine Isogilletine N-oxide Aromoline Atherospermoline Baluchistine Base A (Chondrodendronlimaciifoliurn) Berbivaldine Chitraline Chondrocurine Curine Daphnandrine Demerarine 7-O-Demethy lisothalicberine Dihydrowarifteine Dinklageine Dryadodaphnine Epivaldiberine Hayatine Isochondrodendrine Khyberine Krukovine Macolidine

594 594

N-Methyl-7-0-demethylpeinamine

596

C36H40NZ06

Neoprotocuridine 2-N-Norberbamine Norpanurensine Obamegine Peinamine Porveniramine Protocuridine Sepeerine Thalbadenzine Tomentocurine Toxicoferine Tubocurine Valdiberine Berbamunine Dauricoline (continued)

KEITH T.BUCK

168


Formula

600

C36H3ZN208

600 605

C37H37N206

606

C36H34N207

606

C37H38N206

608 608

C37H32N206 +

Alkaloid Espinine Guattegaumerine Magnoline 10-Oxocancentrine Daphnine Berbacolorflammine Colorflammine Tetradehydrolimacine Tetradehydrolimacusine Cancentrine 0-Methylpunjabine Stepinonine Cepharanthine Cissampareine Coclobine Epistephanine ( -)-Epistephanine Insulanoline 0-Methylthalmethine Methylwarifteine Ocotosine Pseudorepanduline Beccapoline Base L (Colubrinafaralaotra spp. faralaotra) Belarine Berbamine Chondrofoline Cycleadrine Cycleanorine Cycleapeltine N-Desmethylcycleanine Dryadine Fangchinoline Faralaotrine Hayatidine Hayatinine Himanthine Homoaromoline Homothalicrine Isothalicberine Johnsonine Kalashine Lauberine Limacine (continued)

1. THE BISBENZYL,ISOQUINOLINE ALKALOIDS

169

TABLE IV (Continued)

Mol. wt.

608 609

610

610

Formula

Alkaloid Lirnacusine Macoline Menisidine (R,R)-12’-0-Methylcurine 0-Methyldihydrowarifteine Nemuarine Norcycleanine 2’-Norisotetrandrine Norrodiasine 2-Nortetrandrine Ocodernerine Ocotine Otocamine Oxyacanthine Pakistanine Panurensine Patagonine Pendulipe Phlebicine Pycnamine Repandine Sciadenine Thalicberine Thalictine Thalmine Thalrugosamine Thalrugosine Tiliageine Valdivianine Jolantinine Protochondrocurarine Tubocurarine (-)-Tuhocurarine Jhelumine Cuspidaline Dauricinoline Daurinoline Daurisoline N’-Desmethyldauricine Dirosine Espinidine Grisabine Isodaurisoline Isoliensinine (continued)

170

KEITH T. BUCK


Formula

Alkaloid Liensinine

Northalibrine 612 616 620

C 3 6 H d 2 0 7 (?) (537) C37N32N207 C37N36N207

620

C38H40N206

622 622

C36H34N208 C37H38N207

622

623 623 624

Temuconine Aztequine Daphnine Oxoepistephanine Repanduline 0,O-Dimethylwarifteine Insularine Gilgitine De-N-methyltenuipine Nortenuipine Oxandrine Pseudoxandrine Thalsimidine Cycleanine (R,R)-0,O-Dimethylcurine 0,O-Dimethyldihydrowafteine Funiferine Isotetrandrine Melanthioidine Menisine 2’-N-Methylberbamine O-Methylisothalicbenne 1-0-Methy lpakistanine 0-Methylrepandine 0-Methylthalicberine Obaberine Pakistanamine Phaeanthine Rodiasine Tetrandrine ( ?)-Tetrandrine (R ,5’)-Tetrandrine Beccapolinium 2‘-N-Methylberbamine Oblongamine Chenabine N-Desmethylthalidezine

N-Desmethylthalrugosidine

624

C38H44N206

Thaligosidine Thalisopidine Dauricine Neferine Thalibrine (continued)

1.


171

TABLE IV (Conrinued)

Mot. wt.

Formula

624

626 626 632 632 634 636 636

637 638

638

638 640 646 648 652

652

C39H44N207

Alkaloid Chondrocurarine Isochondrocurarine Neochondrocuratine Chillanamine Magnolamine Neothalibrine Pycnarrhenamine Phaeantharine 0-Methylthalibrine Secocepharanthine Calafatimine Isotenuipine Repandinine Tenuipine Thalsimine Cycleahomine Monomethyltetrandrinium salt Baluchistanamine Dihydrosecocepharanthine Sindamine Berbibuxine Cycleanine N-oxide N-Desmethylthalidasine Funiferine N-oxide Isothalidezine Osomine 2’-N-Oxyisotetrandrine Tetrandrine N-2’-monoxide Thalfetidine Thalidezine Thaligosine Thaligosinine Thalisamine Thalisopine Thalrugosidine 0-Meth yldauricine Thalirugine Pycnanhenine Thalfine Revolutinone Thalibrunimine Thalpindione Calafatine Hemandezine Thalidasine (continued)

172

KEITH T.BUCK


Mol. wt.

Formula

652

654 654 656 664 664 666 666

668

C39&INZ08

670

674 680 682 682

683 692

CaH47N~ox CaH40Nz09

+

Alkaloid Thaliracebine Thalrugosaminine Funiferine dimetho salt 2’-Northalibrunine Thaliruginine Vateamine Thalictrinine Tiliacoridine Dihydrothalictrinine Oxothalibrunimine 0-Methylthalibrunimine Pennsylpavoline Thalfinine Thalrugosinone Calafatine 2’a-N-oxide Calafatine 2’P-N-oxide Hernandezine N-oxide Istanbulamine Pennsylvanamine Revolutopine Thalibrunine Thalictrogamine Thalipine Thalistine Thalmirabine Uskudaramine Malekulatine Thalirugidine Vanuatine Bisjatronhizine Dehydrothalmelatine Pennsylpavine Curacautine N-Desmethylthalisty line Fetidine Northalicarpine Pennsylvanine Thalictropine Thalidoxine Thalilutidine Thalirevolinc Thalmelatine Thalirabine Oxothalicarpine (continued)


173


Mol. wt. 694

Formula c4 I H46N208

697 698

710 712 712

c41 H46NZ09 C40H44N2010 c 4 lH48N209

712 720 726 738 740 742 750

C42H5d209

Alkaloid Dehydrothalicarpine Thalicqine Thalifaberine Thalirevolutine Thalistyline Bursanine Iznikine Thaldimerine Thalifabine Talcamine 0-Desmethyladiantifoline N-2’-Noradiantifoline Thaliadanine Thalilutine Methothalistyline Chelidimerine Sanguidimerine Adiantifoline Huangshanine Todda1idimerine Thalmelatidine Thalmineline Bis( 11-hydrochelerythrine)acetone

XI. Appendix The appendix covers the period from mid-1984 to mid-1986, as defined by Chemical Abstracts coverage (Volumes 101-104). The structure designations and the reference numbering of the main body of the chapter are retained, and the presentation follows the same format but in less detail. No tabulation is given for new alkaloids in this section, but CA registry numbers (if assigned) and molecular formulas are included in the discussion. For our immediate purposes an alkaloid or botanical source is defined as “new” if it is not described in Chemical Abstracts prior to Volume 101. A. STRUCTURE REVISIONS

1. Thalisamine Comparison of the NMR N-methyl resonance of N’-norhernandezine (234) with that of thalisamine (6 2.31), formerly thought to be the isomer 454, has shown that these alkaloids are identical (538).

174

KEITH T. BUCK

2. Thalpindione The revision of the structure of thalrugosinone (see below) from 345 to 455 necessitates a corresponding correction for thalpindione from 344 to 456, since CH,N, methylation of 456 yielded 455 (539).

455 R=Me 456 R = H

3. Thalrugosamine Thalrugosamine, originally thought to have the (lS, 1'R) configuration, has now been assigned structure 457, and is therefore identical to the well-known (+)-hornoarornoline. The revised structure is in accord with the observation that all dimeric Thalictrum alkaloids so far isolated [except (-)-isothalidezine (170)] possess the (1's) configuration (538).

457

4. Thalrugosinone

A chemical investigation of thalrugosinone has shown it to have structure 455 rather than 345. Hydrolysis of 455 with refluxing 18% HCl gave 2-northalidasine (458), while LiAlH, reduction of 455 yielded thalidasine (459). Proton NOE and 13C NMR confirmed the structure assignment (539).

, 1 . THE BISBENZYLISOQLJLNOLINEALKiUOIDS

175

'H

458 R = H 459 R=Me

B. CONFIRMATORY AND ADDITIONAL STRUCTURAL DATA ON KNOWNALKALOIDS 1. Beccapoline (81) and Beccapolinium (83)

An expanded discussion of beccapoline and beccapolinium has appeared (540).

2. Chondrofoline (460), Curine (79, and Isochondodendrine (212) Completely resolved 250-MHz NMR spectra were obtained for the title alkaloids. ORD data previously reported (82) for 212 were confirmed (541).W - N M R values, differing slightly from those previously reported (304),are given for 75; the '3C-NMR spectrum of the derivative, 0,O-dimethylchondrocurine (= 0,O-dimethyltubocurine, 427), is cited (542).

460

3. Dihydrosecocepharanthine(140), 0-Methyldeoxopunjabine (216), 0-Methylpunjabine (217), and Secocepharanthine (141).

A full paper detailing structure proofs has appeared (543). 4. Hernandezine N-Oxide (166) and Tetrandrine 2'-N-Oxide (294)

176

KEITH T. BUCK

Both alkaloids have been assigned the 2'-P-N-oxide stereochemistry by NMR NOEDS comparisons (544).

5. Huangshanine (167), Thalifaberine (302), and Thalifabine (304) The structure proofs of huangshanine, thalifaberine, and thalifabine are discussed in detail (545). 6. Insularine (451) and Insulanoline (461) IR, NMR, and MS data are given for insularine and insulanoline (546).

451 R = M e 461 R = H

7. N-Methylpachygonamine (222), Pachygonamine (221), Tiliacorinine (40), and Tiliamosine (350) Details of the isolation of the title alkaloids from Pachygone ovata have been published. The ceric ammonium nitrate degradation of N.0-dimethyltiliamosine (351) is described for the first time (547). 0-Acetyltiliacorinine has been found to have [a167 +290° (c 0.41, pyridine), rather than the higher value previously reported (547). 8. Tiliarine (462) Although (+)-tiliarhe (462) had been first described as an alkaloid of Tiliacoru racemosa Colebr. (Menispermaceae) in 1960, its complete structure was not elucidated until 1985, The MS fragmentation pattern suggested a close relationship between tiliarine and the isomeric alkaloids (+)-2'-nortiliacorinine (= (+)-nortiliacorinine A, 44) and (+)-2'-nortiliacorine (= (+)-nortiliacorine A, 463). NMR NOEDS studies of 44 and 462 revealed that they differ only in the relative location of the benzylic oxygen functions. The CD curve of 462 indicated the (S,S)configuration, in accord with the high-resolution NMR data, which showed conformational effects consistent with equivalent stereochemistry of the asymmetric centers (548).

1. THE


177

OMe

Me

OH

462

463

C. NEWALKALOIDS 1. Ambrimine [ 104330-67-81 Hernundiu peltuta Meissner yielded ambrimine (464), C,,H,N,O,, amorphous, [a], f128' (c 0.78, CHCI,). Structure proof was based on NMR and NOE observations, and conversion of the alkaloid with CH,N, to a trimethyl ether identical to that obtained from efatine (465, see Section XI,C,ll). The configuration was assigned by analogy to malekulatine (199) (549,550).

H' /

464 R' = Me, R2 = H 465 R' = H, RZ =Me

2. Antioquine [93767-27-21 Antioquine (466), C,,HJ'J,O,, mp 197°C [aID+214" (c 0.9, CHCI,), was isolated from a sample of Pseudoxundru aff. lucidu Fries (Annonaceae) collected in Colombia. Structure proof was by spectral characterization of the 0,O-diacetate, the 0,O-dimethyl ether, and the 7-0-methyl ether, and by degradation of derivatives with KMnO,/Me,CO, with ceric ammonium nitrate, and with Na/NH, (551).

466

178

KEITH T.BUCK

3. Beccapolydione [91794-12-61 Polyalthia caulijlora var. beccarii (Annonaceae) provided beccapolydione (467), C,,H,,N,O,, as an orange powder. Its structure was deduced from instrumental data and comparison with beccapoline (81), previously isolated from the same plant (540).

4. Candicusine [99945-41-21

(+)-Candicusine (468),C,,H,,N,O,, for which no instrumental data are cited, was obtained from Curarea candicans. The structure was suggested from comparison of MS, NMR, and CD patterns with those of limacusine (105) (544).

H ' Me

M H,"e N K\ -

'OH

o \ 468

5. Cheratamine 192664-88-51 Cocculus pendulus (Forsk.) Diels (Menispermaceae) afforded (+)-cheratamine (469), C,,H,,N,O,, [a165 +190° (c 0.33, MeOH). The structure assignment was based on analogy with co-occuning alkaloids, on NOEDS, IR,CD, MS, and on the large UV base shift (552).

1,


179

6. Cocsuline N-Oxide [91106-34-21 Cocsuline N-oxide (470), C,,H,,N,O,, amorphous, mp 182-187°C (MeOH), [a165 +125" (c 0.5, MeOH), was found in Cocculus hirsutus D.C. (Menispermaceae). Sulfurous acid reduction yielded cocsuline (29). The N-oxide appears to be a metabolic product as it was not formed from 29 in vitro under the isolation conditions. It is the first diphenyl ether-linked dibenzodioxin N-oxide alkaloid and the first N-oxide from a Cocculus species (553).

OMe

470

7. Coyhaiquinine [ 101242-45-91 Berberis empetrifalia yielded the unstable base coyhaiquinine (471), C,,H2,N0,. The structure was proposed principally from the completely resolved 200-MHz FT NMR spectrum, and the alkaloid was shown to have syn geometry at the spiro center by NMR correlations with the related syn compounds 46, 107, 149,262, and 359 and with the anti alkaloids 108 and 109. Insufficient material was available for exact determination of optical rotation, but the general form of the CD curve resembles that of coyhaiquine (107), indicating the absolute configuration shown (554).

zM

"""'00

/ #

471

8. Dehydrohuangshanine [9 1948-29-71

Dehydrohuangshanine (472), C4,H4BNz09, (a163 t42.2" (c 0.17, MeOH), isolated from Thalictrumfaberi Ulbr. (Ranunculaceae), was assigned its structure from instrumental data (IR, UV, MS, NMR, CD) and comparison to the co-occurring huangshanine (167) (545).

E,p

KEITH T.BUCK

180 MeNg::

OMe

H'

Me

'

\

'OMe

Me0

'

472

9. Dehydrothalifaberine [91926-01-11 amorphous, [a164 +95.9" (c 0.143, MeOH), Dehydrothalifaberine(473), C,,H,N,O,, is a minor alkaloid of Thalictrumfuberi. The structure was deduced by NMR, MS, and CD, and by partial synthesis of 473 by oxidation of the companion alkaloid thalifaberine (302) with DDQ. The dehydro base does not appear to be an artifact of air oxidation of 302 during isolation (545).

NT::s

MeH'

Me

0'

Me0

' OMe

473

10. 6a,7-Dehydrothalmelatine[ 16624-99-01 Although earlier described from 3-year-old Thulictrum minus extracts as a probable artifact of air oxidation (555) of thalmelatine (3144, 6a,7-dehydrothalmelatine (474), C&,N,O,, was only recently isolated as a natural product from Hernandiu peltutu. Identification was by comparison of spectral data with published values (549).

M H'

e

N

'OMe

K

Me0

OMe

p Me

' 0

474

1.

THE BISBENZYLISOQU~OLINEALKALOIDS

181

11. Efatine I104330-66-71 Efatine (465), C,,H,N,O,, amorphous, [aID+70° (c 0.86, CDCI,), isomeric with ambrimine (W),was also isolated from Hernundiu peltutu. The substitution patterns of ring C in efatine and 464 could be distinguished by NOE measurements and by NMR base shift with NaOMelDMSO-d, (549,550).

12. Epiberbivaldine [96245-07-71 Berberis uctinucuntha Mart. ex Schult. (Berberidaceae) furnished (+)-epiberbivaldine (475), C3,H,,N,0,, amorphous, [a165 +45.7" (c 0.12, CHCI,). Epiberbivaldine is diastereomeric to the known berbivaldine (89). Structure proof was by NOEDS and dienone-phenol rearrangement to an aporphine-benzylisoquinoline dimer (556).

475 R = H 476 R = M e

13. Epivaldivianine [98604-30-91 (+)-Epivaldivianine (476), C,,H,N,O,, amorphous, from Berberis vuldiviuna Phil., has [a165 +69.4" (c 0.1, MeOH). Structure proof consisted of NMR correlations and rearrangement of the alkaloid in acid to the known (-)-kalashine (177). Epivaldivianine is the third epi proaporphine-benzylisoquinoline dimer (the fiist two being 108 and 475) (557).

14. Faberidine [91925-99-41 Tulictrurn fuberi Ulbr. yielded the base faberidine (477), C,H,,N,O,, amorphous, [a162 +105.5" (c 0.675, MeOH). Structure proof was by MS, NMR, and CD correlations with related alkaloids (545).

15. Faberonine [91926-00-01 Also from Thalictrurnfuberi, faberonine (478), C4,H4,N,0,, [a164 +82.8" (c 0.498, MeOH), was isolated as a yellow solid. Structure proof was principally by NMR and MS correlations with the known alkaloid huangshanine (167) (545).

182

KElTH T.BUCK

477 R = H 478 R=OMe

16. Gyroamericine [102487-17-21 One of the several alkaloids from Gyrocarpus americanus Jacq. (Hernandiaceae) is mp 210°C (MeOH), [aID -238" (c 1, CHCI,). Digyroamericine (479), C,,H,,N,O,, azomethane methylation furnished (-)-phaeanthine (184), the principal alkaloid of G. arnericanus. Placement of the lone OH group was by NMR data (tabulated for this and related alkaloids) (558).

MeH,N,'

4

:T Me

/

\

'OMe

0

479

17. Gyrocarpine [102487-16-11 Gyrocarpine (480), C,,H,,N,O,, from Gyrocarpus americanus, has mp 192°C (MeOH-Et,O), [aID -239" (c 1, CHCI,). NMR comparison with gyrolidine (194, see Section XI,C, 19) showed that gyrocarpine is 6'-demethylgyrolidine; CH,N, methylation of gyrocarpine gave gyrolidine, establishing the absolute configuration (558).

480 R'= H. RZ = H481 R' = H. RZ = H--482 R' =Me, R 2 = H---

1.


183

18. Gyrocarpusine [102518-66-11

Also from Gyrocarpus americunus, gyrocarpusine (481), C,,H&,O,, amorphous, has [a], +66" (c 1 , CHCl,) and is isomeric in 0-methylation pattern to the known alkaloid limacusine (105). 0-Methylation of 481 with CH,N, yielded (+)-0-methyllimacusine (482), also isolated from G . americanus. Placement of the hydroxy function was by NMR comparisons (558). 19. Gyrolidine [39020-36-51 Gyrolidine (194), C,,H,,N,O,, amorphous, [a], - 115" ( c 1 . 1 , CHCl,), from Gyrocarpus americunus, proved identical by IR, 1H NMR, and UV patterns to the known alkaloid obaberine (80), but showed opposite optical rotation; it is accordingly the enantiomer (558).Gyrolidine should be identical to the 0,O-dimethyl derivative of macolidine (193), but no direct comparison was reported.

20. Hebridamine [ 102487-24-11 Hebridamine (483), C,,H,,N,O,, [a], positive (value unstated), from Hernandia peltata showed an NMR spectrum resembling that of thalicarpine, with the notable exception of the highly deshielded phenanthrene ring singlet (6 9.39), two central phenanthrene ring doublets, and three N-methyl singlets. These data, as well as MS and UV measurements, allowed assignment of structure 483 to the alkaloid. Hebridamine is the first benzylisoquinoline-phenanthrene alkaloid (549).

OMe

483

21. Kohatine [92664-90-91 Cocculus pendulus yielded (+)-kohatine (484), C,,H,,N,O,, [a155 + 183" (c 0.2, MeOH). Kohatine strongly resembles the co-occumng cocsoline (32), except for expected differences in NMR and MS caused by the extra OH function. NOEDS confirmed the structure assignment, and the CD curve indicated the absolute configuration of kohatine (552).

184

KEITH T.BUCK

Me

484

22. Kurramine [92664-89-61 [a165 + 8 3 O (c 0.13, MeOH), also from Coccufus Kurramine (485), C,,H,,N,O,, pendulus, is the diphenolic analog of the co-occurring 1,2-dehydroapateline (= dehydrococsuline, 121). Its structure was deduced by NMR and CD comparison to 121 (552).

23. Limacine 2'a-N-Oxide (486) [99877-67-51, Lirnacine 2P-N-Oxide (487) c99883-66-63,and Limacine 2'P-N-Oxide (488) [99877-66-41 The title alkaloids, C,,H,N,O,, were isolated from Cururea candicans by TLC. The complete structures were deduced by NMR NOEDS (544).

486 R' = 0: R2 = Me 488 R' = Me, R 2 = 0-

487

1.


185

24. Medelline [102505-09-91

Medelline (489), C3,H3,N,0,, amorphous, [aID-38" (c 0.16, MeOH), from Pseudoxandra aff. Zucida (Annonaceae), is the first methylenedioxy-bridgedbisbenzylisoquinoline alkaloid. Its 1H-NMR spectrum shows strong resemblance to that of antioquine (466), with the notable exception of a W AB system (J = 4 Hz) for the methyienedioxy. The structure was confirmed by 13C NMR and by NOE on the alkaloid and its 0-acetate. The CD resembles that of 466,indicating the same absolute configuration. It is likely that 489 is formed biogenetically via 466, the major co-occurring alkaloid (559). OMe

OH 489

25. 1-0-Methylchitraline [84423-09-61 Berberis danvinii Hook. afforded (+)-1-0-methylchitraline (263), C,,H,,N,O,, amorphous, [a165 +29" (c 0.4, MeOH), previously obtained (28) as a rearrangement product of patagonine (262) (557). 26. 7'-0-Methylcuspidaline [94410-10-31

This alkaloid (490), C,,H,N,O,, amorphous, [aID -105" (c 0.001, CHCI,), was obtained from Aristolochiu elegans Mast. (Aristolochiaceae). MS data established that the OH is in the left-hand head unit; final placement was by NMR correlations with published data. The strongly negative rotation is in accord with the indicated (R,R) configuration (560).

490

27. 0-Methyllimacusine [13017-15-71 Previously known as a derivative of limacusine (105), 0-methyllimacusine (4821, C,,H,,N,O,, was isolated from Gyrocarpus urnericanus Jacq. (Hemandiaceae). It was

186

KEITH T. BUCK

also formed by CH,N, methylation of the co-occurring (+)-gyrocarpusine (481). Identification was from spectral data and comparison of properties with literature values (558). 0-Methyllimacusine is the enantiomer of 0-methylrepandine (64). 28. 0-Methylthalmine [7682-67-91 Thulictrum culrratum Wall. (Ranunculaceae) was the source of 0-methylthalmine (61), C,,H,,N,O,, [a]&5 -25" (c 0.26, MeOH), previously known as a derivative of thalmine (62). Structure proof was by comparison of NMR data with literature values and by complete NOEDS study (539).

29. Natalinine [101219-60-73 Natalinine (491), C,,H,,NO,, amorphous, is a minor alkaloid of Berberis empetrifoliu Lam. MS and high-resolution NMR established the skeletal structure, and CD indicated the (R) configuration (561).Natalinine may be derived biogenetically from catabolism of an aporphine-benzylisoquinoline dimer [such as pakistanine (92), a major co-occurring alkaloid] (561),or by rearrangement of a coyhaiquine (107)-type dimer (562).

491

30. (R,S)-Nor-Nb-chondrocurine 196738-71-51 A sample of Peruvian curare [possibly derived from Chondrodendron roxiferum (Wedd.) Kruk, et Mold. (Menispermaceae)] provided (R,S)-nor-Nb-chondrocurine(492),

492 R = H 493 R = M e

1. THE


187

C,,H,,N,O,, mp 159-16loC, [a160 -242" (CHCI,). Instrumental identification was by ORD,MS, UV, 1H NMR, and 13C NMR. Additionally, CH,O/HCO,H N-methylation of 492 gave the known (R,S)-chondrocurine (493), identified by comparison with an authentic sample (542). 31. 2-Norlimacusine [96744-71-71 2-Norlimacusine (494), C36H38N206,mp 172°C (MeOH), [a],+ 167" (c 0.7, CHCI,), was found in roots of Sciadotenia eichlerianu Moldenke (Menispermaceae). N-Methylation with CH,OIHCO,H gave (+)-limacusine (105), identified by rotation, IR, NMR, and comparative TLC (563).

494

32. 2'-Norpakistanine [98618-06-51 Berberis valdiviana Phil. yielded 2'-noqakistanine (499, C3,H3,N20,, mp 148°C (MeOH), [a165 +9.1" (c 0.05, MeOH). Structure proof was by MS and NMR correlations with related alkaloids and by conversion to (+)-pakistanine (92) with CH,O/HCO,H. The lack of a 2'-NMe in 495 causes significantconformationallyrelated NMR shifts, notably of 1'-H, 8'-H, and 7'-OMe (557).

495

33. Norpenduline [92760-68-41 Norpenduline (4%), C,,H,,N,O,, [a165 +260" (c 0.09, MeOH), occurs in Cocculus pendulus. Its NMR spectnim resembles that of penduline (497), with the notable exception of the absence of the higher field (6 2.32) NMe (552).

188

KEITH T.BUCK

496 R = H 497 R = M e

34. 6-Northalicarpine [102487-21-81

6-Northalicarpine (498), C,&,,N,O,, from Hernandiu peltutu Meissner, was identified by MS and l T NMR. It is the first nor aporphine-benzylisoquinoline dimer demethylated on the aporphine (rather than the benzylisoquinoline) nitrogen (549).

498

35. 2-Northalmine [101488-79-31 Thalictrurncultruturn Wall. was the source of 2-northalmine (499), C,,H,,N,O,, [a]g5 -31.8' (c 0.43, MeOH), and the related alkaloids 61, 62, 130, 131, and 455. The structure was deduced from MS and from a NOEDS study, which showed absence of the higher field (6 2.19) NMe of thalmine (62). N-Methylation (CH,O/NaBH,) of 499 gave 62 (539).

499

36. Nortrilobine [91897-39-11 Nortrilobine (500), C,,H,,N,O,, mp 177-180°C (MeOH), [ ( ~ ] & 5 +216" (c 0.44, CHCl,), from Puchygone ovutu Miers ex Hook. f. & Thorns. (Menispermaceae), is the first bis-secondary dibenzo-p-dioxin bisbenzylisoquinoline alkaloid. It was examined by


189

NMR and MS and N-methylated (CH,O/HCO,H) to isotrilobine. The CD curve indicated

(S,S) stereochemistry (564). OMe

500

37. Oxofangchirine [ 102516-53-01 Stephania tetrandra S . Moore provided oxofangchirine (501), C,,H,,N,O,, mp 184186"C, [a160+47' (c 0.42, CHCl,), IR 1680 cm-1, 13C NMR 194.3 ppm (s) (C==O). MS and NOE 1H-NMR measurements established the substitution pattern of the alkaloid. The 1H NMR spectrum (tabulated) shows strong similarities to that of thalictrinine (143) (84, except for the obvious substituent differences. The structure of 501 was c o n f i i e d by X-ray analysis (565). The stereochemistry is undetermined.

501

38. Pachyovatamine [96910-84-81 Pachygone ovata yielded in addition to 221, 222, and 350 the new dibenzo-p-dioxin amorphous, mp 182biophenyl-linked dimer pachyovatamine (502), C,,H,,N,O,, 185"C, [a165 +259" (c 0.29, CHCl,). Structure proof was based on spectral data and conversion to 0-acetyltiliacorinine (503), a known derivative (547).

39. Pisopowine, Pisopowidine, Pisowiarine, Pisopowiaridine, Pisopowetine, and Pisopowamine These related alkaloids were obtained from Popowia pisocarpa (BI.) Endl. (Annonaceae). Pisopowine (504), C,,,HH,,N,O,, amorphous, [a], - 152" (c 0.4, MeOH), showed completely symmetrical 1H- and 13C-NMR spectra and a MS fragmentation pattern indicating identical head units. The structure was confirmed via ceric ammonium

190

KElTH T.BUCK

502 R ~ = R ~ = H 503 R’ = Me. RZ = Ac

nitrate degradation (236). The (R,R) configuration for 504 was inferred from the optical rotation and CD curves, as well by analogy to diphenyl ether-linked dimers such as 17, but this assignment is not unequivocal. The structures of the co-occumng dimers pisopowidine (505), C,,H,,N,O,, pisowiarine (506), C38H44N206, pisopowiaridine (507), C37H42N206, pisopowetine (508), C,,H,N,O,, and pisopowamine (509), C,,H4,N,06, were established by chemical interrelation and spectral comparisons, but no data are given. Singly bridged dimers resulting from C - C coupling had been produced by in vitro oxidation of benzylisoquinoline monomers, but this is the first report of their natural occurrence. Pisopowine-type dimers may be biogenetic intermediates in the formation of alkaloids of the funiferine (71)and tiliacorine (65)groups (566).

40.

ilybeccarine [9179 11-51

Polybeccarine @lo), C,,H,,N,O,, amorphous, IR 1650 cm- 1 (C==O), was isolated from Polyalthia cauliflora var. beccarii (Annonaceae). The principal evidence for structure 510 was provided by the NMR spectrum, which strongly resembles that of beccapoline (81),also newly found in this plant, except-for the expected differences caused by substitution of an OMe by H (540,567).


191

41. Rupancamine [96203-73-51

Berberis acrinacantha Mat. ex Schult. (Berberidaceae) provided rupancamine ( S l l ) , C,,H,,,N,O,, amorphous, [a165 +116.9" (c 0.12, CHCl,). Structure proof was by MS, NMR, and rearrangement with HCl to an aporphine-benzylisoquinoline, which showed an 11-H aporphine singlet at 6 8.10 (556).

g!2Me

MeHN '

'

/I

51 1

42. Secantioquine [93767-29-41 Secantioquine (SlZ),C,,H,,N,O,, amorphous, [aID- 15" (c 1, CHCl,), was obtained from PseudoxQndra aff. lucida (Annonaceae). The structure was deduced from the UV base shift, NMR, and formation of secantioquine 0,O-diacetate by oxidation (KMnO,/Me,CO) of the 0,O-diacetyl derivative of antioquine (466).Secantioquine is the first biphenyl-linked seco bisbenzyltetrahydroisoquinolinealkaloid (551,568).

M eHN'

!

:

?

0

Me

CHO

'OMe

HO

'

512

43. Seco-obaberine [55085-45-51 Known as an in vitro oxidation product of obaberine (80) (39), seco-obaberine (378) has recently been isolated from Pseudoxandra aff. lucida as an amorphous material,

192

KEITH T.BUCK

C,,H,N,O,, [a],-5" (c 0.2, CHCI,). It was characterized by UV, IR, NMR, CI-MS, and comparison with a semisynthetic sample (551,568).

44. Thalicarpine 2'-N-Oxide [ 102487-22-91 Another of the new alkaloids from Hernundiu peltutu Meissner (Hernandiaceae) is thalicarpine 2I-N-oxide (513), C,,H,,N,O,, [a], 15" (c 0.14, CHCI,). Structure proof was by MS, NMR, and reduction (Zn/HCI) to thalicarpine (94). By NMR, the stereochemistry is most likely p (as shown), but has not been confirmed (549).

+

513

45. Thalifabatine [91926-03-31 [a162+60.5" (c 0.154, MeOH), is a trace alkaloid Thalifabatine (514), C,,H,,N,O,, of Thalictrurn fuberi. By MS and NMR comparison, it was deduced that 514 is the hydroxylated analog of thalifaberine (302), which was extensively studied by NOEDS. The CD curve indicated the same absolute configuration as 302 (545).

Me M H'

e

,N \ 12'

0

q Me0

z

'

s 8

OMe

514 R' = O H , R2 = Me 515 R 1 = R Z = H 516 R ' = OH, R 2 = H

46. Thalifabomine [92047-65-91

Thalifabomine, C,,H,N,O,, [a166 +67.5" (c 0.16, MeOH), from Thulictrurnfuberi, has not yet been completely characterized (545).

1. THE


193

47. Thalifarapine [91926-02-21 Thalifarapine @IS), c,H4,Nz0,, amorphous, [a]b4 +98.6" (c 0.422, MeOH), was isolated from Thalictrumfaberi. MS and NMR comparisons with related co-occurring alkaloids, as well as a UV base shift, established the position of the lone OH substituent (545).

48. Thalifasine [9 1926-04-41 Thalifasine (516), C,,H4,N,0,, {a165 [67.9" (c 0.80, MeOH), is the last of the six 1 2 ' 4 ether-linked aporphine-benzylisoquinoline dimers (the others being 302,304,473, 514, and 515) isolated from Thalictrumfuberi. The UV base shift of the alkaloid and a NMR study of its 0,O-diacetate suggested the indicated location of the hydroxy substituents. The CD curve, closely resembling that of thalifaberine (302), indicated the same configuration (545). 49. Thaligrisine [93780-78-01 Thaligrisine (517), C,,H,,N,O,, [ei]&5 +57" (c 0.13, MeOH), from Thalicrrum minus var. microphyllum, showed the same NMR and mass spectra as (-)-grisabine (159) but opposite rotation. It is accordingly the enantiomer 517 (538).

M

H,'

e

\

N

yl

K

'OMe

/

' 0 517

50. Thaliphylline [93780-79-11

+

Thaliphylline (518), C,,H4&06, [a165 198" (c 0.12, MeOH), also from Thalictrum minus var. microphyllum, gave with diazomethane 0-methylthalicberine (274), previously reported from this plant. MS and N M R evidence established the substitution pattern (538).

Me ' HN

w

\

l y /

'OMe

'0 518

Me

194

KEITH T. BUCK

51. Thalivarmine [101312-86-11

Thalictrum minus var. minus provided thalivarmine (519), C,,H,,N,O,. NMR comparison with the co-occurring known alkaloid thalicberine (520) showed thalivarmine to be 7-0-desmethylthalicberine. Diazomethane converted 519 to 0-methylthalicberine (274), proving the stereochemistry. No optical rotation data, however, are cited for these compounds (569).

519 R = H 520 R = M e

52. Thalsivasine 1101219-59-41

Along with thalivannine (519), Thulictrum minus var. minus yielded the new alkaloid thalsivasine (521), C,,H,,N,O,. MS and NMR data showed 521 to be 7-O-desmethyl-Omethylthalmethine. Methylation (CH,N,) of 521 gave the known 0-methylthalmethine (522), a co-occurring alkaloid (569).

M H'

e

N

w

'OMe

3

'0

521 R = H 522 R=Me

53. Vilaportine [ 102487-23-01

Vilaportine (523), C,d-IH,N,O,, an intensely green-colored alkaloid of Hernundiu peltutu, is the first benzylisoquinoline-oxoaporphine dimer. The UV (which shows a

Me ' HN

K

'OMe

p

Me0

OMe

' 0

523

195

1 . THE BISBENZYLISOQUINOLINF! ALKALOIDS

strong shift in acid) and N M R spectra resemble superpositions of a zwitterionic l-hydroxyoxoaporphine and a benzyltetrahydroisoquinolinemoiety having the same substitution pattern as that of thalicarpine (94) (549).

D. KNOWNALKAMIDSFROM NEWSOURCES Table V lists known ahloids isolated from new sources during the period 1984-1986. See Table I (Section In) for alkaloids from new sources, 1975-1984. TABLE V Known Alkaloids Isolated from New Sources, 1984-1986 ______

Plant Albertisia laurifolia Aristolochia debilis Berberis actinacantha B. aristata B. chitria B. cretica

B. hakeoides B . wilsoniae Cleistopholis staudtii Cocculus pendulus

Curarea candicans Gyrocarpus americanus Hernandia peltata Isolona hexaloba Laurelia sempervirens Mahonia siamensis Pseudoxandra aff. lucida Sciadotenia eichleriana Stephania sasakii S . sinica S . tetrandra Thalictrum baicalense T . cultratum

Alkaloid(s) Apateline, aromoline, cocsoline, cocsuline, daphnoline, N-methylapateline Tetrandrine Berbivaldine, pakistanamine, patagonine Aromo1ine Oxyacanthine Aromoline, berbamine, berbamunine, isotetrandrine, obaberine, obamegine, oxyacanthine, thahugosine Pakistanamine, patagonine, valdiberine, valdivianine Berbamine, isotetrandrine Chondrofoline, curine, cycleanine, isochondodendrine Daphnoline, dehydroapateline, isotrilobine, Nmethylapateline, norberbamine, tetrandrine, tricordatine Hernandezine N-oxide, krukovine, limacine, limacusine, tetrandrine N-2'-monoxide Grisabine, isotetrandrine, limacusine, phaeanthine 2'-Northalicarpine, thalicarpine, thalmelatine Cycleanine, isochondodendrine, norcycleanine Obaberine, oxyacanthine, thalrugosine Isotetrandrine Obaberine Grisabine Obaberine, thalrugosine Cepharanthine Berbamine N-Demethylthalistyline, thalirabine N-Desmethylthalidasine, thalidasine, thalmine, thalrugosinone

Reference 570 571 556 572 573 574

575 576 541 552

544 558 549 577 578 579 551 563 543 580 581 582 539

(continued)

KEITH T.BUCK

196

TABLE V (Continued) Plant

T . faberi T. isopyroides T . javanicum T. longipedunculatum T. minus var. microphyllum

T. minus var. minus T . sultanabadense

Alkaloid(s)

Reference

0-Methylthalibrine, 0-methylthalicberine, thalisopine, thalrugosidine Thaligosinine Thalisopine, thalrugosaminine 0-Methylthalicberine, thalicberine Aromoline, homoaromoline, O-methylthalicberine, obamegine, thalicberine, thaligosine, thalirugine 0-Methylthalicberine, 0-methylthalmethine, thaliphylline, thalmelatidine, thalmethine Thalictine, thalmine

583 584 585 586 538

569 587,588 588

E. REACTIONS 1 . Akylation Dauricine (116) reacted under phase-transfer conditions (benzyltrimethylammonium chloride, benzene, diethyl sulfate, 15% aqueous NaOH, 45 min reflux), giving the ethyl ether in 60% yield (589).

2. Oxidation Reaction of tetrandrine (48) with 30% H,O, gave a mixture of two monoxides [524 and 294 (complete stereochemistry shown)] and two dioxides (525 and 526) (590).Cepharanthine (288) resisted X-ray degradation in MeOH-CHC1,-H,O (2 : 1 : 0.8); it was also a weak inhibitor of lipid peroxidation (591). Ceric ammonium nitrate degradation of N,Odimethyltiliamosine (351) has been reported (547).

294 R' = 0; R 2 = Me 524 R' = Me. R' = 0-

525 R' = 0; R' = Me 526 R' = Me, R' = 0-

3. Sodium/ Ammonia Cleavage An improved procedure for Na/NH, cleavage has been developed in which a minimum amount of Na is added in small portions to a solution of the alkaloid in liquid NH, at


197

-78°C (as opposed to the usual method of adding the alkaloid to the NalNH, mixture). This variation allowed reactions to be run on a very small scale, with good recovery of cleavage products by TLC (538).

F. SYNTHESIS Details of the syntheses of stebisimine (409)and racemic forms of obaberine (80) and isotetrandrine (236), using enaminothioethers and the Willgerodt-Kindler reaction, have been described (592,593).

G. SPECTROSCOPY AND SEPARATION TECHNIQUES 1. Spectrometry a. MS. Tubocurarine chloride (73a) hydrochloride was a model compound for liquid secondary ion time-of-flight MS (594).

b. NMR. High-field (250 MHz) NMR allowed resolution of all protons of isochonand curine (75) (541). These alkaloids show dodendrine (212), chondrofoline (a), conformationally related shielding similar to that noted in cycleanine (112) (206). Antioquine (466) has been studied by two-dimensional 1H-lH (COSY 45) NMR and by two-dimensional 1H-13C NMR. 0,O-Diacetylantioquine and 0,O-dimethylantioquine show doubling of all proton signals at room temperature due to slow conformational equilibration, but at 90°C in pyridine-d, the spectra are normalized (551); this effect is similar to that noted earlier with thalsimine (58) (13). NMR base shift with NaOMe in DMSO-d, c o n f i i e d the locations of the phenolic groups of efatine (465) and ambrimine (464).The data supplemented the conclusions of NOE investigation (550).

c. Other SpectrometricTechniques. A colorimetric method with o-hydroxyhydroquinonephthalein, zirconium, and flouride ions has been used to assay tubocurarine chloride (595). Polarizing microscopy is cited in the Japanese Pharmucopeiu as a method for determining the purity of tubocurarine chloride hydrochloride (596). 2. Chemical Methods Beside the use of chromatography in isolation of new alkaloids, several analytical chromatographic determinations of bisbenzylisoquinoline alkaloids have been reported. A TLC method for resolution of components of commercial curare is described; an unidentified impurity (-l%), prisms, mp 275°C (dec.) (MeOH), which interferes with crystallization of d-tubocurarine can be removed in this manner (597). Four TLC systems for evaluation of tubocurarine chloride preparations have been developed (598). TLC-UV methods for analysis of tetrandrine in extracts of Stephaniu tetrundru are described (599,600). Low-pressure column chromatography and pH gradient extraction were used to separate fangchinoline and tetrandrine from S. tetrundru root extracts (601). A quantitative method for determination of thalicqine in pharmaceutical preparations using TLC-UV

198

KEITH T.BUCK

is reported (602).TLC-densitometric and HPLC methods are described for dauricine and dauricinoline in extracts of Menispermum dauricurn (603,604). An assay for guattegaumerine by TLC with detection by densitometry after development with Dragendorff's reagent has been developed (605).Paper electrophoresis has been used to characterize tubocurarine (606).

H. BIOSYNTHESIS 1 . Isotope Labeling Studies

1-%I-reticuline (444)and with Feeding experiments on Thalictrurn minus with (*)-[ [8'-3H]-thalicarpine (527) showed that both are incorporated into adiantifoline (233) and thalmelatidine (528), supporting the biosynthetic sequence: reticuline to thalmelatine to thalicarpine to adiantifoline, thalmelatidine (607).

528

2. Other Biochemical Studies Vanuatine (360), the first example of a bisbenzylisoquinoline alkaloid derived from two (+)-reticdine (430a) units, present in Hernandia peltatu, is largely supplanted by thalicarpine (94) late in the growing season, suggesting that 360 is a precursor of 94 in this species (562). Of the bisbenzylisoquinoline alkaloids known to occur in Curarea cundicans, limacine (86) is the only one for which the corresponding N-oxides are also isolated as natural products, indicating that the oxides are true biochemical products rather than artifacts of air oxidation (544). Daphnoline (529) is a possible precursor of triply bridged dimers such as cocsuline (29), and is so far the only doubly linked alkaloid with this type of bridging to be isolated from Cocculus pendulus, possibly because related dimers readily suffer further oxidation.


199

529 In contrast, dimers of the tetrandrine (48) type, which are sterically prevented from forming additional head linkages, are common in C. pendulus (552). All aporphine-benzylisoquinoline dimers so far isolated from Thalictrum species have identical configurations, suggesting common biogenesis (545). Rules for predicting the configurations of Thalictrum bisbenzylisoquinoline alkaloids have been derived; the sole exception is isothalidezine (170), which may be formed by epimerization via an iminium salt of the major co-occurring alkaloid thalidezine (53)(538). I. PHARMACOLOGY Pharmacological activities of bisbenzylisoquinoline alkaloids that have appeared between mid-1984 and mid-1986 are given in Table VI. Table VI provides an update of Table I1 (Section VIII).

TABLE VI Pharmacological Activity of Bisbenzylisoquinoline Alkaloids: Update for 1984- 1986 ~

Alkaloid Berbamine

Cepharanthine


Reference

Study of serum lysozyme levels in berbamine-induced macrophage activation Berbamine did not affect rat brain monoamine levels Noncompetitive antagonist of histamine, isoproterenol, and Ca*+ in isolated guinea pig atria; decreased contractile force and attenuated adrenalin response Skin stimulant in cosmetics Suppressed antibody production in mice at dosage below anesthetic level Prevented membrane lipid peroxidation and stopped peroxidation induced by ascorbate, ATP, and Fe3 + in combination (rat) Effect on spleen, thymus weight, peripheral leukocytes, and hemocrit values in mice after single whole-body 500-R (roentgen) dose

608

609 610

61I 612 613

614

(continued)

KEITH T. BUCK

TABLE VI (Continued) ~~

Alkaloid

Cycleanine

Dauricine

0-Methy ldauricine Tetrandrine

Pharmacological activity Accelerated recovery of granulocytes and peripheral leukocytes after 300-R whole-body X-irradiation Inhibited lipid peroxidation induced by radiation in egg lecithin liposomes and by Fez+ in mitochondria In rabbit platelets, inhibited Ca influx and collageninduced aggregation; inhibited induced arachidonate release Protected rat liver from damage by anoxia in vifro Increased the cytotoxic activity of lung macrophages enhanced by OK-432 in rat Inhibited teratogenesis induced by hypervitaminosis A in rat Increased intracellular uptake of adriamycin by mouse NIH 3T3 cells Potentiated effectiveness of colchicine toward Mycobacterium-induced amyloidosis in mice, produced lower death rate Increased number of T cells in mouse parathymic lymph nodes Suppressed formation of lipid peroxides in homogenate of regenerating rat liver, but did not affect serum lipid peroxide concentration or serum lipid concentration, except for phospholipids Appeared not to stimulate granulocyte-macrophage colony formation in bone marrow mononucleocytes Binds to dopaminergic receptors of rat striatal membranes Inhibited platelet aggregation Appeared to stimulate pituitary-adrenocortical system in rats Binds to dopaminergic receptors less strongly than dauricine and cepharanthine; inhibited binding of [3H]spiperoneto rat striatal membranes Binds more strongly than cepharanthine and dauricine to dopaminergic receptors; inhibited binding of [3H]spiperone to rat striatal membranes Lowered arterial blood pressure in cats Decreased contractile force and amplitude in isolated guinea pig auricle and papillary muscle Study of plasma concentration and excretion rate of tritiated 0-methyldauricine [2202-17-71 in rats Antiallergic in rats and guinea pigs; antagonizes allergen response and blocks altergenic release

Reference

615 616

617

618 619 620 621 622

623 624

625 626,627 628 629 626,627

626,627

629a 629b 630 631

(continued)


20 1

TABLE VI (Continued) ~

Alkaloid

Thalicarpine

Tubocurine


Reference

Antagonized noradrenalin-inducedcontractions of isolated rabbit vascular strips and inhibited K + -induced contraction of thoracic aorta strips, apparently by Ca*+ antagonism Did not alter production of DNA single-strand breaks by y rays; inhibited repair of these breaks in L7712 cells Inhibited electrocardiogram alterations caused by isoprenaline damage in rats Ca2+ antagonist, decreasing 0 2 consumption in heart In guinea pig, increased dosage of ouabain necessary to induce arrhythmia Decreased experimental myocardial ischemia and infarction in dogs Potent arteriolar vasodilator in dogs Antiasthmatic on human and guinea pig tracheal and lung strips Inhibited induced contractions of isolated rabbit pulmonary artery similarly to verpamil In rats, acted as vasodilator, weakening hypoxic pulmonary vasoconstriction Not antipyretic in rats Synergistic with cyclophosphamide against L1210 leukemia in mice; but in combination with BCNU gave reduced longevity Mutagenic effects of 137Csy-irradiation and thalicarpine were. synergistic in rats Superadditive with y-irradiation in rat bone marrow cells, inducing aberrations and polyploidy In mice, effective in combination with cyclophosphamide against thalicarpine-resistant lymphoid leukemia L1210 Inhibited growth of lung metastases in mice In mouse leukemia P388, activity was enhanced when used with surfactants In isolated rabbit ear artery, antagonized dopamineinduced inhibition of adrenergic neurotransmission

632

633

634 635 636 637 638 639 640 641

642 643

644 645 646

647 648 649

J. REVIEWSOF BISBENZYLISOQUINOLINE ALKALOIDS 1. H. Guinaudeau, M. Leboeuf, and A. CavC, J . Nor. Prod. 47,565 (1984). Dimeric aporphinoid alkaloids. Cites 23 new dimeric alkaloids and 8 related synthetic derivatives for 1979-1984; 48 references. 2. P. L. Schiff, Jr., in “Alkaloids: Chemical and Biological Perspectives” (S. W. Pelletier, ed.), Vol. 5 , Wiley (Interscience), New York, (1987). Chemistry and pharmacology of Thalicrrurn al-

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KElTH T. BUCK

kaloids. An extensive review, including all Thalicrrum alkaloids reported through 1984; includes 98 dimeric alkaloids. 3. M. Shamma and H. Guinaudeau, Tetrahedron 40, 4795 (1984). Biosynthesis of aporphinoid alkaloids. In addition to monomeric alkaloids, discusses proaporphine- and aporphine-benzylisoquinoline dimers, dimeric oxidized aporphines, and types derived by catabolism of benzylisoquinoline-derived dimers. 4. H. Guinaudeau, A. J. Freyer, and M. Shamma, Nar. Prod. Rep. 3, 477 (1986). Spectroscopy of bisbenzylisoquinolinealkaloids. Tabulation and analysis of high resolution NMR spectra of over 100 bisbenzylisoquinoline alkaloids, arranged by structural types; 27 references.

Acknowledgments The author is grateful to the many people who helped during preparation of this chapter. A partial list includes the following: Professors P. L. Schiff, Jr., M. Shamma, J. L. Beal, A. Cav6, H. Guinaudeau, and M. P. Cava, for sharing research results; Dr. M. V. Lakshmikantham, for chemical information; Edward Ketchledge, Jr. (NERAC), Professor J. L. Caruso, Dr.P. M. Weintraub, and the library staffs of the University of Cincinnati, Drexel University, the University of Michigan, and the Lloyd Library, for assistance with the literature search; Ms. Margaret Dvoretsky and Ms. Elizabeth Tu, for translations; Roger 0. Sage and Dr. M. J. Mitchell, for technical assistance; the editor, for his patience and helpful suggestions; Fries and Fries management, particularly James V. Mazetis, Director of Chemical Research, for indulgence during this project; and his wife, Sylvia, for enduring “chapter widowhood.”

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46. D. Dwuma-Badu, S. F. Withers, S. A. Ampofo, M. M. El-Azizi, J. B. Reighard, J. E. Knapp, D. J. Slatkin, and P. L. Schiff, Jr., Lloydiu 41, 658 (1978). 47. C. D. Reynolds, R. A. Palmer, B. A. Gorinsky, and C. Gorinsky, Biochim. Biophys. Actu 404,341 (1975). 48. C. D. Reynolds and R. A. Palmer, Actu Crystullogr., Sect. B 32, 1431 (1976). 49. J. Naghaway and T. 0. Soine, J. Phurm. Sci. 68, 655 (1979); CA 91, 175589. 50. 1. R. C. Bick and S. Sotheeswaran, Aust. J. Chem. 31, 2077 (1978). 51. G. A. Miana, J. E. Foy, R. D. Minard, and M. Shamma, Experientiu 35, 1137 (1979). 52. A. Jossang, M. Leboeuf, and A. Cave, Tetiuhedron Lett. 23, 5147 (1982). 53. T. A. Van Beek, R. Verpoorte, and A. B. Svendsen, J. Org. Chem. 47, 898 (1982). 54. M. Shamma, private communication; J. E. Leet, A. J. Freyer, R. D. Minard, and M. Shamma, J . Chem. Soc., Perkin Truns. 1, 1565 (1985). 55. H. Guinaudeau, A. J. Freyer, R. D. Minard, M. Shamma, and K. H. C. Baser, Tetrahedron Lett. 23, 2523 (1982). 56. V. Fajardo, M. Ganido, and B. K. Cassels, Heterocycles 15, 1137 (1981). 57. J. E. Lett, V. Fajardo, A. J. Freyer, and M. Shamma, J. Nut. Prod. 46, 908 (1983). 58. V. Fajardo, A. Urzua, and B. K. Cassels, Heterocycles 12, 1559 (1979). 59. J. E. Leet, A. J. Freyer, R. D. Minard, and M. Shamma, J. Chem. SOC.,Perkin Truns. I , 651 (1984). 60. J. E. Leet, V. Elango, S. F. Hussain, and M. Shamma, Heterocycles 20, 425 (1983); J. E. Leet, Diss. Abstr., Int. B 44, 1458 (1983). 61. S. F. Hussain, L. Khan, and M. Shamma, Heterocycles 15, 191 (1981). 62. S. F. Hussain, M. T.Siddiqui, and M. Shamma, Terruhedron Lett. 21, 4573 (1980). 63. S. F. Hussain, L. Khan, K. K. Sadozal, and M. Shamma, J . Nut. Prod. 44, 274 (1981). 64. V. Fajardo, H. Guinaudeau, V. Elango, and M. Shamma, J. Chem. SOC., Chem. Commun., 1350 (1982). 65. F. C. Ohiri, R. Verpoorte, and A. Baerheim Svendsen, Pluntu Med. 47, 87 (1983). 66. J. Guilhem and I. R. C. Bick, J . Chem. SOC., Chem. Commun., 1007, (1981). 67. D. Neuhaus, H. S. Rzepa, R. N. Sheppard, and I. R. C. Bick, Tetrahedron Lett. 22, 2933 (1981). 68. X.-W. Zheng, Z.-D. Min, and S.-X. Zhao, KO Hsueh Tung Puo 24,285 (1979); CA 91,27216. 69. A. Jossang, M. LeBoeuf, P. Cabalion, and A. CavB, Pluntu Med. 49, 20 (1983). 70. I. R. C. Bick, H.-M. Leow, and M. J. Richards, Aust. J. Chem. 33, 225 (1980). 71. I. R. C. Bick, H. M. Leow, and S. Sotheeswaran, Tetrahedron Lett., 2219 (1975). 72. M. Leboeuf, M. L. Abouchacra, T.Sevenet, and A. CavC, Plunru Med. Phytother. 16, 280 (1982). 73. R. Torres, F. Della Monache, and G. B. Marini-Bettolo, Guzz. Chim. Itul. 109, 567 (1979). 74. C. Galeffi, P. Scarpetti, and G. B. Marini-Bettolo, Furmco, Ed. Sci. 32, 853 (1977); CA 89, 6465. A table assigning the OMe and NMe NMR resonances (CDC13) of 17 0-permethylated bisbenzylisoquinolines having two ether bridges (head-to-head and tail-to-tail) is included in this paper. 75. D. S. Bhakuni and S. Gupta, J . Nut. Prod. 45, 407 (1982). 76. L.-Z. Lin, Z.-Y. Fan, C.-Q. Song, C.-F. Du, and R.-S. Xu, Hua Hsueh Hsueh Puo 39, 159 (1981); CA 95, 76882. 77. W.-N. Wu, J. L. Beal, and R. W. Doskotch, Tetrahedron Lett., 3687 (1976). 78. W.-N. Wu, J. L. Bed, R.-P. Leu, and R. W. Doskotch, Lloydiu 40, 281 (1977). 79. W . 4 . Wu, J. L. Beal, and R. W. Doskotch, J. Nut. Prod. 43, 372 (1980). 80. H. Ishii, E. Kawanabe, H. Seki, K. Yamaguchi, M. Akasu, K. Kodama, J.-I. Kunitorno, H. Fumkawa, M. Suzuki, K.-I. Harada, N. Takeda, A. Tatematsu, N. Fukasaku, Y.Yokoshima,


205

Y. Watanabe, and M. Matsui, Tennen Yuki Kagobutsu Toronkai Koen Yoshishu 26, 102 (1983); CA 100, 156852. 81. J. Wu, 3. L. Beal, and R. W. Doskotch, J . Org. Chem. 45, 213 (1980). 82. C. Galeffi, G. B. Marini-Bettolo, and D. Vecchi, Gazz. Chim. Ital. 105, 1207 (1975); CA 85, 33241. 83. D. A. Kidd and J. Walker, J. Chem. SOC., 669 (1954). 84. L. J. Haynes, E. J. Herbert, and J. R. Plimmer, J. Chem. SOC. C . , 615 (1966). 85. D. Dwuma-Badu, J. S. K. Ayim, N. Y. Fiagbe, A. N. Tackie, J. E. Knapp, D. J. Slatkin, and P. L. Schiff, Jr., Lloydia 39, 213 (1976). 86. B. Anjaneyulu, T. R. Govindachari, and N. Viswanathan, Tetrahedron 27, 439 (1971). 87. D. Dwuma-Badu, S. Withers, S. A. Ampofo, M. M. El-Azizi, D. J. Slatkin, P. L. Schiff, Jr., and J. E. Knapp, J. Nut. Prod. 42, 116 (1979). 88. M. M. El-Azizi, Diss. Abstr. In?. B 40,3674 (1980). 89. H. Guinaudeau, M. Leboeuf, M. Debray, A. Cave, and R. R. Paris, Pluntu Med. 27, 304 (1975). The physical properties reported herein for limacine are somewhat different from previous literature values. 90. H. Guinaudeau, M. Leboeuf, A. C a d , S. Duret, and R. R. Paris, Pluntu Med. 30,201 (1976); CA 86, 13839. 91. A. N. Tackie, J. B. Reighard, M. M. El-Azizi, D. J. Slatkin, and P. L. Schiff, Jr., Phytochemistry 19, 1882 (1980). 92. J. B. Reighard, Diss.Abstr. In?. B 41, 2128 (1980). CA 94, 79994. 93. D. Dwuma-Badu, T. U. Okarter, A. N. Tackie, J. A. Lopez, D. J. Slatkin, J. E. Knapp, andP. L. Schiff, Jr., J. Pharm. Sci. 66, 1242 (1977). 94. J. A. Lopez, Diss. Abstr. In?. B 37, 2168 (1976). 95. J. E. Leet, S. F. Hussain, R. D. Minard, and M. Shamma, Heterocycles 19, 2355 (1982). 96. D. Dwuma-Badu, J. S. K. Ayim, A. N. Tackie, P. D. Owusu, J. E. Knapp, D. J. Slatkin, and P. L. Schiff, Jr., Heterocycles 9, 995 (1978). 97. R. Ahmad and M. P. Cava, J . Org. Chem. 42, 2271 (1977). 98. H. Dehaussy, M. Tits, and L. Angenot, Plunfu Med. 49, 25 (1983); CA 100, 48554. 99. S.-T. Lu and I.-S. Chen, Heterocycles 4, 1073 (1976). 100. S. Mukhamedova, S. Kh. Maekh, and S. Yu. Yunusov, Khim. Prir. Soedin., 250 (1981); CA 95, 58078. 101. L. Z. Lin, H. Wagner, and 0. Seligman, Plantu Med. 49, 55 (1983); CA 100, 64968. 102. P. D. Owusu, D. J. Slatkin, J. E. Knapp, and P. L. Schiff, Jr., J. Nut. Prod. 44,61 (1981). 103. I. R. C. Bick and H. M. Leow, Aust. J. Chem. 31, 2539 (1978). 104. A. M. Usmanov, M. K. Yusupov, and Kh. A. Aslanov, Khim. Prir. Soedin., 422 (1977);CA 88, 23221. 105. S. F. Hussain and M. Shamma, Tetrahedron Lett. 21, 3315 (1980). 106. J. M. Saa, M. V. Lakshmikantham, M. J. Mitchell, and M. P. Cava, J . Org. Chem. 41, 317 (1976). 107. J. Siwon, R. Vetpoorte, T. van Beek, H. Meerburg, and A. Baerheim Svendsen, Phytochemistry 20, 323 (1981). There are slight differences between the properties reported for krukovine here and in Ref. 106. 108. S.-T. Lu and I.-S. Chen, J . Chin. Chem. SOC. (Taipei) 24, 187 (1977). 109. C. Galeffi and G. B. Marini-Bettolo, Atti Accad. Naz. Lincei, Cl. Sci. Fis.,Mat. Nut., Rend 62, 825 (1977); CA 89, 103755. 110. J. Bruneton, M. Shamma, R. D. Minard, A. J. Freyer, and H. Guinaudeau, J. Org. Chem. 48, 3957 (1983). 111. A. Karimov, M. V. Telezhenetskaya, K. L. Lutfullin, and S. Yu. Yunusov, Khim. Prir. Soedin. 14, 227 (1978); CA 89, 215623.

206

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112.I. R. C. Bick and S. Sotheeswaran, Aust. J. Chem. 31,2077 (1978). 113. S. Dasgupta, A. B. Ray, S. K. Bhattachaqa, and R. Bose, J . Nut. Prod. 42,399 (1979). 114.M. Uvais S. Sultanbawa, S. Sotheeswaran, S. Balasubramaniam, M. Abd El-Kawi, D. I. Slatkin, and P. L. Schiff, Jr., Heterocycles 20,1927 (1983). 115. J. M. Saa, M. J. Mitchell, M. P. Cava, and J. L. Beal, Heterocycles 4,753 (1976). 116.R. Ahmad, Islamabad J. Scr. 5 , 38 (1978);CA 94,30976. 117.For a listing of physical data for 0-methylthalibrunimine, see also P. L. Schiff, Jr., J . Nut. Prod. 46, l(1983). 118. I. Wu, J. L. Beal, W.-N. Wu, and R. W. Doskotch, J . Nut. Prod. 43,270 (1980). 119. W.-N. Wu, J. L. Beal, and R. W. Doskotch, J. Nut. Prod. 43,143 (1980). 120. H. Guinaudeau, M. Shamma, and K. H. C. BaSer, J . Nut. Prod. 45,505 (1982). 121. A. CavC, M. Leboeuf, R. Hocquemiller, A. Bouquet, and A. Foumet, Pluntu Med. 35,31 (1979);CA 90, 183164. 122.M. P.Cava, J. M. Saa, M. V. Lakshmikantham, and M. J. Mitchell, J. Org. Chem. 40,2647 ( 1975). 123.W.-N. Wu, I. L. Beal, and R. W. Doskotch, J. Nut. Prod. 43,567 (1980). 124. A. Karimov, M. V. Telezhenetskaya, K. L. Lutfullin, and S. Yu. Yunusov, Khim. Prir. Soedin. 11,433 (1975);CA 84, 14662. 125. A. Karimov, M. V. Telezhenetskaya, K. L. Lutfullin, and S. Yu. Yunusov, Khim. Prir. Soedin. 13,80 (1977);CA 87,65334. 126.J. Saez, D. Cortes, R. Hocquemiller, and A. Cav6, C. R. Acud. Sci. Paris 298(Series II), 591 (1984); A. Cave, private communication. 126a. D. Cortes, R. Hocquemiller, A. Cav6, J. Saez, and A. CavC, Can. J. Chem. 64,1390(1986). 127. H. L. Holland, D. W. Hughes, D. B. MacLean, and R. G. A. Rodrigo, Can. J. Chem. 56, 2467 (1978). 128. S. M. Kupchan, A. J. Liepa, V. Kameswaran, and K. Sempuku, J. Am. Chem. SOC. 95,2995 (1973). 129. T.-H. Yang, S.-C. Liu, and T . 3 . Lin, J. Chin. Chem. SOC. (Taipei) 24, 91 (1977). 130. T.-H. Yang, S.-C. Liu, T.-S. Lin, and L.-M. Yang, J. Chin. Chem. SOC. (Taipei) 23,29 (1976). 131. C. Galeffi, P. Scarpetti, and G. B. Marini-Bettolo, Furmaco, Ed. Sci. 32,665(1977);CA 87, 180683. 132. J. Wu, J. L. Beal, W.-N. Wu, and R. W. Doskotch, Lloydiu 40,593 (1977);CA 88, 133241. 133. J. Wu, J. L. Beal, W.-N. Wu, and R. W. Doskotch, Heterocycles 6, 405 (1977). 134. C. Galeffi, R. La Bua, I. Messana, and R. Zapata Alcazar, Guzz. Chim. Itul. 108,97 (1978). 135. K. Takahashi, M. J. Mitchell, and M. P. Cava, Heterocycles 4,471 (1976). 136. K. Takahashi and M. P. Cava, Heterocycles 5 , 367 (1976). 137. H. Guinaudeau, B. K. Cassels, and M. Shamma, Heterocycles 19,1009 (1982). 138. H. Guinaudeau, A. J. Freyer, and M. Shamma, private communication of M. Shamma. 139.K. Dahmen, P.Pachaly, and F. Zymalkowski, Arch. Phurm. (Weinheim) 310,95 (1977). 140. S. Abdizhabbarova, S. Kh. Maekh, and S. Yu. Yunusov, Khim.Prir. Soedin. 139 (1978);CA 89,39368. 141. G. P.Moiseeva, S. Kh. Maekh, and S. Yu. Yunusov, Khim. Prir. Soedin., 818(1979);CA 93, 168452. 142. S. Mukhamedova, S. Kh. Maekh, and S. Yu.Yunusov, Khim.Prir. Soedin., 393 (1983);CA 99, 85119. 143. K.H.C. Baser, Dogu, Seri, A 5 , 163 (1981);CA 96, 65701. 144. An alkaloid designated “thalictrinine,” mp 17OoC,was fmt isolated from Thulictrum simplex in 1950,and was assigned two different molecular formulas, neither matching that of the present material (CA 45, 1306;56, 11646). Chemical Abstracts currently lists two compounds

1. THE


207

under this name: CzlHzsN04 [1361-54-21 and C38H3&1209[72187-01-01; the latter material is described in this section. 145. Confusion due to synonyms is further aggravated by the proliferation of names beginning with “thal” (over 100 as of 1986), designating several different types of Thalictrum alkaloids. (See Ref. 354 and Section XI,J, Review 2, for a listing.) 146. W.-N. Wu, J. L. Beal, E. H. Fairchild, and R. W. Doskotch, J. Org. Chem. 43,580 (1978). 147. W.-N. Wu, J. L. Bed, and R. W. Doskotch, Tetrahedron 33, 2919 (1977). 148. M. Shamma, J. L. Moniot, and P. Chinnasamy, Heterocycles 6, 399 (1977). 149. P. Chinnasamy, Dim. Abstr. Int. B 39, 3836 (1979). 150. The properties reported in Ref. 148 are different from those in Ref. 132. The Ohio State University values (ZZ8,132,133), which were determined on larger quantities of material from more than one source, may be presumed to be more accurate. 151. L.-C. Lin, C.-C. Sung, C.-Y. Fan, C.-F. Tu, M.-L. Chou, C.-C. Ma, and J.-S. Hsu, Yuo Hsueh Tung Puo 15, 46 (1980); CA 95, 86198. 152. See Ref. ZI, footnote 4. 153. The structure of fetidine was incorrectly represented in Vol. 16 (1977) of this treatise. 154. W.-N. Wu, J. L. Beal, and R. W. Doskotch, Lloydiu 40, 508 (1977). 155. W.-N. Wu, J. L. Beal, G. W. Clark, and L. A. Mitscher, Lloydiu 39, 65 (1976). 156. P. Wiriyachitra and B. Phuriyakom, Aust. J. Chem. 34, 2001 (1981). 157. J. S. K. Ayim, D. Dwuma-Badu, N. Y.Fiagbe, A. M. Ateya, D. J. Slatkin, J. E. Knapp, and P. L. Schiff, Jr., Lloydiu 40, 561 (1977); CA 88, 141559. 158. A,-M. M. Ateya, Diss. Abstr. In?. B 40, 2143 (1979). 159. L. Claisen, Liebigs Ann. Chem. 418, 96 (1919). 160. B. K. Cassels and M. Shamma, Heterocycles 14, 211 (1980). 161. P. N. Sharma, A. Shoeb, R. S. Kapil, and S. P. Popli, Phytochemistry 20, 2781 (1981). 162. D. Dwuma-Badu, J. S. K. Ayim, A. N. Tackie, M. A. El Sohly, J. E. Knapp, D. J. Slatkin, and P. L. Schiff, Jr., Experientiu 31, 1251 (1975). 163. M. A. Elsohly, Dim. Abstr. Int. B 36, 6086 (1976). 164. H. Guinaudeau, A. J. Freyer, R. D. Minard, M. Shamma, and K. H. C. Baser, J. Org. Chem. 47, 5406 (1982). 165. M. I. Khan, M. Ikram, and S. F. Hussain, Pluntu Med. 47, 191 (1983). 166. R. Ver Poorte, J. Siwon, G. F. A. Van Essen, M. Tieken, and A. B. Svendsen, J. Nat. Prod. 45, 582 (1982). 167. G.-S. Liu, B.-Z. Chen, W.-Z. Song, and P.-G. Xiao, Chih Wu Hsueh Puo 20,255 (1978); CA 90, 12202. 168. C. Liu, G. Liu, and P. Xiao, Zhongcuoyuo 14, 45 (1983); CA 99, 32628. 169. P. Petcu, E. Andronescu, and D. Runcan-Egri, Clujul Med. 50, 356 (1977); CA 89, 56431. 170. P. Petcu, E. Andronescu, and D. Runcan-Egri, Furmucia (Bucharest) 26, 25 (1978); CA 89, 87154. 171. G.-S. Liu and B.-Z. Chen, Yuo Hsueh Tung Puo 16, 7 (1981); CA 95, 138691. 172. C. Liu, Zhongcuoyuo 14, 45 (1983); CA 99, 32628. 173. K. Drost, M. Szaufer, and 2. Kowalewski, Herbu Pol. 20,301 (1974); Biol. Abstr. 61,39416. [A review (in Polish) of Occurrence of several Berberis alkaloids, containing references to 1972.1 174. R. Torres, F. Delle Monache, and G. B. Marini-Bettolo, Pluntu Med. 37, 32 (1979). 175. P. Majumder and S. Saha, Phytochemistry 17, 1439 (1978). 176. V. Fajardo, A. Leon, M. C. Loncharia, V. Elango, M. Shamma, and B. K. Cassels, Bol. SOC. Chil. Quim. 27, 159 (1982); CA 96, 214302. 177. V. Fajardo, C. Prats, and M. Garrido, Contrib. Cient. Technol. (Univ. Tec. E s t d o , Santiago) 11, 61 (1981); CA 97, 36122.

208

KEITH T.BUCK

177a. A. Karimov, M. V. Telezhenetskaya, K. L. Lutfullin, and S. Yu. Yunusov, Khim. Prir. Soedin., 558 (1976); CA 85, 174272. 178. M. Haroon-Ur-Rashid and M. N. Malik, Puk. J . Forest. 22, 43 (1972); CA 77, 149688. 179. D. Kostalova, B. Brazdovicova, and J. Tomko, Chem. Zuesti 30,226 (1976); CA 86, 185942. 180. D. Kostalova, B. Brazdovicova, and J. Tomko, Chem. Zuesti 32, 706 (1978); CA 91, 20853. 181. J . E. L e t , Diss. Abstr. In?. B 44, 1458 (1983); CA 100, 48588. 182. B. Brazdovicova, D. Kostalova, J. Tomko, and H. Y. Jin, Chem. Zvesti 34, 259 (1980); CA 93, 91881. 183. M. Ikram and F. Khan, Pluntu Med. 32, 212 (1977). 184. A. R. Chowdhury, Sci. Cult. 38, 358 (1972); CA 78, 82058. 185. D. Dwuma-Badu, J. S. K. Ayim, C. A. Mingle, A. N. Tackie, D. J. Slatkin, J. E. Knapp, and P. L. Schiff, Jr., Phytochemistry 14, 2520 (1975). 186. V. J. Tripathi, A. B. Ray, and B. Dasgupta, Zndiun J. Chem. 14B, 62 (1976). 187. M. Ikram, N. Shai5, and M. Abu Zarga, Pluntu Med. 45, 253 (1982); CA 97, 195793. 187a. It has been claimed that C . pendulus and C. leube are synonymous [N.C. Gupta, D. S. Bhakuni, and M. M. Dhar, Experientiu 26, 12 (1970)], in which case this is not a new source of these alkaloids. 188. H. Guinaudeau, M. Leboeuf, A. CavC, S. Duret, and R. R. Paris,Pluntu Med. 29,54 (1976); CA 84, 147659. 189. X.-C. Tang, J. Feng, Y.-E. Wang, and M.-Z. Liu, Chung-kuo Yuo Li Hsueh Puo 1, 17 (1980); CA 94, 132153. 190. X.-X. Zhang, Z.-J. Tang, Y.-L. Gao, R. Chen, A.-N. Lao, and C.-G. Wang, Chih Wu Hsueh Puo 23, 216 (1981); CA 95, 192262. 191. F.-X. Zhou and X.-J. Xu, Actu Bot. Sin. 21, 41 (1979). Biol. Abstr. 69, 12249. 192. F.-H. Chou, C.-C. Chen, P.-Y. Liang, and C. Wen, Yuo Hsueh Tung Puo 16,50 (1981); CA 95, 121036. 193. X. Zhou, Z. Chen, P. Liang, and J. Wen, Zhongcuoyuo 12, 439 (1981); CA 96, 177948. 194. S.-T. Lu and E.-C. Wang, Tui-wan Yuo Hsueh Tsu Chih 29, 49 (1977); CA 90, 148496. 195. B. D. Gupta, S. K. Banerjee, and K. L. Handa, Phytochemistry 15, 576 (1976). 196. R. Hocquemiller, P. Cabalion, A. Bouquet, and A. CavC, C. R. Acud. Sci. Paris 285C, 447 (1977); CA 88, 152821. 197. C. Moulis, J . Nut. Prod. 44, 101 (1981); CA 94, 99819. 198. T. R. Suess and F. R. Stermitz, J. Nut. Prod. 44,680 (1981); CA %, 82703. 198a. V. 0. Marquis, T. A. Adanlawo, and A. A. Olaniyi, Pluntu Med. 31, 367 (1977); CA 90, 132737. 199. S. S. N. Murthy and A. Der Marderosian, Lloydia 36, 440 (1973). 200. R. Verpoorte, A. H. M. Van Rijzen, J. Siwon, and A. B. Svendsen, Pluntu Med. 34, 274 (1978); CA 90, 69100. 201. R. S. Singh, P. Kumar, and D. S. Bhakuni, J . Nut. Prod. 44, 664 (1981); CA 96, 118988. 202. J.-X. Huang and Y. Chen, Yao Hsueh Hsueh Puo 14, 612 (1979); CA 92, 203472. 203. U. Prawat, P. Wiriyachitra, V. Lojanapiwatna, and S. Nimgirawath, 1. Sci. SOC. Thuilund 8, 65 (1982); CA 97, 107084. 204. M. Matsui, T. Kabashima, K. Ishida, T. Takebayashi, and Y. Watenabe, J. Nut. Prod. 45,497 (1982); CA 97, 123971. 205. M. Matsui, M. Uchida, I. Usuki, Y. Saionji, H. Murata, and Y. Watanabe, Phytochemisny 18, 1087 (1979). 206. F. Scheinmann, E. F. V. Scriven, a n d 0 . N. Ogbeide, Phytochemistry 19, 1837 (1980); CA 94, 192515. 207. R. E. Perdue, Jr., Lloydiu 40, 607 (1977). 208. R. E. Perdue, Jr., J. Nut. Prod. 45, 418 (1982);Biol. Abs:r. 76, 66403.

1. THE BISBENZYLISOQUlNOLINE ALKALOIDS

209

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366. N. Shiraishi, T. Arima, K. Aono, B. Inouye, Y. Morimoto, and K. Utsumi, Physiol. Chem. Phys. 12, 299 (1980); CA 94, 76601. 367. Z.-D. Zhou, C.-H. Han, and P. Wang, Yao Hsueh Hsueh Pa0 15,248 (1980); CA 93,179560. 368. 0. N. Tolkachev, S. A. Vichkanova, and L. V. Makarova, Farmatsiya (Moscow) 27, 23 (1978); C A 89, 36464. 369. Chinese Academy of Medical Sciences, Institute of Materia Medica, Laboratory of Medicinal Plants, Acta Bot. Sin. 19, 257 (1977); Biol. Abstr. 69, 11800. 370. F. S. Sadritdinov, Med. Zh. Usb. (2), 54 (1980); CA 92, 174599. 371. T. Yoshioka, K. Sekiba, and K. Utsumi, Cell Strucr. Funct. 5, 209 (1980); CA 94, 741. 372. N. Shiraishi, Igaku To Seibutsugaku 98, 141 (1979); C A 92, 1055. 373. S. Watanabe, Okayama Igakkai Zasshi 85, 145 (1973); Biol. Absrr. 57, 69427. 374. K. Utsumi, M. Miyahara, M. Inoue, M. Mori, K. Sugiyama, and J. Sasaki, Cell Strucf.Funct. 1, 133 (1975); CA 85, 41759. 375. K. Utsumi, M. Miyahara, K. Sugiyama, and J. Sasaki, Actu Histochem. Cytochem. 9, 59 (1976); C A 85, 87995. 376. K. Utsumi, K. Sugiyama, M. Miyahara, M. Naito, M. Awai, and M. Inoue, Cell Strucr. Funct. 2, 203 (1977); Biol. Abstr. 65, 44029 377. A. Makidono, Igaku Kenkyu 50, 475 (1980); CA 95, 54759. 378. K. Sugiyama, J. Sasaki, K. Utsumi, and M. Miyahara, Arerugi 25,685 (1976); CA 86,41683. 379. T. Kasajima, M. Yamakawa, K. Maeda, M. Matsuda, M. Dobashi, and Y. Imai, Gun ro Kagaku Ryoho 10, 1188 (1983); CA 99, 32825. 380. B. Inoue, M. Doi, J. Akiyama, S. Kobayashi, and K. Utsumi, Igaku To Seibursugaku 95,305 (1977); CA 89, 191909. 381. 0. N. Tolkachev, L. D. Yakhontova, E. A. Romanenko, G. A. Firsova, V. G. Mazaeva, L. A. Sedakova, and Z. P. Sof'ina, Sin?. Izuch. Nov. Orechesrvennykh Protivoleikoznykh Prep., Tezisy Konf., 81 (1979); CA 92, 121585. 382. X. Y. Jin, D. J. Sun, J . N. Sheng, and 2. B. Chu, Jpn. J . Anesthesiol. 31, 1016 (1982);Biol. Abstr. 76, 59322. 383. Y. Kanaho, T. Sato, and T. Fujii, Cell Srruct. Funct. 7, 39 (1982); CA 97, 49446. 384. Y. Kanaho, T. Sato, T. Fujii, M. Kanzaki, and K. Yasunaga, Naika Hokan 30, 15 (1983); CA 99, 319. 385. T. Kawasaki, Juzen Igakkai Zusshi 82, 275 (1974); CA 82, 41580. 386. K. Fujii, S. Takasugi, and N. Toki, Jpn. J . Physiol. 31, 613 (1981); Cd 95, 215196. 387. K. Fujii and S. Takasugi, J. Physiol. SOC.Jpn. 43, 394 (1981); Biosis Previews 22, 53984. 388. K. Fujii, S . Takasugi, and N. Toki, Jpn. J. Physiol. 31, 613 (1981); CA 95, 215196. 389. R. Fujiwara, M. Ono, N. Tanaka, H. Miwa, T. Mannami, E. Konaga, and K. Orita, Gun To Kagaku Ryoho 7, 481 (1980); C A 93, 61432. 390. R. Fujiwara, M. Ono, and K. Orita, Igaku No Ayumi 114, 1056 (1980); C A 94, 58248. 391. R. Fujiwara, K. Kojima, Y. Yata, M. Ono, N. Tanaka, T. Mannami, and E. Konaga, lgaku No Ayumi 122, 1049 (1982); CA 98,46603. 392. T. Fujii, T. Sato, A. Tamura, M. Wakatsuki, and Y. Kanaho, Biochem. Pharmucol. 28, 613 (1979); C A 91, 133788. 393. K. Aono, S. Morimoto, K. Hashimoto, K. Sato, I. Joja, S. Kimoto, H. Ezoe, Y. Takeda, M. Miyake, et al., Okayama Igakkai Zasshi 92, 1015 (1980); CA 95, 1064. 394. K. Aono, N. Shiraishi, T. Arita, B. Inouye, T. Nakazawa, and K. Utsumi, Physiol. Chem. Phys. 13, 137 (1981); CA 95, 125951. 395. M. Asano, C. Ohkubo, K. Sawanobori, and K. Yonekawa, Biochem. Exp. Biol. 16, 341 (1980); CA 97, 174785. 396. N. Mealy, Drugs Future 4, 481 (1979); Biosis Previews 18, 28317. 397. N. Tomita, Igaku Kenkyu 47, 1 (1977); Bioresearch Index 15, 14661.

1. THE BISBENZYLISOQUWOLINE ALKALOIDS

215

398. T. Kuramochi, T. Shimada, M. Inouchi, S. Kojima, M. Murayama, and M. Ishida, Sei Marianna Iku Duigaku Zusshi 9, 253 (1981); CA 96, 174057. 399. Y. Tagashira, R. Fujiwara, M. Ono, K. Ohashi, Y. Kamikawa, N. Tanaka, H. Miwa, T. Mannami, E. Konaga e? ul., Gun To Kuguku Ryoho 8, 234 (1981); CA 95,73702. 400. T. Matsui, Y. Kobayashi, Y. Mizoguchi, T. Monna, S. Yamamota, S. Ootani, K. Nakai, and S . Morisawa, Nipon Shokukibyo Gukkui Zasshi 78, 1053 (1981); CA 95, 197377. 401. M. Miyahara, K. Utsumi, K. Sugiyama, and K. Aono, Okuyuma Igukkui Zasshi 89, 749 (1977); CA 88, 130791. 402. M. Miyahara, K. Aono, J. S. Queseda, K. Shimono, Y. Baba, and S. Yamashita, Cell Struct. Funct. 3, 61 (1978); CA 89, 174738. 403. M. Mori, S. Nakamoto, Y. Arashima, and S. Seno, Gun To KugukuRyoho 6 , 175 (1979): CA 90, 197551. 404. S. Nagatsuka and T. Nakazawa, Biochim. Biophys. Actu 691, 171 (1982). 405. S. T. Ohnishi, Br. J. Huemutol. 55, 665 (1983). 406. K. K. Sadanaga, M. E. Junnan, and S. T. Ohnishi, 67th Annu. Mtg., Fed. Am. SOC. Exp. Biol., Chicago, April 10-15, 1983; Fed. Proc. 42,P Abstr. 4454 (1983). 407. M. Ono, R. Fujiwara, Y. Tagashira, T. Matsui, K. Oohashi, Y. Kamikawa, N. Tanaka, E. Konaga, and K. Orita, Gun To Kuguku Ryoho 8, 1565 (1981); CA 96, 135416. 408. T. Sakamitsu and M. Takaya, Jpn. Kokui 73 31901 (1973); CA 80, 100112. 409. T. Sat0 and S. T. Ohnkhi, Eur. J. Pharmucol. 83, 91 (1982). 410. T. Sato, M. Ikeda, Y. Kanaho, and T. Fujii, Yukuguku Zusshi 101, 1129 (1981); Biol. Abstr. 74, 43466. 411. S. Shinozawa and Y. Araki, Nzppon Yukuriguku Zusshi 75, 207 (1979); CA 91, 117185. 412. T. Shio, Okuyumu Igukkai Zusshi 92, 1205 (1980): Biol. Abstr. 73, 63494. 413. Academia Sinica, KO Hsueh Tung Puo 24, 574 (1979); CA 91, 181330. 414. D. Guang-Sheng, Proc. US.-China Pharmucol. Symp., 103-121 (1980); CA 94, 114701. 415. F. Zhou, F. Liang, J. Fang, K. Zhang, C. Liang, A. Tian, X. Fang, 2. Shi, and 2. Gu, Xuoxue Tongbuo 17, 135 (1982); CA 97, 60870. 416. C. Wambede and 0. N. Ogbeide, Drugs Future 7, 467 (1982). Biosis Previews 24, 10752. 417. S. A. Vichkanova, V. V. Adgina, S. B. Izosimova, L. D. Shipulina, and L. I. Lyutikova, Khim.-Farm. Zh. 12, 101 (1978); CA 89, 100745. 418. S. Chen and C. Wu, Zhongcuoyao 12,450 (1981); CA 97,440. 419. S. Chen and C. Hu, Zhongguo Yuoli Xuebuo 3, 178 (1982); CA 97,174780. 420. S. Chen and C. Hu, Wuhan Yixueyuun Xuebuo 11, 75, (1982); CA 98, 100919. 421. 2. Dai, S. Hou, L. Guo, and C. Hu, Youxue Tongbuo 18, 278 (1983); CA 99, 63785. 422. 2. Dai, M. Yi, J. Li, and C. Hu, Wuhun Yixueyuun Xuebao 12,290 (1983); CA 100,96061. 423. G. Li, D. Fang, C. Hu, and F. Lu, Zhongguo Yuoli Xuebuo 5 , 20 (1984); CA 100, 167970. 424. G. Li, D. Fang, C. Hu, and F. Lu, Yuoxue Xuebuo IS, 660 (1983); CA 100, 17458. 425. G. Li, C. Hu, and F. Lu, Wuhun Yixueyuun Xuebao 12, 280 (1983); CA 100, 61541. 426. A. B. Ray, S. Chattopodhyay, R. M. Tripathi, S. S. Gambhir, and P. K. Das, Plunru Med. 35, 167 (1979): CA 91, 9399. 427. F. Sadritdinov, Furmukol. Alkuloidov Ikh. Proizvod., C , 154 (1972); CA 80, 91211. 428. F. S. Sadritdinov, Vsb., Furmkol Rustitel'n. Veshcheslv, 32 (1976). Abstract: Ref. Zh. Biol. Khim., Abstr. 16CH304 (1976); CA 86, 40209. 429. Z. S . Akbarov, Kh. U. Aliev, and M. B. Sultanov, Furmukol. Prir. Veschestv, 11 (1978), Izd. "Fun" Uzb. SSR, Tushkent, USSR; CA 91,32777. 430. F. Sadritdinov, Furmukol. Alkaloidov Serdechnykh Glikozidov, 117-120 (1971); CA 78, 79629. 431. S . A. Tursunova, Kh. I. Tashbaev, and M. B. Sultanov, Dokl. A W . Nuuk Uzb. SSR 25, 34 (1968); CA 72, 41440.

216

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432. Sh. U. Ismailov and D. A. Asadov, Furmukol. Alkuloidov Ikh Proizvod., C, 171-173 (1972), ‘‘Fun,’’Tushkent, USSR; CA 80, 103857. 433. M. Zhu and X. Tang, Yuo Hsueh Tung Puo 16, 3 (1981); C A 96, 28497. 434. M. Hiyashi, K. Tsurumi, and H. Fujimura, Cifu DuigukuIgukubu Kiyo 17,257 (1969); CA 73, 43657. 435. J . Yamahara, T. Sawada, M. Kozuka, and H. Fujimura, Shoyukuguku Zusshi 28, 83 (1974); C A 83, 53481. 436. J. Yamahara, T. Sawada, and H. Fujimura, Shoyukuguku Zusshi 28,96 (1974); CA 83,53482. 437. M. Proca-Bioban, Bucteriol. Virusol. Puruzitol. Epidemiol. (Bucharest) 23, 129 (1978); Bioresearch Index 16, 17743. 438. G. B. Marini Bettolo, “Recent Advances in Receptor Chemistry,” p. 147. Elsevier, Amsterdam, 1979. 439. D. M. Norris, ACS Symp. Ser. 62, 215 (1977); CA 88,60336. 440. J. W. Banning, K. N. Salman, and P. N. Patil, J. Nut. Prod. 45, 168 (1982); CA 97, 482. 441. R. S. Gupta, J. J. Krepinsky, and L. Siminovitch, Mol. Pharmacol. 18, 136 (1980); CA 93, 160962. 442. Wuhan Medical College, Department Pharmacology, Chin. Med. J . (Engl. Ed.) 92, 193 (1979); Biol. Abstr. 70, 11464. 443. G. Xia, J. Jia, Z. Wu, D. Fang, and M. Jiang, Zhongguo YaoliXuebuo 3,230 (1982); CA 98, 119407. 444. X. Yu, C. Zou, and M. Lin, Ecotoxicol. Environ. Suf. 7, 306 (1983); CA 99, 65469. 445. B. Liu, C. Zou, and Y. Li, Ecotoxicol. Environ. Suf 7, 323 (1983); CA 99, 65470. 446. S. Yu, L. Cao, Y. Feng, Q. Guo, Y. Liu, H. Guo, B. Zhou, Y. Gao, Y. Li, and H. Mao, Wuhan Yixueyuun Xuebuo 11, 71 (1982); CA 98, 27632. 447. S. Yu, L. Cao, Y. Feng, Q. Guo, B. Zhou, and H. Guo, Zhonghuu Xinrueguunbing Zuzhi 11, 147 (1983); C A 100, 79618. 448. W. Yao, G. Xia, D. Fang, and M. Jiang, Zhongguo YuoliXuebao 4,29 (1983); CA 99, 16286. 449. W. Yao, D. Fang, G. Xia, L. Qu, and M. Jang, Wuhan YixueyuunXuebuo 10,81 (1981); CA 96, 62790. 450. W. Yao, D. Fang, J. Zhao, and M. Jiang, Zhongguo YuoliXuebuo 4, 130 (1983); CA 99, 82393. 451. J. Ke, S. Weng, G. Zhang, Y. Yang, J. Wang, and R. Fu, Zhongguo Yuoli Xuebuo 2, 235 (1981); C A 96, 62791. 452. F. Zeng, D. Fang, D. Leng, and F. Lu, Yuoxue Xuebuo 17, 561 (1982); CA 97, 208016. 453. G. Zhang and T. Liu, Zhonghuu Xinrueguunbing Zuzhi 11, 224 (1983); C A 100, 61536. 454. X. Zong, M. Jin, G. Xia, D. Fang, and M . Jiang, Zhongguo YuoliXuebuo 4,258 (1983); CA 100, 61569. 455. R. Z. Wang and Q. Q. Pan, Chung-Huu Chung Liu Tsu Chih 3, 86 (1981); CA 95, 161864. 456. J. R. Smythies, Psychoneuroendocrinology (Oxford) 4, 177 (1979); CA 93, 93106. 457. M. Slavik, Lloydiu 39, 468 (1976). 458. M. Gosalvez, R. Garcia-Canero, M. Blanco, and C. Gurucharri-Lloyd, Cancer Treat. Rep. 60, 1 (1976); C A 84, 159552. 459. V. P. Arya, Drugs Future 4, 749 (1979); Biosis Previews 19, 59405. 460. F. S. Sadritdinov, Med. Zh. Usb., 54 (1974); CA 82, 80578. 461. J. Q. Qian, M. J. M. C. Thoolen, J. C. A. Van Meel, P. B. M. W. M. Timmermans, and P. A. Van Zwieten, Pharmacology 26, 187 (1983). 462. L.-L. H. Liao, Proc. Nutl. Sci. Counc., Repub. China 4, 285 (1980); CA 93, 197657. 463. L.-L. Liao, Fed. Proc., Fed. Am. SOC.Exp. Biol. 36, 335 (1977). 464. Q. Li, Y. Xu, H. Jiang, G. Ma, T. Hu, and B. Wang, Chin. J. Tuberc. Respir. Dis. 5 , 243 (1982); Biol. Abstr. 78, 31824.


217

465. Q. Li, Y. Xu, 2 . Zhou, X. Chen, X. Huang, S. Chen, and C. Zhang, Chin. J. Tuberc. Respir. Dis. 4, 321 (1981); Biol. Abstr. 74, 78195. 466. T. Li, T. Hu,C. Zou, P. Yao, and Q. Zheng, Ecotoxicol. Environ. Suf. 6,528 (1982); CA 98,

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218

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1. THE


219

531. Z. S. Akbarov, Kh. U. Aliev, and M. B. Sultanov, Furmukol. Alkuloidov Ikh Proizvod., C, 129 (1972); CA 81, 20880. 532. F. S. Sadritdinov, Furmukol. Toksokol. (Moscow) 32, 598 (1969); CA 72, 1988. 533. L. Zheng, I. Tan, and X . Tang, Zhongguo Yuoli Xuebuo 5 , 11 (1984); CA 100, 150997. 534. P. V. Diwan, P. L. Sharma and Y.S. Varma, Zndiun J. Exp. Biol. 21, 614 (1983); CA 100, 44923. 535. S. H. Nelson and D. S. Steinsland, Fed. Am. SOC.Exp. Biol.,66thAnnualMtg., New Orleans, April, 1982; Fed. Proc. 41, Abstr. P 8395 (1982). 536. C. Gorinsky, D. K. Luscombe, and P. J. Nicholls, J. Phurm. Pharmucol. 24 (Suppl.), 147P (1972); CA 78, 52800. 537. T. Kametani, H. Terasawa, M. Ihara, and J. Iriarte, Phytochemistry 14, 1884 (1975). These workers failed to obtain aztequine from the reported source, Tuluumu mexicum. 538. H. Guinaudeau, A. J. Freyer, M. Shamma, and K. H. C. BaSer, Tetruhedron40,1975 (1984). 539. S. F. Hussain, H. Guinaudeau, A. J. Freyer, and M. Shamma, J . Nut. Prod. 48, 962 (1985). 540. A. Jossang, M. Leboeuf, A . Cuve', T. Stvenet, and K . Pudmuwinutu, J . Nut. Prod. 47, 504 (1984). 541. P. G. Waterman and I. Mohammed, Pluntu Med. 50, 282 (1984); CA 102, 163723. 542. J. Lemli, C. Galeffi, I. Messana, M. Nicoletti, and G. B. Marini-Bettolo, Pluntu Med., 68 (1985); CA 103, 3705. 543. J. Kunitomo, Y. Murakami, M. Oshikata, M. Akasu, K. Kodama, N. Takeda, K. Harada, M. Suzuki, A. Tatematsu, E. Kawanabe, and H. Ishii, Chem. Phurm. Bull. 33, 135 (1985); CA 102, 163694. 544. M. Lavault, A. Foumet, H. Guinaudeau, and J. Bruneton, J. Chem. Res.. Synop., 248 (1985); CA 104, 48692. 545. H. Wagner, L. Z. Lin, and 0. Seligmann, Tetrahedron 40, 2133 (1984). 546. X. Fang, L. Qian, P. Shen, and 2. Shi, Zhongcuoyuo 16, 536 (1985); CA 104, 145508. 547. M. U. S. Sultanbawa, S. Sotheeswaran, S. Balasubramaniam,M. Abd El-Kawi, D. J. Slatkin, and P. L. Schiff, Jr., Phyrochemisrty 24, 589 (1985). 548. H. Guinaudeau, A. J. Freyer, M. Shamma, S. K. Mitra, A. K. Roy, and B. Mukhejee, J. Nut. Prod. 48, 651 (1985). 549. M.-C. Chalandre, J. Bruneton, P. Cabalion, and H. Guinaudeau, Can. J. Chem. 64, 123 (1986). 550. M.-C. Chalandre, H. Guinaudeau, and J. Bruneton, C. R. Acud. Sci. Paris,Ser. II 301, 1185 (1985). 551. D. Cortes, J. Saez, R. Hocquemiller, A. Cave, and A. Cave, J. Nut. Prod. 48, 76 (1985). 552. S. F. Hussain, L. Khan, H. Guinaudeau, J. E. Leet, A. J. Freyer, and M. Shamma, Tetruhedron 40, 2513 (1984). 553. A. 0. El-Shabrawy, P. L. Schiff, Jr., D. J. Slatkin, B. Das Gupta, A. B. Ray, and V. J. Tripathi, Heterocycles 22, 993 (1984). 554. V. Fajardo, F. Podesta, M. Garrido, and A. Urzba, Bol. SOC. Chil. Quim.30, 51 (1985); CA 104, 145455. 555. H. B. Dutschewska and N. M. Mollov, Chem. Ber. 100, 3135 (1967). 556. I. Weiss, A. J. Freyer, M. Shamma, and A. Urzba, Hererocycles 22, 2231 (1984). 557. S. Firdous, E. Valencia, M. Shamma, A. U d a , and V. Fajardo, J. Nut. Prod. 48,664 (1985). 558. M. C. Chalandre, J. Bruneton, P. Cabalion, and H. Guinaudeau, J. Nut. Prod. 49, 101 (1986). 559. D. Cortes, J. Saez, R. Hocquemiller, A. CavC, and A. Cave, Heterocycles 24, 607 (1986). 560. N. El-Sebakhy and P. G. Waterman, Phytochemistry 23, 2706 (1984). 561. V. Fajardo, F. Podesta, M. Shamma, and S. F. Hussain, Rev. Latinoam. Quim. 16,59 (1985); CA 104, 145471. 562. M. Shamma and H. Guinaudeau, Tetrahedron 40, 4795 (1984).

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563. P. Damas, J. Bruneton, A. Fournet, and H. Guinaudeau, J. Nut. Prod. 48, 69 (1985). 564. M. AM El-Kawi, D. J. Slatkin, P. L. Schiff, Jr., S. Dasgupta, S. K. Chattopadhyay, and A. B. Ray, J . Nut. Prod. 47, 459 (1984). 565. T. Hu and S. Zhao, Yuoxue Xuebuo 21, 29 (1986); CA 104, 221975. 566. A. Jossang, M. Leboeuf, and A. CavB, C. R. Acud. Sci. Paris, Ser. II 297, 853 (1983). 567. The NMR spectrum of 81, previously measured in CDC1, 10% CD30D, is here reported in

+

568. 569. 570. 571. 572. 573. 574. 575. 576. 577. 578. 579. 580. 581. 582. 583. 584. 585. 586. 587. 588. 589. 590. 591. 592. 593. 594. 595. 596. 597. 598. 599.

CF3COZH. D. Cortes, J. Saez, R. Hocquemiller, and A. CavB, C . R. Acud. Sci., Ser. II 298,591 (1984). K. H. C. Baser, and N. Kirimer, Plunta Med., 448 (1985); CA 104, 145467. Z. Xue, Y. Wu, P. Zhang, J. Ma, and J. He, Zhiwu Xuebuo 27,630 (1985); CA 104, 106299. G. Riicker and R. Mayer, Pluntu Med., 183 (1985); CA 103, 138516. Atta-Ur-Rahman and A. A. Ansari, J. Chem. SOC. Puk. 5, 283 (1983); CA 101, 3974. F. A. Hussaini and A. Shoeb, Phytochemistry 24, 633 (1985). S. A. Ross, T. Gozler, A. J. Freyer, M. Shamma, and B. Cubukcu, J. Nut. Prod. 49, 159 (1986). A. Urzba, R. Torres, B. K. Cassels, and V. Fajardo, Rev. Lntinoum. Quim. 16,66 (1985); CA 104, 65955. V. Hrochova and D. Kostalova, Cesk. Funn. 34, 412 (1985); CA 104, 106264. R. Hocquemiller, P. Cabalion, A. Foumet, and A. C a d , Pluntu Med. 50,23 (1984); C A 101, 126870. B. K. Cassels and A. Ulzba, J. Nut. Prod. 48, 671 (1985). N. Ruangrungsi, W. De-Eknamkul, and G. L. Lange, Pluntu Med. 50,432 (1984); C A 102, 59373. M. Zhi-da, L. Ge, X.Guang-xi, M. Iinuma, T. Tanaka, and M. Mizuno, Phytochemistry 24, 3084 (1985). Y. Feng and H. Chen, Yuowu Fenxi Zuzhi 5, 28 (1985); CA 102, 172482. Y. Lu, Zhongcuoyuo 15, 195 (1984); CA 101, 187944. H. Wagner, L. Z. Lin, and 0. Seligmann, Pluntu Med. 50, 14 (1984); CA 101, 69384. S. Al-Khalil and P. L. Schiff, Jr., Phyfochemistry 25, 935 (1986). M. Sahai, S. C. Sinha, A. B. Ray, S. K. Chattopadhyay, S. Al-Khalil, D. J. Slatkin, andP. L. Schiff, Jr., J . Nut. Prod. 48, 669 (1985). S. Mukhamedova, S. Kh. Maekh, and S. Yu. Yunusov, Khim. Prir. Soedin., 260 (1984); CA 101, 69363. K. H. C. Baser, M. Ogutveren, and N. G. Bisset, J. Nut. Prod. 48, 672 (1985). S. Mukhamedova, S. Kh. Maekh, and S. Yu. Yunusov, Khim. Prir. Soedin., 397 (1984); CA 102, 92937. L. Li and X. Guan, Wuhan Yixueyuun Xuebuo 13, 355 (1984); CA 103, 123750. M. Lin, W. Zhang, X. Zhao, and 1. Lu, Huuxue Xuebuo 42, 199 (1984); CA 101, 7491. N. Shiraishi, I. Joja, M. Kuroda, M. Fujishima, M. Miyake, and K. Aono, Physiol. Chem. Phys. Med. NMR 17, 243 (1985); C A 104, 144669. E. Nakova and 0. N. Tolkachev, Khim. Prir. Soedin., 86 (1985); CA 103, 71570. E. Nakova and 0. N. Tolkachev, Khim. Prir. Soedin., 91 (1985); CA 103, 71571. R. J. Cotter, Anal. Chem. 56, 2594 (1984). Y. Fujita, I. Mori, S. Kitano, and Y. Kamada, Bunseki Kuguku 32, E 375 (1983); CA 100, 7427. A. Watanabe, Y. Yamaoka, K. Kuroda, T. Yokoyarna, and T. Umeda, Yukuguku Zashi 105, 481 (1985); CA 103, 27214. K. F. Taha and F. M. Soliman, J. Drug Res. 15, 235 (1984); CA 104, 24118. A. E. Kuz’mitskaya and V. P. Kramarenko, Farm. Zh. (Kiev), 67 (1986); C A 104, 156074. Y. Yang, Zhongcuoyuo 16, 281 (1985); CA 103, 147222.

1. THE


22 1

600. D. Shi, Z. Wan, Z. Bi, and Q . Yu, ShanghaiDiyi YixueyuunXuebuo 11,284 (1984); C A 102, 50988. 601. X . Chen, G. Liu, J. Zeng, A. Sheng, Q. Zhou, and B. Zhou, Zhongcuoyuo 16, 8 (1985); CA 104, 56278. 602. B. Dimov, Furmatsiyu (Sofia) 34, 37 (1984); CA 101, 157747. 603. Y. Sun, C. Gao, L. Zhang, A. Zhang, F. Li, L. Wang, and H. Cai, Shenyung Yuoxueyuan Xuebuo 1, 223 (1984); CA 103, 128883. 604. Y. Sun, F. Li, L. Wang, H. Cai, C. Gao, A. Zhang, and L. Zhang, Sepu 2, 169 (1985); C A 103, 92933. 605. J. Leclerq, H. Dehaussy, M. C. Goblet, J. N. Wauters, and L. Angenot, J . Pharm. Belg. 40, 251 (1985); CA 104, 39568. 606. L. V. Pesakhovich, G. S. Kartashova, E. Yu. Babenysheva, and R. G. Babenysheva, Khim.Farm. Zh. 18, 755 (1984); CA 101, 177623. 607. A. Sidzhimov and N. Marekov, Phytochemistry 25, 565 (1986). 608. B. Du and Y. Zhang, Zhongcuoyuo 15, 309 (1984); CA 101, 203771. 609. G. Liu, Y. Jiang, G. Peng, Ibrahim, and L. Zhou, YuoxueXuebuo 20, 566 (1985); CA 103, 206254. 610. F. Li, L. Bao, and W. Li, Yaoxue Xuebuo 20, 859 (1985); CA 104, 199836. 611. M. Akasu, Jpn. Kokai Tokkyo Koho, Jpn. Patent 60,209,508 (1985) (85,209,508); CA 104, 74820. 612. R. Fujiwara, Y. Yata, K. Hirose, K. Gotoh, N. Tanaka, and K. Orita, lgaku No Ayumi 130, 673 (1984); CA 102, 307. 613. K. Goto and R. Tanaka, Biochem. Phurmucol. 33, 3912 (1984); CA 102, 39880. 614. S. Iida, Okayuma Igukkui Zasshi 96, 891 (1984); CA 103, 19138. 615. S. Iida, Okayamu Igukkai Zusshi 96, 883 (1984); CA 103, 19139. 616. I. Joja, Okayuma Igukkui Zusshi 97, 235 (1985); CA 104, 144760. 617. M. Kometani, Y. Kanaho, T. Sato, and T. Fujii, Eur. J. Pharmacol. 111,97 (1985); CA 103, 16838. 618. M. Miyahara, E. Okimasu, H. Mikasa, S. Terada, H. Kodama, and K. Utsumi, Arch. Biochem. Biophys. 233, 139 (1984). 619. S . Morioka, M. Ono, N. Tanaka, and K. Orita, Gun To Kugaku Ryoho 12, 1470 (1985); CA 103, 115848. 620. H. Nagai, S. Uveda, K. Suzuki, T. Yamamoto, Y. Masuda, and Y. Ogura, Shiku Kiso Igukkai Zusshi 27, 353 (1985); CA 103, 86877. 621. S . Nagaoka, S. Kawasaki, K. Sasaki, and T. Nakanishi, Iguku No Ayumi 133,260 (1985); CA 103, 134382. 622. T. Nagasawa, T. Ishihara, and F. Uchino, Yumuguchilgaku 34,369 (1985); CA 104, 102034. 623. Y. Nihashi, Y. Koga, H. Gondo, K. Taniguchi, and K. Nomoto, Irnmunobiology (Stuttgurt) 170, 351 (1985). 624. Y. Takehara, M. Yamasaki, Y. Fujii, and T. Yoshioka, Geka To Tuishu, Eiyo 19, 323 (1985); CA 104, 123125. 625. N. Uno, N. Matsuoka, T. Uchida, N. Shimizu, N. Katayama, N. Minami, and S. Shirakawa, lgaku No Ayumi 135, 595 (1985); CA 104, 144766. 626. H. Watanabe, H. Uramoto, M. Maeda-Hagaiwara, and T. Kukuchi, Arch. Int. Pharmacodyn. Ther. 278, 53 (1985). 627. H. Uramoto, Y. Watanabe, M. Hagiwara, T. Kikuchi, and K. Watanabe, Wukan Iyuku Gukkaishi 2, 246 (1985); CA 104, 61307. 628. S . Watanabe, Acta Med. Okuyumu 38, 101 (1984); CA 101, 17048. 629. N. Yoshikawa, Y. Seyama, S. Yamashita, M. Akasu, and H. Inoue, Nippon Yukurrguku Zusshi 87, 99 (1986); CA 104, 141780.

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629a. F. Zeng, W. Z a g , D. Leng, and C. Hu, W h n Yixueyuun Xuebuo 13,205 (1984); CA 101, 143821. 629h. X. Zong, M. Jin, D. Zhao, C. Hu, and F. Lu, Zhongguo YuoliXuebuo 6,30 (1985); CA 102, 178897. 630. Z. Dai, Z. Li, J. Li, and C. Hu, W u h n Yixueyuun Xuebuo 13, 352 (1984); CA 102, 197491. 631. R. Bian, H. Zhou, Q. Xie, F. Tong, W. Yang, and Y. Wang, Zhongcuoyuo 15,262 (1984); CA 101, 163356. 632. W. Hu, Z. Zhou, C. Hu, and F. Lu, Zhongguo Yuoli Xuebuo 5, 257 (1984); CA 102, 89840. 633. N. Liu and X. Zheng, Zhongguo Yuoli Xuebuo 6, 209 (1985); CA 103, 174687. 634. X. Yang, D. Fang, and M. Jiang, W u h n YixueyuunXuebuo 13,201 (1984); CA 101, 143820. 635. W. Yao, G. Xia, D. Fang, and M. Jiang, Zhongguo Yuoli Xuebuo 5 , 97 (1984); CA 101, 32992. 636. W. Yao, G. Xia, H. Han, D. Fang, and M. Jiang, Zhongguo YuoliXuebuo 7 , 128 (1986); CA 104, 161754. 637. S. Yu, M. Wang, C. Ke, Y. Liu, L. Cao, Y. Gao, X. Wu, R. Fu, and Y. Wang, Zhonghuu Yixue Zuzhi 66, 29 (1986); CA 104, 218866. 638. F. D. Zeng, D. H. Shaw, Jr., and R. I. Ogilvie, J. Curdiovusc. Phurmucof. 7 , 1034 (1985). 639. H.Zhang and R. Bian, Yuoxue Xuebuo 19, 616 (1984); CA 102, 55819. 640. X. Zheng and R. Bian, Zhongguo Yuoli Xuebuo 7 , 40 (1986); CA 104, 141957. 641. A. Zou, D. Wang, and F. Wu, W u h n Yixueyuun Xuebuo 13, 282 (1984); CA 102, 17335. 642. P. Pachaly, Dtsch. Apoth.-Ztg. 124, 1357 (1984); CA 101, 136862. 643. M. Damyanova and I. Stoichkov, Probl. Onkol. 12,45 (1984); CA 102, 17217. 644. B. Ivanov, D. Benova, V. Khadzhidekova, I. Rupova, M. Mileva, and M. Koleva, Suvrem. Med. 35, 500 (1984); CA 102, 109012. 645. V. B. Khadzidekova, D. K. Benova, B. A. Ivanov, M. S. Mileva, and M. Y. Koleva, Rudiobiologiyu 25, 656 (1985); CA 104, 17142. 646. A. Milushev and M. Damyanova, Probl. Onkol. 11,40 (1983); CA 101, 122657. 647. I. Mircheva, Exsp. Onkol. 6, 48 (1984); CA 101, 16948. 648. D. Todorov, K. Maneva, and M. Ilarionova, Probl. Onkol. 12, 37 (1984); CA 102, 39558. 649. S. H. Nelson and 0. S. Steinsland, Eur. J. P h r m c o l . 108, 209 (1985); CA 102, 125104.

-CHAJTER2 THE ALKALOIDS FROM PAURZDZANTHA R. A. JACQUESY Centre National de la Recherche Scientifque 75700 Paris, France AND

J. LEVESQUE U.E.R. de Medecine et de Pharmacie Poitiers, Frunce

I. Introduction 11. Taxonomic Position of the Genus Pauridiuntha 111. Alkaloids in the Genus Puuridianthu

A. Harman-Type Alkaloids B . Indole Pyridine-Type Alkaloids C. Glucoalkaloids D. Alkoyl-Glucoalkaloids IV. Biosynthesis V. Conclusion References

1. Introduction The majority of indole alkaloids have been isolated from the three plant families, Loganiaceae, Apocynaceae, and Rubiaceae. Among this last family, the genus Puuridiunthu has received limited attention, although about 30 different species have been identified and some of them are still being used in native medicine. The genus Puuridiuntha is found exclusively in tropical Africa (Table I). Madagascar deserves a special mention as the species P. Lyullii [formerly Urophyllum Lyullii ( l ) ]is the only Puuridiunthu reported to be growing on this island and has not been found elsewhere (2,3).It is of interest that ethnic groups of different origin and culture had used different but closely related Puuridiunthu species for their magic significance, e.g., following circumcision, and are still using them for identical therapeutical purposes, such as the treatment of various inflammatory deseases (4-7).The well-known anti-serotonin activity of harman223

THE ALKALOIDS, VOL.30 Copyrighi 0 1987 by Academic Press, Inc. All rights of reproduction in any form reserved.

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TABLE I Repartition of African Pauridiunthu P . cunthiiflora Hook.: Gabon, Nigeria, Cameroon, Congo (1,2) P. microphylla R. Good: Angola, Congo (1,2) P.pyrumiduta (K. Krause) Brem.: Gabon, Congo, Cameroon ( 1 2 ) P. Afzelii (Hiem) Brem.: Nigeria (1,2) P. Bequertii de Wild.: Gabon (1,2) P. Holstii K. Sch.: Tanzania, Zaire, Kenya (1) P . symplocoides S . Moore: East Africa ( I ) P . divaricuta K. Sch.: Gabon, Nigeria, Cameroon ( 1 2 ) P. sylvicolu (Hutch. et Dalz.) Brem.: Guinea to Ghana (1,2) P . puucinetvis Hiern: Fernando Po0 (1) P . micrunthu (Hiern) Brem.: Gabon (I,.?) P . mult#ora K. Sch.: Cameroon (1,2) P . muyumbensis (R. Good) Brem.: Gabon, Congo (I,2) P. bitocularis (R.Good) Brem.: Congo ( 1 , Z ) P . Cluessenssii Brem.: Zaire ( I ) P. butaguensis (de Wild.) Brem.: Uganda, Kenya ( 1 ) P . kisuensis Brem.: Gabon, Congo, Zaire ( I ) P . Dewevrei (de Wild. et Th. Dur.) Brem.: Gabon, Congo, Zaire (1,2) P . insculptu (Hutch. et Dalz.) Brem.: Nigeria ( I ) P . Lyallii (Baker) Brem.: Madagascar (1,3,4) P . rubens (Benth.) Brem.: Gabon, Niger, Cameroon (I,2) P. hirtella (Benth.) Brem.: Guinea to Cameroon, Niger ( f ) P . cullicurpoides (Hiern) Brem.: Gabon, Congo, Cameroon (I,2) P. viridifloru (Sch. ex Hiern) Hepp.: Nigeria to Uganda, Congo (2) P. insularis (Hiern) Brem.: Annobon island (I) P. floribundu (K. Sch., K. Krause) Brem.: Gabon, Cameroon ( 1 2 ) P. venustu N. HallC: Gabon (2) P. efferuta N. HallC: Gabon (2) P. siderophylla N. HallC: Gabon (2) P . verticilluta (de Wild. et Dur.) N. HallC: Gabon (2)

type alkaloids may be ascribed, at least partly, to the “magic” properties of suspension barks in alcohol, yet little is known about the compounds responsible for the reported therapeutical activities. The chemical and related studies undertaken mainly on the indole alkaloids (8)of the four major species commonly used in native medicine, namely, P . callicarpoides, P . Dewevrei, P . mayumbensis, and P . Lyallii, have brought no answer to this question.

11. Taxonomic Position of the Genus Pauridiantha The classification into subfamilies, tribes, and genera of the very large family Rubiaceae has been the subject of much controversy, and is still far from being definitive. Typically, the relative position of the genus Pauridiantha has

2. THE ALKALOIDS FROM PAURIDIMHA

225

changed, depending on the criteria retained. The f i s t classification was primarily based on morphological characters, namely, the number of ovules in each ovary locule. Following this definition, the genus Pauridiantha was placed in the subfamily Cinchonoideae, the group which is characterized by two or more ovules per ovary locule. They were a part of the tribe Mussaendeae, near the Gardeniae and the Naucleae, and belonged to the subtribe Urophylleae (1,2). A more recent subdivision, defended by Verdcourt (9,10),and on a slightly different basis by Bremekamp ( I I ) , made use of the presence or absence of raphides as a major characteristic. Subsequently, Pauridiantha has been moved to the subfamily Rubioideae, while the tribe Mussaendeae still remained in the subfamily Cinchonoideae. Therefore, the Urophyllae became a tribe of their own, near the Psychotrieae. It is clear that the use of a limited number of morphological characters may lead to artificial subdivisions in a family as complex as the Rubiaceae, and thus to an erroneous classification. A thorough understanding of plant interrelationships requires the accumulation and comparison of numerous data originating from complementary disciplines, e.g., anatomy, cytology. The contribution of chemotaxonomic correlations may be of help for clarifying the present situation.

111. Alkaloids in the Genus Puuridiunthu

Four major classes of alkaloids have been found in the Pauridiantha species studied. The first class consists of harman and harman-type alkaloids, which appear to be ubiquitous in this genus. As far as chemotaxonomic considerations are concerned, it can be noted that these alkaloids have also been found in at least four tribes of the subfamily Cinchonoideae, namely, Naucleae (12), Cinchoneae (13),Gardenieae (Id), and Rondeletieae (12),and in two tribes of the subfamily of Rubioideae as defined by Verdcourt, namely, in the Urophylleae (15) and in the Ophiorrhizeae (12). Formerly, the Ophiorrhizeae were a part of the Hedyotideae, a tribe classified near the tribe Mussaendeae in the subfamily Cinchonoideae (2). The other three classes of alkaloids arise from the complex iridoid tryptamine biogenetic pathway. The majority of the alkaloids which have been characterized from the Rubiaceae have the same early precursor. An alternative pathway, involving dopamine instead of tryptamine (16),leads to emetine-type alkaloids, which were found only in Cephaelis, a member of the tribe Psychotrieae. A. HARMAN-TYPE ALKALOIDS Harman (1)has been isolated from all parts of many of the indole alkaloidbearing plants and from some of other plant families. Its skeleton is of the

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R'O J J J N

(tryptophan + C,) type, and harman is often associated with other tricyclic pcarboline alkaloids, such as harmine (2), and hannaline (3). In the genus Pauridiantha, however, harmine (2) and harmaline (3) seem to be absent, harman (1) being accompanied instead by a 3-carboxy derivative norharman (4). Norharman (4) leads to 5 in the course of extraction with ammonia, similar to the transformation described by McLean and Murray (17) in the case of barks of Nauclea diderrichii, another genus of the family Rubiaceae. Harman itself is the most abundant alkaloid found in the plants studied. As an example, it represents about 16, 8, and 5% of the alkaloids extracted from the root bark, trunk bark, and leaves, respectively, of P . Lyallii. Along with the harman compounds, the substituted pyridine 6, already characterized by McLean and Murray (13, has been isolated from P . Lyallii.

B. INDOLEF'YRIDINE-TYPE ALKALOIDS Root bark of P . callicarpoides contains, beside harman, two main alkaloids in which a P-carboline group is linked to a pyridine ring, namely, pauridianthine (7) and its pentacyclic isomer pauridianthinine (8) (15). These two compounds are absent in P . Lyallii, in the root and stem bark of which occurs a reduced analog, pauridianthinol (9) (18). The chemotaxonomic relationship between P . callicarpoides, a plant found in the Congo, and P . Lyallii, growing exclusively in Madagascar, is thus established. Apart from these structurally related alkaloids, P . Lyallii contains a number of other compounds exhibiting, instead of a pyridine unit, either a dihydropyridine ring or a pyridone ring, both of which have a characteristic methylcarboxy group at the C-16 position. Lyaline (10) and lyadine (11) (19),which are representative of the dihydropyridine-bearing class of compounds, are found in all parts of P . Lyallii, while lyalidine (12) and hydroxylyalidine (13) (20) are extracted exclusively from root bark. A few chemical conversions between members of these alkaloids have been

2. THE ALKALOIDS FROM P A U R I D I M H A

O?&

CH,O,C 13

227

0 \

NH

carried out in order to support their structural elucidation, which was essentially based on lH-NMR and mass spectroscopy. (1) Compounds having a carbonyl group at C- 14 disclose a typical fragmentation pattern in mass spectrometry, where the P-carboline-derived ions at mass 167 and/or 168 and 140 (P-carboline - HCN) are observed. On the other hand, compounds 10 to 13 and their derivatives exhibit a specific fragmentation with hydrogen transfer to give an

228


abundant peak at mlz 182, corresponding to harman. (2) The presence of two doublets (coupling constant 5 Hz) in the 'H-NMR spectrum of each of these alkaloids is consistent with an aromatic C ring. The chemical shift assigned to H-6 and to H-5 ranges between 7.6 and 7.8 ppm for the first proton and between 8.1 and 8.35 ppm for the second one. The pertinent 'H-NMR data regarding the nitrogen-containing moiety of alkaloids 7 to 12 are listed in Table 11. It is interesting to note that the presence of a dihydropyridine unit, analogous to the one observed in lyaline (10) and lyadine ( l l ) , has also been identified in nauclefoline (14), an alkaloid isolated from the leaves of Nauclea lutifolia (21). On the other hand, the structural analogy between the angustine bases (15) and

:1

-

15

pauridianthine (9) is striking, and should bear some chemotaxonomic significance. Angustine bases are found in a number of species of Strychnos (22,23) and Nauclea (23-26); for example, naucletine (15, R = COMe, R' = H) occurs in N. latifolia (24), and nauclefine (15, R = R' = H) has been isolated from both N. latifalia and N. Pobeguinii (26). It is reasonable to assume that the unique precursor of angustine bases is strictosidine lactam (16), the intramolecular cyclization product of strictosidine (17). The prerequisite for cyclization is the presence of a secondary amino group in the C ring of strictosidine, that is to say, the presence of a hydrogen atom on N-4. Indeed, compound 18, the N-benzyl-substituted aglycone of strictosidine, is not subject to cyclization, but is rather in equilibrium with the open form (19) (27). Similarly, replacement of a tetrahydro-P-carboline unit, such as one finds in strictosidine, by a P-carboline moiety inhibits the cyclization step and thus leads to tetracyclic derivatives, typical of the alkaloids of the genus Pauridiantha . In summary, strictosidine (17) is likely to be the unique precursor of angustine bases (15) on the one hand and of alkaloids 7 to 13 on the other. The alternative pathway which produces cyclization to strictosidine lactam, namely, aromatization of the C ring, should most probably occur at an early stage of the biosynthetic route to the indole alkaloids of Pauridiantha. The replacement of the oxygen atom of the secologanoside moiety (20) of strictosidine by a nitrogen atom in angustine bases 15 and in compounds 7 to 13 raised the question of their natural Occurrence in plants. The usual extraction

TABLE I1 IH-NMR Chemical Shiftsu and Coupling Constants of Pauridianthine (7), Pauridianthinol (9), Lyaline (lo), Lyadine ( l l ) , and Lyalidine (12) Proton

7

9

11

12

1.42 6.43

5.55

10

3.41

14a

= l8

J14*14b

HZ

3.53

14b

= 10 HZ 2.43 1 = 4 ~3.5 HZ

JlSl4b

15 J 1 ~

16 17

18a 18b 19 21

2.61 9.18

5.90 8.63

JZI-NH

COOMe NH Chemical shifts (ppm), in CDC13 from TMS, recorded at 250 MHz.

= 5 HZ

3.74

3.81 7.86

230


16 -

w

OGlu

procedure, namely, the use of ammonia, may be responsible for their immediate synthesis in v i m (Fig. l), as suggested for the observed transformations of loganin 21 (28) and of swertiamarin 22 (29). More recently, however, naturally occurring cantleyine has been described, as well as its oxygen-containing congeners (30). There is yet no definite proof of the in vivo synthesis of these pyridino-indoloalkaloids; however, several arguments militate in favor of this hypothesis. (a) Some experiments have been performed with extraction procedures involving alkalies other than ammonia. No major qualitative or quantitative difference in the alkaloid distribution has been observed (31,32).It is therefore unlikely that pyridine-containing alkaloids are artifacts. (b) The action of ammonia on a glucosidic precursor, followed by acidic treatment, seems to lead readily to fully aromatic derivatives, such as cantleyine and gentianine. Besides, the occurrence of the lactam lyalidine (12) and hydrox-

2. THE ALKALOIDS FROM PAURIDIANTHA

23 1

FIG. 1. Examples of the formation of artifacts during the extraction procedure.

ylyalidine (13) can hardly be explained by chemical amination of lyaloside (23), their likely precursor. (c) The structural similarity between oxylyadine (24), the photochemically induced oxidation product of lyadine (ll),and pauridianthinol (9), on the one side, and camptoneurine (25), on the other, is striking. It is stated (33,34), however, that camptoneurine, originally obtained from Strychnos camptoneura, is not an artifact.

23 -

232

R. A. JACQUESY AND J. LEVHQUE

C . GLUCOALKALOIDS The glucoalkaloids extracted from different parts of species of Pauridiantha may be divided in two subclasses, depending on the species studied. Pauridianrha Lyallii contains lyaloside (23) in all parts of the plant, but accumulation in the root bark is observed (31). In the leaves, two epimeric glucoalkaloids, namely, pauridianthoside (26, R = H) and isopauridianthoside(27, R = H), are present in addition to lyaloside (35-37). Pauridiantha Dewevrei and P . mayumbensis lack these three glucoalkaloids, but two other compounds are isolated, especially from the leaves, cadambine (28) and dihydrocadambine (29). No glucoalkaloids were found in P. callicarpoides, in which glucocoumarins are abundant instead.

OR

233

2. THE ALKALOIDS FROM PAURIDIAhTHA

1. Alkaloids Containing Seven-Membered D Ring Cadambine (28) and its congener (29) are characterized by a seven-membered ring, in which N-4 is joined to C-18. The absolute configuration of each of the chiral centers present in these compounds is consistent with a biosynthetic precursor derived from strictosidine, (S)-18,19-epoxy-strictosidine(30) (38). Cadambine as well as some of its analogs are found in a number of species of Naucleae, e.g., Nauclea latifolia (32), Nauclea diderichii (39,40), and Anthocephalus cadamba (38,41,42). Pertusadina euryncha (= Adina rubescens) (43,44)contains rubenine (31), a glycoside structurally related to dihydrocadambine.

31

-

R'

OCH,

OCH,

354

Among. the reported cadambine-type alkaloids should be included several natural non-glucosidic derivatives, such as 32 (40),nauclefoline (14), and the numerous compounds of basic skeleton 33 [e.g., naufoline, R = R' = H (21,26); nauclechine, R = CO,Me, R' = OH (21,45,46)] found in various species of Nauclea. Again, chemotaxonomic correlations seem to favor a reassembling of the genus Pauridiantha and the tribe Naucleae into a unique subfamily. 2. Glucoalkaloids Having a P-Carboline Moiety P-Carboline-containing glucoalkaloids can be divided into two subgroups, depending on whether or not they have a carbonyl function at the C-14 position.

234


To the first subgroup belong pauridianthoside (26), to which pauridianthine (7) and pauridianthinol (9) are obviously related, and isopauridianthoside (27). Acetylation of the sugar moiety is necessaq to achieve separation of the two epimers, of which the UV, IR, and mass spectra are identical (3637).Their 'HNMR spectra, however, are substantially different, the glucosidic protons as well as the terpenic ones showing very specific chemical shifts and coupling constants, depending on the stereochemistry of the chiral centers (Table 111). On biosynthetic grounds, a 15 (S) configuration has been assigned for the two compounds. The weak coupling constant (3 and 1 Hz, respectively) for H-15 and H-20 is consistent with quasi-orthogonalhydrogen atoms, and is therefore indicative of a 20~-configurationin both alkaloids. On the other hand, a dramatic difference is observed for the H-20-H-21 coupling constant. Pauridianthoside

TABLE 111 'H-NMR Chemical Shiftso and Coupling Constants of Pauridianthoside (26, R = Ac) and Isopauridianthoside (27, R = Ac) Proton 5 6 9 10 I1 12 15 17 18a 18b 19 20 21 COOMe 1' 2' 3' 4' 5' 6'a 6'b

26 (R = Ac)

27 (R

=

Ac)

7.52 JiI-lZ = 8 HZ 7.52

Ac

a

Chemical shifts (ppm), in CDC13 from TMS, recorded at 250 MHz.

235


(26, R = Ac), with a constant of 6.5 Hz, can be correlated to the regular a,a,P stereochemistry encountered in all secologanin-derived alkaloids; isopauridianthoside (27, R = Ac), with its small coupling constant of 1.8 Hz, more likely belongs to the a,a,aseries. Furthermore, while a W-type long-range coupling, J,,-,, ,is observed in the 'H-NMR spectrum of pauridianthoside (26, R = Ac), the isomeric 27 (R = Ac) lacks this coupling, as a result of a corresponding dihedral angle of about 70°,but in turn diplays a Weak dlyk coupling for J,,-,, of 0.6 Hz (47). As is clearly seen in Table III, not only coupling constants but also chemical shifts are of great significance for configurational and conformational studies of this type of compound. Dreiding models and a Newman projection along the C-20-C-21 axis are particularly revealing (Fig. 2). It appears at first that the oxygen atom of the heterosidic link is closer to the vinylic double bond in isopauridianthosidethan in pauridianthoside. As a consequence, the C- 18 hydrogen atoms, and to a lesser extent that at C-19, are expected to be significantly deshielded as compared with the corresponding protons of pauridianthoside. The deshielding is dramatically important for the 18a hydrogen (0.82 ppm), which is therefore lying closer to the C-0-glucose linkage than do the cis 18b and 19 hydrogen atoms. This result implies restricted rotation around the C-20-C-19 bond in these conformationally flexible molecules. In turn, the C-15-H and C-2 1-0-glucose bonds assume an approximate 1-3 diaxial interaction in pauri-

I

& CHpOC

2

CH,OOC

A

H@-j H

B

Gt,

0-Glu

FIG. 2. Dreiding models and Newman projections of the terpenic unit present in pauridianthoside (26) (A) and in isopauridianthoside (27) (B).

236


dianthoside which should lead to the deshielding of the hydrogen linked to the C-15 carbon atom, relative to the same hydrogen atom in the epimeric isoalkaloid. Such a deshielding (0.54 ppm) is indeed observed. Last, it has often been reported that in most secologanoside-derived compounds, such as iridoids and glucoalkaloids, the hydrogen atoms of the glucosidic unit, especially those located at the 2, 3, and 4 positions, are hardly differentiated. Pauridianthoside follows the general rule, but, because of its configurational peculiarity, isopaurithianthoside exhibits a different behavior. All hydrogen atoms of its glucosidic unit have been identified, by the way of a systematic sequential irradiation starting from the hydrogen 1' , which resonates as a characteristic doublet (J1,-2,= 8 Hz). The 13C-NMR spectra of the two epimers are very similar (see below, Table IV) and deserve no special comment. The inversion of configuration at C-21 does not notably affect the chemical shifts of the carbon atoms of the monoterpenic and of the sugar units. Lyaloside (23) appears to be a glucoalkaloid structurally close to pauridianthoside (26) (35,37). Only the salient features of its 'H-NMR spectrum TABLE IV 13C-NMR Chemical Shifts" of Harman (l),Secologanoside (20, R = Ac), Lyaloside (23, R = Ac), Pauridianthoside (26, R = Ac), and Isopauridianthoside (27, R = Ac) Carbon

1

2 3 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

140.5 142.0 137.3 112.2 121.1 127.2 121.2 119.0 127.5 111.5 134.6 18.4

COOMe COOMe

20

,198.6

43.0 25.0 109.2 150.9 120.7 131.9 43.5 95.6 166.3 51.0

23

26

27

140.31 143.82 137.33 112.40 121.04 126.90 121.45 119.02 127.63 111.82 134.56 32.12 30.06 109.98 151.53 118.61 134.04 42.99 95.90 166.65 50.66

135.36 141.09 138.21 121.55 120.52 131.32 119.03 120.52 129.05 112.12 135.02 201.78 38.99 108.96 150.89 119.55 132.53 42.42 95.82 51.40 167.00

135.82 141.71 137.52 121.71 120.62 131.67 118.79 120.41 129.12 112.59 134.79 199.45 41.64 106.51 151.21 118.13 134.79 41.39 95.04 51.64 167.29

" Chemical shifts (ppm), in CDCI3 from TMS, recorded at 68.86 MHz

237


(37,57) will be discussed. The replacement of a carbonyl group at the C-14 position by a methylene group has a profound effect mainly on H-15 and H-20, which are shielded by 2.1 and 0.9 ppm, respectively. On the contrary, a small deshielding effect, ranging between 0.2 and 0.4 ppm, is observed for the three vinylic protons. This means that H-15 is most probably lying in the plane of the trigonal carbon atom of the carbonyl group, while the double bond should be above or below this plane (48).To account for these data, it must be assumed that rotation not only around the C-20-C-19 bond but also around the C-15-C-14 bond bond may be restricted in the case of pauridianthoside. As far as biosynthesis is concerned, it is clear that lyaloside (23) and pauridianthoside (26) readily derive from strictosidine (17). These three molecules display identical stereochemistry at the three chiral centers, namely, a,a,pfor the hydrogen atoms at the 15, 20, 21 positions, respectively. They are closely related to a number of glucoalkaloids identified in Pertusadina euryncha (= Adina rubescens), e.g., rubenine (31) and desoxycordifoline (34, R = H) (49), and in Adina cordifolia, e.g., cordifoline (34, R = OH) (50). Palinine (35),

-

34

OH

-

35

isolated from Palicourea alpina, a member of the Psychotrieae, shows the same basic structure (51). On the other hand, the occurrence of isopauridianthoside, an (Y,(Y,(Y epimer, is unusual enough to raise the question of its origin. It is now well known that glucolysis of strictosidine (17)(52,53) gives an unstable dialdehydic intermediate. Intramolecularcyclization may then lead to harman-derived compounds with concomitant isomerization of the vinylic double bond (31,54,55),as illustrated in Fig. 3. Consequently, it seems unlikely that biosynthesis of isopauridianthoside implies a complex pathway involving, successively, enzymatic deglucosylation, opening of the iridoid ring followed by epimerization at the 21 position, recyclization of the monoterpenic ring, and, finally, enzymatic reglucosylation. Most probably, such a pathway would lead to an ethylenic instead of a vinylic compound. Significantly, a few ethylidene-containing iridoids have been isolated and characterized (56).An alternative hypothesis would involve two different metabolic pathways deriving from the same iridoid alkaloid: the major one

238


FIG. 3. Intramolecular cyclization following the deglucosylation of the monoterpenic unit of glucoalkaloids.

leading to secologanoside, and the minor route leading to the hypothetical isosecologanoside (36), itself the precursor of an unknown isostrictosidine.

6 HNt'

CH&C

\ o

OGlu

:3

D. ALKOYL-GLUCOALKALOIDS Finally, a fourth class of alkaloids has been discovered, apparently specific to the leaves of P. Lyallii (57). It consists of two unseparable products, 37 and 38, in the ratio 2 to 1, which readily give lyaloside (23) on mild methanolysis, along with two esters, namely, methyl ferulate and methyl sinapate (39 and 40, respectively). Elucidation of their structure was essentially based on NMR considerations (57). Graphical correlations between 'H- and 13C-NMR spectra, associated with analysis of the residual constant coupling during a step by step [200 Hz per 200 Hz from 0 (TMS) to 2000 Hz] off-resonance procedure, permitted the precise assignment of all the carbon atoms of the products (58). The characteristic pattern of the harmane monoterpene moiety of the mixture of molecules, lyalosidoferine(37) and lyalosidosinapine(38) (R = H or R = Ac), is easily recognized in the 'H-NMR spectrum of the mixture. Interestingly, the usually complex multiplet displayed by protons H-15, H-19, and H-20 are clearly resolved as a doublet of doublets (J15-14a= 10 Hz; J15-,,, = 0 Hz; J15-20 = 6.5 Hz) at 3.3 ppm, a doublet of triplets (J19-20= J19-18b= 9.5 Hz; J19-18a= 17.5 Hz) at 5.7 ppm, and a doublet of triplets = 9.5 Hz; 15 = 6.5 Hz) at 2.6 ppm, respectively. The chemical shifts of the corresponding carbon atoms of this part of the molecules are similar to those of harman (59,60),secologanoside (61),lyaloside, pauridianthoside, and isopauridianthoside (Table IV) . Alkoyl substitution in compounds 37 and 38 is assumed to occur on the primary alcohol of the sugar part of lyaloside, namely, at the 6' position, on the following grounds. The 'H-NMR spectrum of the mixture lacks the triplet (J = 6

+

239


OH

33

R = H

-

R

40

noW

=

OCH,

O CH, OCH,

Hz) at 4.81 ppm present in the spectrum of lyaloside and which disappears after addition of heavy water. In addition, the two hydrogen atoms at the 6’ carbon atom are deshielded by 0.4 to 0.6 ppm in the spectrum of the mixture 37 + 38, as compared with their chemical shift in the spectrum of lyaloside. A similar effect is observed by Sticher et al. for glucoiridoids (62). Furthermore, the chemical shift of the carbon atoms of the sugar moiety undergo the effect expected as a result of alkoylation, e.g.. the shielding of the ct carbon (C-67, and the deshielding of the p carbon (C-5’) (Table V). For comparison, the data published for catalpol (41) and its 6’-trans-cinnamate derivative, picroside (42) (62,63), are also listed in Table V.

H

o CH,OH @ o

~

O

H

OR

240

R. A. JACQUESY AND J . LEVESQUE

TABLE V W-NMR Chemical Shifts0 of the Glucose Moieties of Lyaloside (23, R = Ac), Pauridianthoside (26, R = Ac), Isopauridianthoside (27, R = Ac), the Mixture of Lyalosidoferine and Lyalosidosinapine (37 + 38), Catalpol (41), and Picroside (42) Carbon

23

26

27

1'

98.79 73.08 77.29' 70.10 76.83' 61.17

95.94 70.69 72.61 68.18 72.28 61.71

95.28 70.52 73.47 67.73 72.28 61.69

2' 3' 4' 5' 6' a

37

+ 38

99.61 73.37 76.85 70.52 74.52 63.60

41

42

99.74 74.82 78.54* 71.74 77.70* 62.90

99.72 74.68 77.40 71.48 75.77 64.15

Chemical shifts (pprn), in CDC13 from TMS, recorded at 68.86 MHz.

A limited number of alkoyl-glucoalkaloids have been reported in the literature so far. The first specimen of this class of compounds to be isolated was rubescine (43), which was found in Adina rubescens (64). More recently another esterified vincoside lactam, rhynchophine (44),was extracted from the leaves of Uncaria rhynchophylla, a member of the tribe Cinchoneae (65). Thus, chemotaxonomic correlations again tend to raise the question whether Pauridianthu should not join, along with Adina and Uncaria, the tribe Naucleae. Despite some differences both in the alkoyl residue itself, either caffeoyl, feruloyl, or sinapoyl, and in the position of alkoylation of the glucose moiety, either C-3' in the case of rubescine or C-6' in the case of rhynchophine, lyalosidoferine, and lyalosidosinapine, the analogies observed between these four alkaloids are important enough to deserve further comment. In all cases, the alkoyl residue is characterized by the presence of a free hydroxyl function at the para position of the aromatic ring. A similar situation is observed in the case of flavonoids (57,66,67), but is not encountered in the case of most alkoyl-iridoids, which are more frequently cinnamoyl rather than caffeoyl derivatives (57,63). On the other hand, all alkoyl-glucoalkaloids up to now have been found exclusively in leaves, where flavonoids also accumulate. These results seem to support the idea of alkoylation arising at a late stage of the whole process of biosynthesis of this type of compound. In other words, the alkoyl-glucoalkaloids should not be synthesized from some alkoyl-secologanoside analog, but should rather result from alkoylation of the glucoalkaloids. The precise function in plants of alkoyl-glucoalkaloids has not yet been studied. They may be useful as intermediate alkaloid carriers and/or an alkaloid reservoir. Transportation, as well as release, may imply a complex processes involving, for instance, reversible binding with ligninlike macromolecules. It is indeed tempting to consider that the structural similarity between the alkoyl substituents of the glucoalkaloids and the basic units of lignin, e.g., syringyl and

241

2. TKE ALKALOIDS FROM PAURIDIANTHA

'CH,OH

-

43

'OCH,

guaiacyl groups (57,68), is not accidental. The presence of a free hydroxyl group may be necessary to ensure efficient linkage between the different molecules, perhaps through reversible glucosylation, as observed in the cases of syringine, liriodendrine, and other similar Iignans (57,69,70). In such an hypothesis, lyaloside would be synthesized mainly in the roots where it is particularly abundant, then transported to the leaves in which its oxidized derivatives, e.g., pauridianthoside and pauridianthinol, are found.

IV. Biosynthesis In the course of this chapter devoted to the alkaloids of Pauridiantha, their biosynthesis has been mentioned and some chemotaxonomic correlations have been proposed. As all glucoalkaloids described here derive from strictosidine, a more systematic analysis of its metabolic evolution in plants seems of interest.

242

R. A. JACQUESY AND J . LEVESQUE

"/

Alkoylation Lyalosidoferine .t-

Lyalosidosinapine

W N V N

H

p

I

/

Pauridian thoside Palicourea

OH

(Psychotrieae)

/ UROPHYLLEAE

PSYCHOTRIEAE

SCHEME

1

Present knowledge suggests that four different pathways involve strictosidine as a common precursor of numerous glucoalkaloids found in various Rubiaceae (Scheme 1). Pathway A implies an early dehydrogenation step leading to an aromatic C ring. The outcome in Pauridiantha (Urophylleae) is the Occurrence of lyaloside, its alkoylated derivatives lyalosidoferine and lyalosidosinapine, and pauridianthoside. Clearly, a similar pathway explains the formation of palinine, a glucoalkaloid extracted from Palicourea (Psychotrieae). A similar scheme could be drawn, using a trytophan rather than a tryptamine unit in a hypothetical precursor analogous to strictosidine. Pathway A would then lead to the cordifoline-type glucoalkaloids found in Adina (Naucleae), whose structure, as

2.

Pauridiantha (Urophylleae) Nauclea, Adina (Naucleae)

UROPHYLLEAE NAUCLEAE

THE ALKALOIDS FROM PAURIDIAhTHA

u

243

NAUCLEAE

SCHEME1 (Continued)

already mentioned, is strikingly close to lyaloside. Finally, because of the presence of the aromatic C ring, no epimerization at C-3 can take place in pathway A-derived compounds. In the case of pathways B to D, a different situation will be encountered where such a process may occur, leading either to strictosidine lactam or to the 3-epimeric vincoside lactam. Pathway B is characterized by intermediate formation of epoxystrictosidine and N-4-C- 18 bonding leading to cadambine-type glucoalkaloids. As already mentioned, such compounds have been found in two species of Paur~dian~ha (P. Dewevrei and P . mayumbensis) and in various species of Nauctea and Adinu of the tribe Naucleae. Pathway C is very similar to pathway B. In this case, however, bonding occurs between N-4 and C-19, leading to a six-membered instead of a seven-membered D ring. To our knowledge, the resulting isocadambine-type glucoalkaloidshave been found only in the genus Anzhocephalus (Naucleae) (71).

244

R. A. JACQUESY AND I . LEVFSQUE

B

A LYALOSIDE Type

CADAMBINE Type

Urophylleae (Pauridiantha)

Naucleae

0

Lyalidine (P. Lyallii)

Lyaline

PAURIDIANTHOSIDE

1 - Nauclechine 2

Pauridianthinol (P. Lyallii)

-

Nauclefoline

/N

SCHEME2

Pathway D implies rotation around the C-14-C-15 bond, followed by lactamrzation. Vincoside lactam is the precursor of esterified derivatives, e.g., rubescine found in Adina (Naucleae) and rhynchophine found in Uncuriu (Cinchoneae). These compounds are alkoyl-glucoakaloids, as are lyalosidoferine and lyalosidosinapine found in Pauridiuntha (Urophylleae). In the state of the art, Scheme 1 shows that the number of Rubiaceae containing glucoalkaloids derived from strictosidine is limited to members of the

2. THE A L W D S FROM PAURIDIANTHA

D

C ISOCADAMBINE Type Naucleae

245

STRICTOSIDINE Laclarn Typc

To Naucleae and Loganiaceae

HC

0

CH3

Naucleidinal and Epinaucleidinal (Nauclea)

Cadamine

Angustine bases (Milragpa, Nauclea, Uncaria Strychnos)

Camptoneurine

SCHEME2 (Continued)

Urophylleae, Psychotrieae, Naucleae, and Cinchoneae. Only some genera of each of these tribes are concerned and constitute thus a rather homogeneous group: Adina, Anthocephalus, Nauclea, Uncaria, Pauridiantha, and Palicourea. A later stage in the in vivo transformation consists of the action of @-glucosidase, which is the essential step linking the glucoalkaloid-type precursor to the aglycone-type alkaloids. When hydrolysis occurs on stristosidine itself, a number of alkaloids are formed, which undergo unusually complex skeletal

246

R. A. J A C Q W Y AND J. LEVESQUE

rearrangements, as observed in the cases of many Apocynaceae, Loganiaceae, and Rubiaceae. When hydrolysis takes place on the modified glucoalkaloids depicted in Scheme I , it appears that the basic skeleton of the precursor remains essentially unchanged. Scheme 2 displays the most significant structures of the alkaloids found in different members of the Rubiaceae which contain glucoalkaloids deriving from strictosidine. The biosynthetic sequences involved are clearly very similar, even when some intermediates are absent in one or another group. As an example, enzymatic hydrolysis is expected to provide alkaloids containing an oxygenated monoterpenic moiety, structurally close to the genuine secologanin. This class of compound is seldom found, except in the pathway Dderived alkaloids. Most such compounds, however, are unstable, as demonstrated by unsuccessful attempts at synthesis, but may well exist under more favorable conditions, e.g., in the plants themselves. In the genera of the Rubiaceae considered, the most frequently isolated alkaloids are actually nitrogen-containing monoterpenoid derivatives. Various states of oxidation of the E ring, and eventually the D ring, are observed; however, the skeletal variations are limited, the ultimate state apparently being the loss of the carbomethoxy function. Interestingly, angustine bases are found in various genera of the Rubiaceae, but also in about 30 species of Strychnos (Loganiaceae), showing the continuity that exists between the Loganiaceae and the Rubiaceae. In this respect it may be relevant that only three alkaloids containing a carbonyl function at the 14 position have been isolated so far: camptoneurine, from Stychnos camptoneura; pauridianthineand pauridianthinol, from P. callicarpoides and P. Lyallii, respectively (72). V. Conclusion The alkaloids found in various species of the genus Pauridiantha are characterized by a nonrearranged secologanin skeleton, with an (S) chirality at C-15 in the nonaromatic E ring compounds. Various stages of oxidation are encountered, depending on the plant studied and on the part of the plant. This lack of “chemical complexity” may be related first to C ring aromatization occurring at an early stage of the metabolism of strictosidine, thus preventing further complex rearrangements. The only deviation from this pathway affords cadambine and dihydrocadambine, which are found in some species. Again, no extensive modification of the basic skeleton of the precursor strictosidine is observed. The structural homogeneity of the alkaloids from Pauridiantha can also be connected to a glucolysis step occurring at a late stage of the biosynthetic evolution. As a consequence, glucoalkaloids are abundant in most Pauridiantha species, but their structure remains primitive, e.g., they are close to that of strictosidine, the first of the alkaloids formed in vivo. This biosynthetic dead end can


247

be bypassed through the biosynthesis of alkoyl-glucoalkaloids. Similarly, rubescine and rhynchophine evolve from the unmodified basic vincoside lactam. Pauridiantha appears, therefore, to be a genus in which the biosynthetic pathways are limited in number and are stopped at primitive alkaloids. It follows a lack of structural specificity, permitting chemotaxonomic correlations with other plants characterized by the same features. From this point of view, the genus Pauridiantha resembles not only many Nauclea, but also a number of Strychnos.

REFERENCES C. E. G. Bremekamp, Bot. Juhrb. 71, 200 (1940). N. HallB, ‘‘more du Gabon,” Vol. 12. Museum National D’Histoire Naturelle, Paris, 1966. J. G. Baker, Flora of Madagascar, J. Bot. Soc. Lin. 20-25 (1888). P. Boiteau, Fitoterupia 3, 113 (1975). A. Bouquet, Thkse Doct. Univ. de Pharmacie, Paris, 1970. A. Bouquet, “FCticheurs et MBdecines Traditionnelles du Congo (Brazzaville)” (Memoire O.R.S.T.O.M. No. 36). Paris, 1969. 7. P. Boiteau, Fitoterupia 1, 29 (1976). 8. R. W. Brimblecombe, in “Advances in Drug Research” (A. B. Simonds, ed.), Vol. 7, p. 170. Academic Press, London and New York, 1973. 9. B. Verdcourt, Bull. Jurd. Bot. Brux. 28, 209 (1958). 10. B. Verdcourt, in “Tropical East Africa,” pp. 1-415. Crown Agents for Oversea Governments and Administrations, London, 1976. 11. C. E. B. Bremekamp, Actu Bot. Neerl. 15, 1 (1966). 12. R. Hegnauer, “Chemotaxonomie der Wantzen,” Vol. 6, pp. 130-145. Birkhauser, Basel, Stuttgart, 1973. 13. R. R. Raffauf, “A Handbook of Alkaloids and Alkaloid Containing Plants.” Wiley (Interscience), New York, 1970. 14. J. D. Phillipson, S. R. Hemingway, and C. E. Risdale, Lloydiu 41, 503 (1978). 15. J. L. Pousset, A. Bouquet, A. Cavt, A. CavB and R. R. Paris, C. R. Acud. Sci. Paris, Ser. C 272, 665 (1971). 16. A. R. Battersby, N. G. Lewis, and J. M. Tipett, Tetrahedron Len., 4349 (1978). 17. S. McLean and D. G. Murray, Can. J . Chem. 48, 867 (1970). 18. J. L. Pousset, J. Levesque, A. Cave, F. Picot, P. Potier, and R. R. Paris, Plant Med. Phytother. 7 (l), 51 (1974). 19. J. Levesque, J. L. Pousset, and A. CavB, C. R. Acud. Sci. Puris, Ser. C 278, 959 (1974). 20. J. Levesque, J. L. Pousset, and A. C a d , C. R. Acud. Sci. Paris, Ser. C 278, 1053 (1974). 21. F. Hotellier, P. Delaveau, and J. L. Pousset, C. R. Acud. Sci. Paris, Ser. C 293, 577 (1981). 22. T. Y. Au, H. T. Cheung, and S. Sternhell, J. Chem. Soc., Perkin Trum. I , 13 (1973). 23. J. D. Phillipson, S. R. Hemingway, N. G. Bisset, P. J. Houghton, and E. Shellard, Phytochemistry 13, 973 (1974). 24. F. Hotellier, P. Delaveau, and J. L. Pousset, Phytochemistry 14, 1407 (1975). 25. M. Sainsbury and B. Webb, Phytochemistry 14, 2691 (1975). 26. M. a c h e s , B. Richard, L. Gueye-MBahia, L. Le Men-Olivier, and C. Delaude, J. Nut. Prod. 48,42 (1985). 27. R. T. Brown and C. L. Chapple, J. Chem. Soc., 740 (1974). 1. 2. 3. 4. 5. 6.

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R. A. JACQUESY AND J. LEVEsQUE

28. N. G. Bisset and A. K. Choudhury, Phytochemistry 13, 265 (1974). 29. A. L. Skaltsounis, S. Michel, F. Tillequin, M. Koch. J. Pusset, and G. Chauvitre, Helv. Chim. Acra 68, 1679 (1985). 30. M. Koch, M. Plat, J. Le Men, and M. M. Janot, Bull. Soc. Chim. Fr. 27, 229 (1964). 31. J. Levesque, T h h e de Doctorat en Pharmacie, Universitk de Poitiers, 1977. 32. F. Hotellier, Thsse de Doctorat es Sciences Pharmaceutiques, Universitk de Paris y, 1980. 33. M. Koch, J. Gamier, and M. Plat, Ann. Pharm. Fr. 30, 299 (1972). 34. R. Verpoorte and A. Baerheim Svendsen, J. Pharm. Sci. 67, 171 (1978). 35. J. Levesque, J. L. Pousset, and A. Cav6, C. R. Acud. Sci. Paris, Ser. C 280, 593 (1975). 36. J. Levesque, J. L. Pousset, and A. Cav6, Fitorerapin 48,5 (1977). 37. J. Levesque, R. Jacquesy, and C. Merienne, J. Nut. Prod. 46, 619 (1983). 38. R. T. Brown and S. G. Fraser, Terrahedron Lett., 1957 (1974). 39. G.I. Dimitrienko, D. G. Murray, and S. McLean, Tetrahedron Lett., 1961 (1974). 40. S. McLean, G. I. Dimitrienko, and A. Szacolcai, Can. J. Chem. 54, 1262 (1976). 41. R. T. Brown and C. L. Chapple, Tetrahedron Lett., 1629 (1976). 42. R. T. Brown and C. L. Chapple, Tetrahedron Lett., 2723 (1976). 43. R. T. Brown and A. A. Charalambides, J . Chem. Soc., Chem. Commun., 765 (1973). 44. R. T. Brown and A. A. Charalambides, J. Chem. Soc.. Chem. Commun., 553 (1973). 45. D. G. Murray, A. Szacolcai, and S. McLean, Can. J. Chem. 50, 1486 (1972). 46. F. Hotellier, unpublished results. 47. S. Uesato, E.Ali, H. Nishimura, I. Kawamura, and H. Inouye, Phytochemistry 21,353 (1982). 48. N. S. Bhacca and D. H. Williams, “Application of NMR Spectroscopyin Organic Chemisw.” Holden-Day, San Francisco, 1966. 49. R. T. Brown and B. M. F. Warambura, Phytochemistry 17, 1686 (1978). 50. W.P. Blackstock, R. T. Brown, C. L. Chapple, and S. B. Fraser, J . Chem. Soc., Chem. Commun.. 1006 (1972). 51. K. L. Stuart and R. B. Woo Ming, Tetrahedron Lett., 3853 (1974). 52. J. Stockigt, H. P. Husson, C. Kan-Fan, and M. H. Zenk, Chem. Commun.,164 (1977). 53. J. Stockigt, M. Rueffer, M. H. Zenk, and G. A. Hoyer, Planta Med. 33, 188 (1978). 54. R. T. Brown, C. L. Chapple, and A. Charalambides, Chem. Commun., 756 (1974). 5 5 . R. T.Brown, C. L. Chapple, R. Platt, and H. Spencer, Chem. Commun., 929 (1974). 56. K. Inouye, T. Tanashi, H. Inouye, F. Murai, and M. Tagaeva, Phytochemistry 21,359 (1982). 57. J. Levesque, R. Jacquesy, and J. P. Foucher, Tetrahedron 38, 1417 (1982). 58. F. W. Werhli and T. Wirthlin, “Interprktation of Carbon-I3 NMR Spectra.” Heyden, London, 1976. 59. L. J. G. Angenot, Thtse de Doctorat, Universitk de Likge (Belgique), 1973;Diss. Abstr. Znt. 34, No. 11338 (1974). 60. C. A. Coune, L. J. G. Angenot, and J. G. Denoel, Phytochemistry 19, 2009 (1980). 61. A. H. Heckendorf, K. C. Mattes, C. R. Hutchinson, E. W. Hagaman, and E. Wenkert, J . Org. Chem. 41, 2045 (1976). 62. 0.Sticher, B. Meier, D. Lehmann, and L. Swiatek, Planta Med. 38, 246 (1980). 63. R. K.Chaudhuri, F. U. Afifi-Yazar, 0. Sticher, and T. Winkler, Tetrahedron 36,2317 (1980). 64. W. P. Blackstock and R. T. Brown, Te?rahedron Lett., 3727 (1971). 65. N. Aimi, T. Shito, K. Fukushima, Y. Itai, C. Aoyama, K. Kunisawa, S. I. Sakai, J. Haginiwa, and K. Yamasaki, Chem. Parm. Bull. 30, 4046 (1982). 66. K. R. Markham, B. Ternai, R. Stanley, H. Geiger, and T. J. Mabry, Tetrahedron 34, 1389 (1978). 67. M. D. Luong, These de Doctorat, Universit6 de Neuchatel (Suisse), 1978. 68. K. Freudenherg and A. C. Neish, “Constitution and Biosynthesisof Lignin.” Springer-Verlag, Berlin, 1968.

2. THE ALKALOIDS FROM PAURIDlANTHA

249

69. S. R. Jensen and B. 3. Nielsen, Phytochemisny 19,2685 (1980). 70. S. D. Jolad, J. J. Hoffmann, J. R. Cole, M. S. Tempesta, and R. B . Bates, J . Org. Chem. 45, 1327 (1980). 71. J. E. Saxton (ed.), “The Chemistry of Heterocyclic Compounds, Indoles Part 4: The Monoterpenoid Indole Alkaloids.” Wiley, New York, 1983. 72. J. D. Phillipson and M. H. Zenk (eds), “Indole and Biogenetically Related Alkaloids.” Academic Press, London, 1980.


-CHAPTER3 -

THE AMARYLLIDACEAE ALKALOIDS STEPHENF. MARTIN The Department of Chemistry The University of Texas Austin. Texas 78712-1167

I. Introduction and Botanical Distribution 11. Lycorine-Type Alkaloids A. Isolation and Structural Studies B. Biological Activity C. Synthetic Studies 111. Lycorenine-Type Alkaloids A. Isolation and Structural Studies B. Biological Activity C. Biosynthetic Studies D. Synthetic Studies IV. Narciclasine-Type Alkaloids A. Isolation and Structural Studies B. Biological Activity C. Biosynthetic Studies D. Synthetic Studies V. Galanthamine-Type Alkaloids A. Isolation and Structural Studies B . Biological Activity C. Biosynthetic Studies D. Synthetic Studies VI. Crinine-Type Alkaloids A. Isolation and Structural Studies B. Biological Activity C. Biosynthetic Studies D. Synthetic Studies VII. Other Structural Types A. Norbelladine Derivatives B. Mesembrane Type C. Augustamine D. Montanine Type E. 4-AryltetrahydroisoquinolineType References

25 1

THE ALKALOIDS, VOL. 30 Copyright 0 1987 by Academic Press, Inc All nghts of reproduction in any form reserved.

252

STEPHEN F. MARTIN

I. Introduction and Botanical Distribution The Amaryllidaceae alkaloids constitute an important group of naturally occumng bases possessing a diversity of functionality and structure (1-4, 227). Indeed, over 100 alkaloids have been isolated from members of the Amaryllidaceae, and most compounds may be classified into eight principal, skeletally homogeneous subgroups although there are several other alkaloids having structures derived from these main molecular frameworks. Representative alkaloids from each of these classes include lycorine (l), lycorenine ( l a ) , narciclasine (215), galanthamine (291), crinine (359), pretazettine (395), latisodine (578), and montanine (584).

Me0

OH

OH 184

1

215

359

291

570

395

584

Some novel additions to this family of alkaloids include: ryllistine (579), the first 4-oxygenated norbelline alkaloid (6); augustamine (582) (26); latifine (594), a biogenetic isomer of cherylline (595) (221); the 0-glycosyl alkaloids lycorine-

253

3. THE AMARYLLIDACEAE ALKALOIDS X

577: R = p-Dglu; X = H

580

5 7 9 R = Me; X = OMe

OMe

Me

tie

582

581

OH

I

Me0

R2

254

STEPHEN F. MARTIN

and pseudolycorine- l-0-P-D-glucosides (4 and 10, respectively) (73); hordenine-4-O-P-~-glucoside(73a); and latisoline (577) (36). Although alkaloids of the joubertiamine and mesembrine type are typically found in the plants of the family Aizoaceae, amisine (580) was isolated from Hymenocallis arenicola Northrop (57), and mesembrenol (581) was discovered in Crinum oliganthum (40. A number of spectroscopic studies have been completed, and 13C-NMR spectroscopy continues to be a useful analytical tool for structural elucidation. Furthermore, CD spectroscopy has proved to be an effective means for providing stereochemical information for the lactone alkaloids of the lycorenine class (33). The plants of the family Amaryllidaceae continue to yield alkaloids (Table I) having interesting biological activities. For example, galanthamine (291) exhibits a number of effects, such as analgesia, upon the central nervous system (152157). Lycorine (1) (5,17,96,97), narciclasine (215) (97,101,141,142), pancratistatin (221) (72), pretazettine (395) (96,97,178-183, and several other alkaloids possess varying degrees of antitumor and antiviral activity, and they also inhibit protein synthesis at the step of peptide bond formation (97,101). Lycorine has been found to inhibit growth in higher plants and yeasts by suppressing cell division and cell elongation (73,99). Pretazettine also inhibited the purified RNA-dependent DNA polymerase (reverse transcriptase) from avian myeloblastosis virus, a typical C-type virus (178). 1,2-P-Epoxyambelline (372) is an immunostimulant producing a moderate activation of mouse spleen lymphocytes (38). There have been only a few reports revealing new aspects of the biosynthesis of the alkaloids of this family. In one significant finding, it was discovered that norpluviine (14) was incorporated into other alkaloids of the lycorine-type as well as the lycorenine-type (137). Support for the intermediacy of 1l-hydroxyvittatine in the biosynthesis of narciclasine (215) has been obtained (143). Other feeding experiments using doubly labeled 3-hydroxy-4-[14C]methoxy-N-methyl-(R)- and -(S)-N-[3H]benzylaminesin King Alfred daffodils produced oduline (186), galanthamine (291), and haemanthamine (381) with high tritium retention (139). This observation suggested that the incorporation of N-methylisovanillamine into these alkaloids occurred by a nonstereospecific process in which hydrogen removal from the benzylic position was governed by a kinetic isotope effect. Major advances in the total synthesis of representative members of this family have been made. Several syntheses of lycorine (1) have been reported (108,109,112,113,117), although there remain problems in the development of a concise strategy for the stereoselectivefunctionalizationof the C ring. Substances prepared during the development of entries to the lycorine-type alkaloids have been exploited as key intermediatesfor the syntheses of clivonine (187) (I10)and hippeastrine (180) (140). Several routes to the di'nydrolycoricidines270 and 271

255

3. THE AMARYLLIDACEAE ALKALOIDS

TABLE I Botanical Distribution of Amaryllidaceae Alkaloids Species Amaryllis belladonna L.

Amaryllis vittata Brunsvigia cooperii Clivia miniata Regel

Clivia nobilis Crinum amabile

Crinum asiaticum L.

Alkaloid(s) Acetylcaranine Ambelline Undulatine Anhydrolycorinium chloride Ryllistine Brunsvigine Clivacetine Clivatine Lycorine Clivimine Clivonine Clivonidine Miniatine Hippeastrine Clivojuline Haemanthamine Clivisyaline Cliviamartine Cliviaaline Cliviahaksine Cliviasindhine Lycorine Galanthaminen Galanthine Crinidine Hippeastrine Lycorine Narwedine Tazettine Lycorine Crinamine

O,N-Diacetyl-N-demethylgalanthamine

Crinum augustum Rox.

Hamayne N-Demethylgalanthamine Crinasiatine Crinasiadine Lycoriside Lycorine Buphanisine 6a-Hydroxycrinine 6P-Hydrox ycrinine 6a-Hydroxybuphanisine 6P-Hydroxybuphanisine

Reference 5

5 5 5 6 7 8 8-10 8-10,17 8,10,17 8-10,17 9 10 10-12 10 11 11 13,17 14 15 16 18 19 19 19 19 19 19 19 20,21 20,21 20 20 21 22 22 73b 23 23 24 24 24 24

(continued)

256

STEPHEN F. MARTIN

TABLE I (Continued) Species

Crinum bulbispermum L.

Crinum bulbispermum Milne

Crinum defixum Ker-Gawl

Crinum jagus Crinum latifatiurn

Alkaloid(s) Crinamine Augustine Augustamine Pratorinine Pratorimine Hippadine Lycorine Crinamine Powelline Bulbispermine (crinalbine) Crinidine Vittatine Crinamine Powelline Lycorine Crinine Hippadine Bulbispennine (crinalbine) Crinamidine Cherylline 0-Acetylcrinine Diacetyllycorine Deacetylbowdensine Bowdensine Lycorine Homolycorine 5a-Hydroxyhomolycorine 9-0-Demethylhomolycorine N-Demethy lgalanthamine Lycorine Hippeastrine Pratorimine 1-0-Acetyllycorine Crinine Powelline Crinamine Hamayne 3-0-Acetylhamayne Undulatine Cherylline Latisodine Latisoline Ambelline Hippadine (pratorine) Pratorinine Pratosine

Reference

24 25 26 27 27 28 28 28 28 28 29 29 29,32 29,32 18,29 32 30 31 32 32 32 32 32 32 33 33 33 33 34,35 32,33,37 33 27,37 32 32 32 32 32 32 32 32 36 36 37,38 37 37 37 (continued)

257


TABLE I (Conrimmi) Species

Crinum longifohm Crinum natans Crinum oliganthum

Crinum ornatum

Crinum pratense

Crinum scabrum Herb.

Crinum zeylanicum L.

Curculigo orchioides Haemanthus kalbreyeri

Hippeastrum ananuca

Hippeastrum bicolor

Alkaloid( s) 1,2-P-Epoxyamhelline (cavinine) Latifine Lycorine Lycorine Crinatine Narcicrinine Lycorine Crinamidine Oliganine Mesemhrenol Lycorine 0mazidine Ornazamine Ornamine F’ratorinine Lycorine 1,2-Diacetyllycorine Ambelline Narcissidine Hippadine Anhydrolycorin-7-one Crinamine 6-H ydroxycrinamine Lycorine Lycorine 6-Hydroxy crinamine 6-Methoxycrinamine 3-Acety lhamayne Hamayne Lycorine Kalbreclasine Kalhretorine Haemanthamine Haemanthidine Hippadine Lycorine Narciclasine F’ratorimine Lycorine Homo1ycorine Maritidine Hippeastidine Epihomolycorine Haemanthamine 1 1-Hydroxy- 1,2-dihydromaritidine Haemanthamine

Reference 38 221 18 42 42 39 40 40 40 41 42 42 42. 42 27,43 43 43 43 43 43 43 33 33 33 44 44 44 44 44 45 46 46 46 46 46 46 46 46 47 47 47 47 47 48 48 49 (continued)

258

STEPHEN F. MARTIN TABLE I (Continued) Species

Hippeastrum equestre

Hippeastrum punecium Hippeastrum vittutum L. Herr.

Hymenocallis arenicola Northrop

Leucojum aestivum L.

Leucojum vernum Lycoris guangxiensis

Lycoris longituba

Alkaloid( s) Lycorine Galanthine Hippeastrine Lycorine Tazettine Galanthamine" Haemanthamine Cavinine Hippadine Lycorine Tazettine Hippeastrine Vittatine Hippacine Lycorine Tazettine Haemanthamine Galanthamine" Zaidine Haemanthidine Varadine Havanine Caribine Amisine Galanthamine" Lycorine Leucotamine 0-Methylleucotamine 3-0-Acetylungiminorine Ungiminorine Pretazettine Demethylhomolycoramine Lycorine Galanthamine" Lycorine Pseudo1ycorine Crinine Galanthamine" Lycoramine Narwedine Demethylgalanthamine N- Allylnorgalanthamine Narciclasine Lycorine Galanthamine" Lycoramine

Reference

49 50a 50a

SOU 50a

50b 50b 51 30,52 52 52 52 52 52 53,54 53,54 53,54 53,54 53 54 54 55 56 57 58,59,88

58,59 59 59 59 59 59 59 58 58 60 60 60 60 60 60 60 60 60 60 60 60 (continued)

259

3. THE AMARYLLJDACEAE ALKALOIDS

TABLE I (Continued) Species Lycoris radiata Herb.

Lycoris sanguinea Maxim

Narcissus papyraceus Kerl-Gawl

Narcissus poeticus

Narcissus requienii Roem.

Narcissus iazetta L.

Alkaloid(s) 0-Methyllycorenine Galanthamine" Lycoramine Dernethylhornolycorine Lycoricidinol Lycoricidine Hippeastrine Lycorine Pretazettine 0-Demethyllycoramine Lycorenine Homo1ycorine Lycorine Galanthamine" Sanguinine Tazettine Haemanthamine Lycoramine Haemanthidine Lycoricidine Lycoricidinol Arolycoricidine Arolycoricidinol Hippadine Papyramine Lycorine Tazettine Galanthamine" Lycoramine Pseudolycorine Maritidine Lycorine Galanthamine" Galanthine Poetinatine Lycorenine Narcissidine Narcirnarkine 1-0-Acetylpseudolycorine 2-O- Acet ylpseudolycorine Pseudolycorine Pretazettine Homolycorine Lycorine Pseudolycorine 0-Methylmaritidine

Reference 61 61 61,63 61,63 61 61 61,63 61.63 61,63 63 63 63 62,64 62,& 62 64 64 64

64 64 64 64 64 30 65 65 65 65 65 65 65 58J9.66 66,67 66,67 66 66 67 67 228 228 228 60,68-71 69.71 68.69,71 68,69,71 60,69 (continued)

STEPHEN F. MARTIN

TABLE I (Continued) ~

Species

Pancratium biforurn Roxb.

Pancratiurn littorale Jacq. Pancratiurn rnaritirnurn Pancratiurn trianthurn

Sternbergia lutea Ker-Gawl

Ungernia severtzovii

Ungernia spiralis

Ungernia tadshicorurn

~~

Alkaloid(s) Tazettine Demethylhomolycorine Galanthamine" Haemanthidine Pluviine Lycorenine Epipapyrarnine Epigalanthamine Lycoramine Maritidine Lycorine Pseudolycorine Pretazettine Tazettine Lycorine- ~-~-p-D-g~ucoside Pseudolycorine-1-0- p-D-glucoside Hordenine-4-0-P-~-glucoside Pancratistatin Lycorine Tazettine Trispheridine Tazettine Hippeastrine Haemanthidine (pancratine) Galanthaminea Lycorine Hordenine Trianthine Lycorine Tazettine Hippeastrine Galanthine Galanthamine" Haemanthidine Hippamine Sternbergine 11-Hydroxyvittatine Lutessine Lycorine Galanthaminen Haernanthidine (pancratine) Nanvedine Lycorine Tazettine Dihydroepimacronine Lycorine

~~

Reference 69.71 69 70 70 71 71 60 60 60 60 73a 73, 73a 73a 730 73a 73a 72 74 74 75 75 75 75 75 75 75 75 76-77 76 76 76 76 76 76 76 78a 786 79 79 79 79c 80 80 80 81

(continued)

26 1


TABLE I (Continued) Species Ungernia victoris Ungernia vvedenskyi

Zephyranthes carinata Herb.

Zephyranthes robusta

Zephyranthes rosea

Zephyranthes sulphurea

Alkaloid(s) Galanthamine” Narwedine Ungvedine Lycorine Tazettine Ungminorine Ungminoridine Hippeastrine GalanthamineO Narwedine Pancratine (haemanthidine) Hordenine Pretazettine Lycorine Galanthine Haemanthamine Carinatine Maritidine Lycorine Haemanthamine Maritidine 3-Epimaritidine Crinamine Haemanthamine Maritidine Tazettine Haemanthamine

Reference 82 79c 83

84 84

84 84 84 84 84 84 84 85 85 85 85

85 86 86 86 87 87

87 87 86

86 86

Other plant sources of galanthamine: Galanthus elwesii, G . nivalis var. gracilis, G. woronowii, Ungernia victoris, Leucojum aestivum, L. vernum, Narcissus gracilus, N . incomparabilis. N . jonquilla, N . lobularis, N . odorus var. rugulosus, N . poeticus, N . pseudonarcissus, N . tazetta, N. tirandus, Sternbergia jischeriana, and Zephranthes andersoniana (88);Eucharis subedentata, Vallota speciosa, and Galanthus nivalis (augustifolius) (89).

have been reported (144,149, and the total syntheses of racemic (148) and enantiomerically pure (149) lycoricidine (214) have been completed. Oxidative aryl coupling reactions or their chemical equivalent have been employed to advantage in the development of syntheses of galanthamine (291) in racemic and opticallypure form (159-164). There have been several accounts of the successful synthesis of lycoramine (299) (165-167), using strategies that should find general utility for the preparation of the galanthamine-type alkaloids. The alkaloids of the crinine group have been the objects of intensive synthetic investigations, and a number of general and useful strategies have been developed. The biogenetic approach to crinine (359) and maritidine (387) has been explored (176,191-196), and an attempt to access pretazettine (395) via an

262

STEPHEN F. MARTIN

oxidative coupling process led instead to 6a-epipretazettine (431) (197). A variety of general strategies for the construction of the crinane skeleton have been developed, which have resulted in, among other things, the total syntheses of elwesine (439) (200,217,218), epielwesine (449) (200,217-219), crinine (359) (203-205,208), buphanisine (361) (208), dihydromaritidine (506) (209, crinamine (376) (216), 6-hydroxycrinamine (379) (216), haemanthamine (381) (21 4 , haemanthidine (382) (202,209,215), pretazettine (395) (209,212,2 15), tazettine (397) (202,210,215), criwelline (398) (216), and macronine (401) (216). Finally on the synthetic front, a number of successful entries to the 4aryltetrahydroisoquinoline alkaloids latifine (594) (222) and cherylline (595) (223-225) have been recorded.

11. Lycorine-Type Alkaloids

A. ISOLATION AND STRUCTURAL STUDIES Lycorine (1) and derivatives thereof have been the subject of a number of spectroscopic studies (42,90-92), and the proton and carbon resonances of lycorine and the a-dihydro derivative 18 have been completely assigned (90). The crystal and molecular structure of lycorine (93) and lycorine hydrobromide (94) have been established by X-ray analysis, and the structure of lycorinechlorohydrin, which had originally been formulated as the cis-chlorohydrin 19, has been corrected and determined to be the trans-chlorohydrin 20 (95). The discovery of lycorine-1-0-P-D-glucoside (4) and the related alkaloid pseudolycorine-1-0-P-D-glucoside (10) in Puncrutium bijlorum represented the Fist report of the natural occurrence of glucosyloxy alkaloids in the family Amaryllidaceae (73). The structures of 4 and 10 were deduced from 'H NMR and mass spectroscopy coupled with the observation that hydrolysis of the glycosides with emulsin afforded lycorine (1) and pseudolycorine (9), respectively, together with D-glucose. Based on spectroscopic evidence and comparisons with the spectra of lycorine (l),the structure of the new alkaloid cliviasindhine has been assigned as 6 (16). Although the existence of an unstable a-hydroxyethyl group on the hydroxyl function at C-2 of 6 is somewhat surprising, its presence was suggested by examination of the mass spectrum, which revealed the loss of an acetaldehyde fragment from the molecular ion of the natural product. A number of other new alkaloids that are closely related to lycorine have been isolated and characterized. The structure of the phenolic base carinatine (ll),which is an isomer of goleptine (13), was deduced from spectroscopicdata together with the observation that 11 was converted to galanthine (16) on treatment with diazomethane (85). The 'H NMR and 13C NMR of sternbergine (12) have been fully assigned, and


263

Lyoxine l-O-A&yllymflne Dacetyllymflne Lyoorine-10 p-Dglymside Hwamine Cliviasindhine Caranine Acetylcaranine Pseudoiymrine Pseudolymnne-1-0-p-D-glumside

Carinatine Sternbergine Goleptine Norpluviine Pluviine

& &\ Galanthine

Zaiine

0 (0

& \ 18: R = H

30: R=Ac

19: R'=CI,R2=H 20: R'=H,R~=CI

further support for its structure was obtained by its transformation to methylpseudolycorine via 0-methylation and deacetylation (76). Similarities in the mass spectra of galanthine (16) and zaidine (17) provided the basis for the structural assignment of the latter (53). Trianthine (21), which is the optical antipode of zephyranthine, has been isolated from Pancratium trianthum (75). Caribine (22), which was found in

264 OH

C"mY 0

AO

STEPHEN F. MARTIN

\

21

N

O

/

\

(0

22

28

'Y

(0 -& O

CI

31: R ' = R * = M ~ 32: R' , R2=CH2

29

OH

I

3. THE AMARnLIDACEAE ALKALOIDS

265

only small amounts from Hymenocallis arencola Northrop, represents a new structural member of the family Amaryllidaceae, the structure of which was based principally on an analysis of its mass spectrum (56). The phenanthndone alkaloids hippadine (23) (30,37,43), pratosine (24) (37), pratorimine (25) (27,37),pratorinine (26)(27,37,43), kalbretorine (27)(46),and anhydrolycorine-7-one (28)(43) have been isolated, but the structures that were originally proposed for the two isomers pratorinine (43) and pratorimine (37) (25 and 26, respectively), which were deduced solely from their 'H- and 13C-NMR spectra, have been revised on the basis of the X-ray analysis of pratorinine (27). Interestingly, anhydrolycorinium chloride (29), which was first described as a degradation product of lycorine (l),has recently been isolated as a natyal product (5).Lutessine (33)represents a novel example of an alkaloid related to lycorine with a substituent on the D ring (78b).

B . BIOLOGICAL ACTIVITY The alkaloids related to lycorine (1) possess a number of interesting and potentially useful biological activities. For example, both lycorine (1) and pseudolycorine (9)exhibit antiviral and antineoplastic activity (5,17,96,97), and dihydrodiacetyllycorine (30) possesses short-term hypotensive action (98). Lycorine (1) has also been found to inhibit growth in higher plants as well as in yeasts by inhibiting cell division and cell elongation (73,99), and it is possible that it could be exploited as an in vivo inhibitor of ascorbic acid biosynthesis (100). Moreover, lycorine (l), pseudolycorine (9), and dihydrolycorine (18) inhibit protein synthesis in eukaryotic cells by inhibiting the peptide bond formation step (97,101),and there is some evidence that suggests that lycorine might be an effective insect antifeedant (61,102).Acetylcaranine (8) and anhydrolycorinium chloride (29)exhibit in vitro antineoplastic activity, and 29 was effective in vivo against murine P388 lymphocytic leukemia ( 3 PS system) (5).Hippadine (23)produces reversible inhibition of fertility in male rats (43,103), and kalbretorine (27)displays antitumor activity (46).

c. SYNTHETIC STUDIES There has been a significant level of activity in the synthetic arena directed toward the preparation of lycorine and related alkaloids, and a number of successes have been recorded. Although a variety of strategies for the elaboration of the tetracyclic skeleton of lycorine have evolved, the most common ones, and those that have ultimately led to the total syntheses of the target alkaloids, are of the general type A .+ C .+ B -+D and A -+ C + D -+ B . Of some importance is an approach which involves prior construction of the C and D rings followed by the elaboration of the A and B rings. At this juncture, it is appropriate to note

266

STEPHEN F. MARTIN

that, although numerous entries to the tetracyclic skeleton of lycorine (1) exist, the efficient, stereoselective functionalizationof the C ring still remains a major challenge, and future studies in this area are warranted. 1. AB --f CB One facile entry to intermediates possessing the y-lycorane skeleton involved the alkoxide-catalyzed cyclization of the isocarbostyril Mb,which was readily accessible by the N-alkylation of 34a, to provide the y-lycorane derivative 35 (104). The amino derivative 36 was available in three steps from the isocarbostyril37 by a similar sequence of reactions, but several attempts to prepare the P-unsubstituted enone lactam 38 by this approach resulted in the loss of the N-(4oxobutyl) appendage by a retro-Michael reaction and were unsuccessful. CO 2 El

*-O

34b: R = ( C H & C W

36:

I

34a: R = H

35: X=OH X=NH2 38: X = H

CN

37

2. A - C - B - D The acid-catalyzed, amino-Claisen rearrangement of substituted N-vinylisoquinuclidenes such as 40 and 41 (Scheme 1) served as the foundation of a novel entry to the molecular framework of lycorine (105). Thus, y-alkylation of the thermodynamic dienolate generated from 40, which was readily available from the Diels-Alder adduct 39, provided 41. Subsequent thermolysis of 41 for 24 hr


267

0

39

40: R = H 41 : R = CHZCOzEt

0 42

SCHEME1

in the presence of p-toluenesulfonic acid furnished directly the tetracyclic lactam 42 as the exclusive product, although other intermediates could be isolated when the reaction was conducted for shorter times ( 1 0 5 ~ )Further . refunctionalization of 42 to lycorine or a derivative thereof has not been reported and may prove

problematic. A concise synthesis of the methobromide of ungeremine (45) featured the oxidative photocyclization of the Schiff base 43 to provide 44 (Scheme 2). When 44 was reduced with LiAlH, followed by treatment of the resulting alcohol with phosphorus tribromide, an alkyl bromide was generated that suffered spontaneous cyclization to furnish 45 (106). The anhydrides 47-49, which were obtained as a mixture from the DielsAlder reaction of the diene that was produced on dehydration of the alcohol 46

268

STEPHEN F. MARTIN

43

44

OMe

I

45

SCHEME2

with fumaric acid in acetic anhydride, served as starting materials for the syntheses of a-,p-, and b-lycoranes 57-59, respectively (Scheme 3) (107).For example, reaction of the anhydride 47 with methanol gave a mixture (7 : 3) of half esters, of which 50 was the major product. When 50 was allowed to react with thionyl chloride followed by sodium azide, the intermediate acyl aide underwent a Curtius rearrangement to yield the isocyanate 51, which cyclized in the presence of tin tetrachloride to furnish the lactam ester 52. Although the attempted conversion of 52 to 54 led surprisingly to the formation of the epimer 55 in which the BC ring was cis-fused, 52 could be successfully transformed to the related dihydro lactam 53 via catalytic hydrogenation of the olefinic bond in the C ring and subsequent hydride reduction of the ester function followed by reaction of the derived tosylate with cyanide ion. Hydrolysis of the nitrile function of 53 in concentrated hydrochloric acid followed by cyclization of the intermediate acid with acetic anhydride afforded the imide 56, which furnished (+-)-a-lycorane (57)on reduction with LiAIH,. A similar sequence of reactions was employed to effect the conversions of 48 to (%)-P-Iycorane (58) and 49 to (+)-b-lycorane (59) (107). A variant of this general strategy has also been exploited for the total syntheses Thus, one-carbon of lycorine (1)and zephyranthine (76) (Scheme 4) (108,109).


46

269

47: a%:a-Hb 48: a-H,:PHb 4 9 P+ia;aHb

0

52

5 0 R=CO,H 51: R=NCO

0

x=o

5 3 1.2-dihydro

56:

54: A','

57: X = H 2

SCHEME 3

homologation of the urethane ester 60, which was available from the isocyanate 51, was effected by hydrolysis of 60 to the corresponding acid followed by an Amdt-Eistert reaction sequence in which the intermediate diazoketone was transformed to 61 through the advantageous use of silver benzoate and triethyl mine as the catalyst for the Wolff rearrangement (110).Sequential treatment of 61 with phosphorus oxychloride and then tin tetrachloride yielded 62. Although the feasibility of converting 52 to 62 via Amdt-Eistert homologation was examined, it was not possible to obtain reproducible results owing to solubility problems. Reduction of 62 with lithium borohydride followed by reaction of the intermediate alcohol with thionyl chloride afforded the chloride 63. Even though

270

STEPHEN F. MARTIN

n

n

0 55

it was not possible to effect the direct cyclization of 63 to 64, the cyclization of the more basic imidate ester that was simply derived from 63 by reaction with Meerwein reagent proceeded smoothly to afford 64. Alternatively, hydrolysis of the ester function of 62 followed by cyclization of the intermediate acid with acetic anhydride afforded the imide 65, which was chemoselectively reduced with LiAlH, to provide 64. Stereoselective oxidation of the double bond in 64 with m-chloroperbenzoic acid (MCPBA) gave the a-epoxide 66 as the sole product. Nucleophilic opening of the epoxide ring of 66 with phenylselenide anion proceeded selectively at C-2 to afford a hydroxy selenide, which was converted to the allylic acetate 67 by sequential oxidative elimination, using sodium periodate followed by acetylation. It is interesting to contrast the regioselectivity in the opening of the epoxide 66 with that of the closely related epoxide 79 (vide infru). The stereoselective formation of the a-epoxide 66 from 64 may be easily understood upon recognition that the C ring of 66 is compelled to reside in a boat conformation in which the carbon-carbon double bond possesses two clearly differentiated diastereotopic faces. Since the a-acetoxy substituent in 67 sterically shields the a face of the carbon-carbon double bond in 67, epoxidation of 67 with MCPBA provided exclusively the P-epoxide 68. Subsequent nucleophilic opening of the epoxide with phenylselenide anion proceeded cleanly at C-3, and the oxidative elimination of the resulting hydroxy selenide afforded lycorine lactam 69. Acetylation of 69 gave the diacetate 70, which was reduced with LiAlH, to furnish (+)-lycorine (1).

27 1


60: R=CO,Me 61: R = CH,CO,Me

66

64: X=H, 65: x = o

68

67 OR

I

69 X=O.R=H X=O;R=AC 1: X = H , ; R = H

m:

SCHEME 4

272

STEPHEN F. MARTIN

It should be noted that a relay synthesis of optically pure (-)-lycorine was also completed commencing with optically pure 66, which had been prepared from naturally occurring lycorine via the dihydrolycorine lactam 71 and the derived tosylate 72. The reduction of optically pure 66 resulted in the formation of adihydrocaranine (73) (108~).A straightforward synthesis of (+-)-zephyranthine OR

73

71: R = H 72: R = T s

(76) commenced with the reaction of the lactam 64 with osmium tetraoxide in pyridine to give a mixture of the two 2-cis-glycols 74 and 75 (in 35 and 15% yield, respectively), both of which were isolated as the corresponding diacetates. Reduction of 74 with LiAlH, provided 76 (I08b,c).

X

74: R‘ =

= OH; R3 E R4= H X = O

75: R’ = $ = H R 3 = d = O H ; X = 0 76: A’ =R2=OH;R3=fP=H;X=Hz

The unsaturated lactam ester 62 was also employed in a modified synthesis of (2)-lycorine (1)(109). In the event, 0-ethylation of 62 with excess Meerwein reagent followed by reduction of the resulting imidate 77 with either sodium borohydride/stannic chloride dietherate (21 I) or sodium borohydnde/stannous chloride gave an intermediate secondary amine, which cyclized on heating in methanol containing K,CO, to provide the lactam 78 (Scheme 5). When 78 was

273


6Et 70

77

80: R = H 81: R=Ac 02: R = W S

79

03

84

SCHEME 5

allowed to react with MCPBA a single epoxide 79 was obtained, in which the (Y configuration of the oxirane ring was verified by hydride reduction to give (-+)-a-dihydrocaranine(73). When the lactam 79 was treated with diphenyl diselenide/sodiumborohydride in ethanol, nucleophilic attack occurred at both (3 : 2) C-2 and C-1 in contrast to the regioselectivity observed for the nucleophilic opening of the closely related lactam 66. Oxidation (NaIO,) and elimination of the phenylselenyl group from the major isomer provided the desired allylic alcohol 80. Whereas the allylic acetate 67 underwent smooth conversion to the P-epoxide 68 on treatment with MCPBA, the isomeric acetate 81 unexpectedly failed to undergo epoxidation. However, the corresponding

274

STEPHEN F. MARTIN

trimethylsilyl ether 82 did suffer facile oxidation with MCPBA to give the pepoxide 83, which was converted to 84 according to the tactics previously described for the conversion of 68 to 70, and the reduction of 84 with LiAlH, provided racemic lycorine (1) (109). Another strategy for the synthesis of lycorine commenced with the DielsAlder reaction of 1-methylenedioxyphenyl-2-nitroethylenewith butadiene to provide the cyclohexene derivative 85, which on reaction with MCPBA gave 86 together with the diastereomeric epoxide (1 : 1) (Scheme 6) (112). Hydrogena-

86

85

87: X=H.OCOPh 88: x = o

91: x = o 5 7 X=H2

94

95: X=H,;Y=O

92: x = o 93: X=H,

96. X=O;Y=H,

SCHEME 6

275


tion of 86 over Raney Ni catalyst followed by treatment with LiAIH, and then benzoyl chloride gave the 0,N-dibenzoyl derivative 87. Selective saponification of the benzoate in 87 followed by oxidation of the intermediate secondary alcohol with chromium trioxide in pyridine produced 88. Ketalization of 88 followed by hydride reduction and a Pictet-Spengler closure to elaborate the C ring provided the amino ketone 89. Removal of the N-benzyl group by catalytic hydrogenolysis followed by N-acylation with chloroacetyl chloride in pyridine gave the chloro acetamide 90, which underwent facile cyclization in the presence of potassium rerr-butoxide to give the lactams 91 and 92 (about 30 : 1). The stereochemistryof 91 and 92 was then established by their conversion to (&)-adesulfurization, and lactam reduction. Under the conditions employed for the base-induced cyclization of 90, there was no observable conversion of 91 to 92, and hence the epimerization at C - l l c presumably occurred via retroMichaeUMichael processes prior to ring closure. Reductive amination of the keto lactam 91 provided 94, which underwent oxidation to the correspondingN-oxide and subsequent Cope elimination to give 95. Hydride reduction of 95 followed by selective oxidation at C-7 with active manganese dioxide afforded 96. Since 96 had previously been converted to (-+)-lycorine (1) via the acetate 67 (108,113), its preparation constituted in a formal sense a total synthesis of the target alkaloid. An alternate route to 90 commenced with the Robinson annelation of the aryl pyruvic acid 97 with methylvinyl ketone followed by dehydration and dissolving metal reduction of the resulting mixture of unsaturated acids to provide the cisketo acid 98 (Scheme 7) (112b). Transformation of 98 to the trans-ketal ester 99

97

98

99: R=CO,Me 1 0 0 A = NHC0,Me

SCHEME 7

276

STEPHEN F. MARTIN

was performed by sequential esterification, ketalization, and epimerization. Saponification of the ester afforded an intermediate acid, which was converted to the urethane 100 via a Curtius rearrangement of the corresponding acid azide. Hydrolysis of the urethane moiety followed by a Pictet-Spengler cyclization of the resulting m i n e provided an intermediate secondary amino ketone, which was converted to 90 by N-acylation with chloroacetyl chloride.

3. A - , C - + D - , B The basic synthetic strategy of constructing the tetracyclic lycorane skeleton according to the sequence of A +-C -+ D + B constitutes a second useful entry to this class. One such approach commenced with the oxazolone 101 (Scheme

bh 101

102

__c

104: X = O 105: X 7 (SCH,),

103

n 0

COPh

106

107

SCHEME8

277


8), which was readily accessible from the condensation of piperonal and hippuric acid in the presence of acetic anhydride and sodium acetate (114).Thus, reaction of 101 with the sodium salt of dimethyl 3-oxoglutarate followed by saponification and decarboxylation provided 102, which was recrystallized from methanol to give the methyl enol ether 103 as the major product together with approximately 10% of the isomeric enol ether. Subjection of 103 to a Reformatsky reaction followed by acidic workup furnished the enone 104, which was converted to the corresponding thioketal 105. When 105 was reduced with LiAlH,, a primary alcohol was produced that was elaborated to 106 by treatment of the derived mesylate with sodium hydride. Reductive removal of the N-benzoyl group followed by cyclization of the resulting secondary amine under PictetSpengler conditions proceeded with concomitant loss of the thioketal group to provide (+)-1-desoxy-Zlycorinone (107). Another concise route to 107 featured the facile construction of the cyclohexanone derivative 109 via the Michael addition of triply deprotonated methyl dioxohexanoate to the nitrostyrene (108 (Scheme 9) (115). Ketalization of 109 followed by hydrogenation of the nitro function and then cyclization of the resulting amino ester by thermolysis in refluxing xylene furnished the lactam 110, which was reduced LiAlH, to the amine 111. All attempts to cyclize 111 via a Pictet-Spengler reaction led to complex mixtures of products. However, when the unstable enone 112, which was obtained by acid-catalyzed hydrolysis of 111,

108

109

n

0

110: x=o 111: X = H ,

112

SCHEME 9

278

STEPHEN F. MARTIN

was allowed to react with formaldehyde in the presence of acid, 107 was produced, albeit in poor yields. An alternative synthesis of (+)-aand (2)-y-lycoranes (57 and 93) commenced with the 2-oxocyclohexyl acetic acid derivative 114 obtained by the alkylation of the enamine derived from 113 (Scheme 10) (116). Refluxing the oxime of 114 with zinc dust in glacial acetic acid afforded a mixture of the lactams 115, 116, and 117 in an approximate ratio of 4 : 6 : 3. The structure of 115 was verified by catalytic hydrogenation to give the lactam 118, which had previously been converted to (2)-a-lycorane (57). When the lactam 116 was subjected to sequential catalytic hydrogenation, hydride reduction, and PictetSpengler cyclization, (5)-y-lycorane (93) was obtained. A more efficient route to (+)-a-lycorane (57) involved refluxing the ketone 114 first with benzylamine in xylene and then with 87% formic acid to furnish the unsaturated lactam 119.

M3 R = H 114: R=CH,CO,H

115: R = H 119 R=CH2Ph

n

118: R = H 1 2 0 R=CH2P11

117

116

SCHEME10

279


Catalytic hydrogenation of 119 afforded 120, which was converted to 57 by sequential reduction with LiAlH,, catalytic hydrogenolysis of the. N-benzyl group, and cyclization via a Pictet-Spengler reaction. The cyclohexene 121, which was readily accessible from the Diels-Alder reaction of methyl hexa-3,5-dienoate and 3,4-methylenedioxy-P-nitrostyrene (lOS), served as the starting point for another formal total synthesis of (&)lycorine (1) (Scheme 11) (113). In the event dissolving metal reduction of 121 with zinc followed by reduction of the intermediate cyclic hydroxamic acid with lithium diethoxyaluminum hydride provided the secondary amine 122. Transformation of 122 to the tetracyclic lactam 123 was achieved by sequential treatment with ethyl chloroformate and Bischler-Napieralski cyclization of the resulting carbamate with phosphorus oxychloride. Since attempts to effect cleanly the direct allylic oxidation of 123 to provide an intermediate suitable for subsequent elaboration to (*)-lycorine (1) were unsuccessful, a stepwise protocol was devised. Namely, addition of phenylselenyl bromide to 123 in acetic acid followed by hydrolysis of the intermediate acetates gave a mixture of two hydroxy selenides. Oxidative elimination of phenylselenous acid from the minor product afforded the allylic alcohol 124, whereas the major hydroxy selenide was resistant to oxidation and elimination. When 124 was treated with a small amount of acetic anhydride and sulfuric acid in acetic acid, the main product was the rearranged acetate 67, which had been previously converted to (+)-lycorine (108).

121

122

123

124

SCHEME11

280

STEPHEN F. MARTIN

Intramolecular Diels-Alder reactions have been used to considerable advantage in the development of concise synthetic approaches to lycorine (1). One such entry commenced with the enamides 126 [At = Ph, 4-(MeO)C,H,l (Scheme 12), which were prepared by the N-acylation of imines derived from homopiperonal with the acid chloride 125 (117). Thermal unmasking of the latent diene moiety of 126 [Ar = Ph, 4-(MeO)C,H,] in refluxing xylene contaia-

127

132:

a -Ha

133:

P-Ha

128: 129: 1%. 131:

Ar = Ph. 4-(MeO)C&14-

SCHEME12

a-Ha:X=O P -Ha;X=O a -H,;X=H* -Ha;X=H;!

28 1


ing bis(trimethylsily1)acetamide(BSA) and bis(3-tert-butyl-4-hydroxy-5-methylpheny1)sulfide provided in situ the trienes 127 [Ar = Ph, 4-(MeO)C,H,], 21 cycloadditions to give mixtures (apwhich underwent intramolecular [4 proximately 1 : 1.5) of the respective cis- and trans-hydroindoles 128 and 129 [Ar = Ph, 4-(MeO)C,H,]. Reduction of the lactams 128 and 129 [Ar = Ph, 4-(MeO)C,H,] with LiAlH, afforded the corresponding tertiary amines 130 and 131 [Ar = Ph, 4-(MeO)C&,]. The structures of the cis-hydroindole 130 (Ar = Ph) and the trans-hydroindole 131 (Ar = Ph) were established by their conversion to (+)-a-and (k)-plycorane (57 and 58), respectively. In the event, catalytic hydrogenation of the double bond in the hydroindoles 130 and 131 (Ar = Ph) over 5% Pd/C in AcOH proceeded with concomitant N-debenzylation to provide the corresponding secondary amines, which were then allowed to react with methyl chloroformate to furnish the corresponding carbamates 132 and 133. On heating in POCl,, 132 and 133 underwent Bischler-Napieralski cyclization to provide the 7-0x0-a- and -p-lycoranes 134 and 135, which were then converted to 57 and 58, respectively, by reduction with LiAlH,. The conversion of the cis-hydroindoles 130 [Ar = Ph, 4-(MeO)C,H,] to (?)lycorine (1) required a suitable protocol for establishing the B ring without reduction of the olefinic bond in the C ring. Whereas the reaction of 130 (Ar = Ph) with ethyl chloroformate gave a mixture (about 4 : 1) of the desired urethane 136 together with the unexpected fragmentation product 137, the ethyl chloroformate-induced N-debenzylation of 130 [Ar = 4-(MeO)C,H,] proceeded smoothly to give 136 in high yield. Cyclization of 136 with phosphorus oxychloride then

+

Ph 136

137

proceeded without event to afford racemic 123, which had been previously converted to (+)-lycorine (1) (113). Another approach to the lycorane skeleton involving an intramolecular DielsAlder reaction commenced with the conversion of the unsaturated nitrile 138 to the imine 139 by sequential reduction with diisobutylaluminumhydride followed by condensation with but-3-enylamine (Scheme 13) (118). When 139 was acylated with chloroethyl chloroformate in the presence of Hunig base and the resulting dienamide heated at 140°C, the bicyclic carbamate 141 was isolated. If it is assumed that the Diels-Alder reaction proceeded via an exo transition state,

282

STEPHEN F. MARTIN

138

139

140

141

142: X = O

143:

x=n2

SCHEME13

it then seems likely that the intermediate dienamide that underwent cyclization was 140 in which the internal double bond was E. Cyclization of the urethane 141 with phosphorus oxychloride gave the amide 142, which was then transformed to 143 by reduction with LiAlH,. An intramolecular [3 + 21 dipolar cycloaddition reaction has also been exploited in the design of a concise, stereospecific synthesis of (*)-a-lycorane (57) (119).Thus, cyclization of the azomethine ylide 145, which was produced in situ by the reaction of 144 with N-benzylglycine, in refluxing toluene furnished the cis-hydroindole 146 as the exclusive product (Scheme 14). The transformation of 146 to racemic a-lycorane (57) was then achieved by N-debenzylation via catalytic, transfer hydrogenation and subsequent Pictet-Spengler cyclization.

283


Bh 144 145

146

SCHEME14

4.A+D+B+C A different approach to the lycorane skeleton has entailed the construction of

an AD subunit followed by the elaboration of the B and C rings, but the only successful applications of this strategy have involved intramolecularDiels-Alder reactions as the key step for the simultaneous construction of the BC ring moiety. One attempt to form the B and C rings in a stepwise fashion commenced with the acid-catalyzed cyclization of 148 to give 149 (Scheme 15) (120); however, the subsequent conversion of 149 to an intact lycorane has not been reported. The first Diels-Alder entry to the lycorane skeleton according to this strategy was only moderately successful. Namely, the triene 150, which was prepared in approximately seven chemical operations from 2-carboxybenzaldehyde, underwent nonstereoselective cyclization in refluxing o-dichlorobenzene to provide the isomeric lactams 151 and 152 in a 1 : 0.84 ratio (121). In contrast, the related triene 156 cyclized in refluxing chlorobenzene to give the lactam 157 as the sole product (Scheme 16) (122). The triene 156 was readily accessible from the acid 153 via a sequence that entailed the Ph,P/CCl,-mediated coupling of 153 with 3pyrrolidinol followed by oxidation with pyridine-SO, complex in dimethyl sulfoxide (DMSO) to give 154. Further elaboration of 154 to 155 was achieved in one step by a Emrnons-Homer reaction or by Wittig olefination followed by equilibration. Conversion of 155 to the triene 156 was then accomplished by

STEPHEN F. MARTIN

147

148

0

_.__,

*(0 O 0 149

SCHEME15

150

151:

a-Ha

152

P-Ha

reduction of the ester function with lithium borohydride followed by treatment with o-nitrophenylselenocyanateand tributylphosphine and subsequent oxidative elimination. Further confirmation of the structural identity of 157 was provided by its transformation via catalytic hydrogenation to give (+-)-7-oxo-cw-lycorane (134).


153

285

154

0 157

SCHEME 16

5.C+D-+A+B Another important entry to the skeletal framework of the alkaloids related to lycorine has involved the formation of the B ring from an ACD precursor by different arylation protocols. Although the first examples of these processes typically involved photocyclizations of substituted N-benzoyl indolines such as 158-160 and enamides such as 165-167, cyclizations of benzyne intermediates and electrochemical oxidative cyclizations have recently proved to be useful. Early workers in this area noted that when 158 was irradiated, it suffered

286

STEPfEN F. MARTIN

primarily N-deacylation and photo-Fries rearrangement rather than the expected cyclization, whereas the photocyclization of the 2-bromobenzoylindoline 159 proceeded in good yield to furnish anhydrolycorine-7-one (161) (123). The related 2-iodobenzoylindoline 160 also underwent photocyclization to provide 162, albeit in lower yield. The corresponding N-benzoyl indole derivatives do not undergo photocyclization to provide the lycorane system, but rather cyclize onto

158: X = H R, R = OCH2O 159: X=&:R.R=OCH20 160: X = I : R = H

161: R, R = OCH,O 162: R = H

C-2 of the indole ring or undergo photo-Fries migration followed by cyclization (124). An important advance was made when it was observed that photolysis of the P-enamido ketone 165, which was readily available from the indoline 163 by Birch reduction followed by N-aryloylation, delivered the lactam 168 as the only photoproduct (Scheme 17) (125). Reduction of 168 with LiAlH, gave (?)-aanhydrodihydrocaranine(143), which was then converted to (*)-y-lycorane (93) on hydrogenation over Adams catalyst in acetic acid. In a similar fashion, irradiation of the bromo or iodo enaminones 166 (Z = Br, I), which were obtained by alkylation of the intermediate imino ether formed on Birch reduction of 163, afforded a mixture (approximately 3 : 2) of the lactam 168 together with the photoreduction product 167 (126). Another useful method for effecting the ring closure of the bromo- and iodoaryl enaminones 166 (Z = Br, I) featured an intramolecular electrophilic arylation process involving benzyne intermediates (127).For example, treatment of 166 (Z = Br, I) with lithium diethylamide at room temperature afforded the pyrrolophenanthridone 169. When 169 was treated with oxygen in aqueous ethanol containing potassium hydroxide, the vinylogous imide 168 was produced (125). Alternatively, direct reduction of 169 with LiAlH, proceeded via stereoselective 1,4-additionto give a mixture (about 3 : 1) of (*)-ol-dihydrocaranone (170) together with (*)-1-epi-y-dihydrocaranine (171). While the cyclization of 167 to 168 may also be effected by preparative electrochemical oxidation at + 1.50 V (SCE) in fair yield, the application of this technique to the vinylogous

287


163

16B: 169:

165: 166:

X=OZ=H X=b;Z=Br~rl

167:

X=H,;Z=H

X=O

170:

X=O

X=Ht

171:

X = a a H , PH

SCHEME17

hide 165 afforded only poor yields of the cyclization product 168, presumably because of the higher potential required to effect the anodic oxidation of 165 (128).

6. Other Synthetic Studies Diacetyllycorine (3) has been stereoselectively transformed to O-demethylungiminorine (174) by a sequence of reactions that was initiated with the oxidation of diacetyllycorine (3) with potassium permanganate under carefully controlled conditions to yield the lactam glycol 172 together with minor amounts of other oxidation products (129). The relative stereochemistry of cis-glycol array in 172 was established by extensive analysis of the 'H-NMR spectra of 172 and its derived triacetate 173. The observed coupling constants were consistent with the assignment of the a-orientation for the cis-glycol moiety on a C ring that resided in a distorted boat conformation. Dehydration of 173 with thionyl chloride in pyridine followed by hydride reduction furnished the unsaturated trio1 174. Ungiminorine (32) was prepared from acetylhippamine (177) by an identical sequence of reactions (129).

288

STEPHEN F. MARTIN

174:

1R: R = H 173:

32

R=Ac

R=H R=Me

An improved method for the conversion of lycorine to hippamine (5)has been developed that commenced with the conversion of 2 to the chloride 175 by the action of phosphorus oxychloride and hydrochloric acid (Scheme 18) (129). The retention of configuration at C-2 was presumably the result of a double inversion sequence involving the participation of the acetate group at C- 1. Brief treatment of 175 with sodium methoxide in methanol at 0°C proceeded readily to provide lycorene a-oxide (176), which furnished hippamine (5) when heated with so-

;

2: R=OH R=CI

176

175:

OR

1

5 17R

178

R=H R=Ac

SCHEME 18


289

dium methoxide in methanol. These results served not only to c o n f m the structure of ungiminorine (32), but they also provided chemical support for the proposed biosynthesis of 32, which had been suggested to proceed via the aepoxide 178 since it had been determined that galanthine (16) was converted into narcissidine (31) via stereospecific loss of the p r o 4 hydrogen at C-4 (130). Oxidation of lycorine (1) with selenium dioxide in acetic acid provided the antitumor agent ungeremine (179) (131). 0-

179

111. Lycorenine-Type Alkaloids A. ISOLATIONAND STRUCTURAL STUDIES The effects of changing solvents on the proton chemical shifts of hippeastrine (180) has been studied (91), and fluorescence studies of lycorenine (184) have been conducted (92). The I3C-NMR spectrum of clivonine (187) has been assigned based on multiplicity, single frequency proton decoupling, lanthanide shift reagents, and empirical calculations of chemical shifts although there remain some ambiguous assignments (132). The crystal and molecular structure of 17-epihomolycorine (194) has been established by X-ray analysis (133). Several new lactone alkaloids (134) have been isolated from the various species of the genus Crinum (33,135), from Clivia miniata Regel (8-11,13-15,17), and from other genera (61,66). For example, the structures of 5-a-hydroxyhomolycorine (182) and 9-0-demethylhomolycorine (183) were deduced by extensive spectroscopic studies (33). These alkaloids exhibited a mass spectral fragmentation pattern that is characteristic of the lactone alkaloids of the benzopyrano[3,4-g]indole series in that these substances typically undergo fragmentation via a retro-Diels-Alder cleavage of the C ring to give abundant ions representing a pyrrolidine ring fragment and another less intense fragment from the portion of the molecule containing the aromatic lactone moiety. The stereochemistry of 182 and 183 was assigned on the basis of 'H-NMR spectroscopy. That 183 was the 9-0-demethyl and not the 10-0-demethyl derivative of homolycorine was supported by a combination of NOE studies coupled with the

290

STEPHEN F. MARTIN

Hweastrine Hmolycwine 5-a-Hydroxyhdymine 40-Dernethylhomolymrine Lymrenine

187: R = H 188: R=CCCH,CCCH, 189 R = COCH*CH(OH)CH, 180: R=COC,H5 191: R = lEC ; ;=

Clivonine Clivacetirm Clivatine Pcetinaline Cliviarnartine

O-Methyllycorenine

Me

Oduline

192

193

194

complete assignment of the 13C chemical shifts of the carbons via ErnestDoddrell INEPT procedures to establish atom connectivities. The absolute configuration of these alkaloids was established by their CD spectra, and a strong case was made for the diagnostic utility of the CD spectra of the lactone bases for providing absolute stereochemical information. Although the CD spectra of a number of lactones were presented, a more extensive compilation is desirable before sector rules can be defined. Finally, it should be noted that the compound


29 1

183 isolated during these investigations was not identical to a compound previously reported as being 9-O-demethylhomolycorine, as judged by a comparison of melting points. In other NMR studies, the diagnostic utility of N-methyl chemical shifts for assigning the stereochemistry of the BC and CD ring junction of the lactone alkaloids has been demonstrated (135). The structure of the lactone alkaloid 199, which was isolated from Clivia noblis and represents the first member of this series of alkaloids possessing the trans-BC and trans-CD ring fusion, was deduced largely from its mass spectral fragmentation pattern and NMR spectra. The stereochemicaldetails were based on careful analysis of the vicinal coupling constants for 199 in comparison with other related alkaloids (135). A number of new ester derivatives of clivonine (187) have been isolated. The structure of clivacetine (188) was initially deduced from spectral data, with further support being obtained by its conversion via hydride reduction followed by acetylation to the 0-acetate derived from clivatine (189) (8). Furthermore, heating a mixture of clivonine (187) and diketene in the presence of triethylamine provided clivacetine (188), thereby confirming the structural assignments previously proposed for 188 and 189 (136). Poetinatine was assigned the structure 190 based on spectral studies coupled with the chemical evidence that its hydrolysis led to the formation of clivonine (187) and propionic acid (66). In a similar fashion, the structure of cliviamartine (191) was deduced from spectral evidence coupled with its degradation by saponification and relactonization to clivonine (187); furthermore, the reductive cleavage of the ester moiety of 191 afforded 3,5-bis(hydroxymethyl)-2,6-lutidine (13). Clivonidine, which is a dehydrated form of clivonine, has been tentatively assigned the structure 193 on the basis of spectroscopic evidence (9). Although the gross features of the structure of clivisyaline (198) were deduced from NMR, IR, and mass spectroscopy, the assignment of stereochemical details appeared to be based solely on CD spectral comparisons (11). Clivojuline (195) (10)represents an unusual structural type since it lacks the 9,lO-aromatic oxygenation pattern, which is ubiquitious among the other lactone alkaloids. The structure of the related alkaloid cliviahaksine (196) was assigned on the basis of spectral comparisons with 195 although its stereochemistry was not specifically indicated (15). Since cliviaaline (197) was isolated in only very small amounts, its structure was deduced principally from its IR spectrum and its mass spectral fragmentation pattern; however, the possibility that it was an artifact was not rigorously excluded (14). B . BIOLOGICAL ACTIVITY During the course of screening plants for insect antifeedants, the extract of the bulbs of Lycoris radiata Herb. was found to exhibit antifeeding activity when tested against the larvae of the yellow butterfly Eurema hecabe mandarina (61).

292

STEPHEN F. MARTIN

Clivojuline Cliviahaksine Cliviaaline

199

198

Whereas hippeastrine (180) and 0-methyllycorenine (185) exhibited slight feeding inhibitory activity, 9-0-dernethylhornolycorine(183) was one of the main antifeedants isolated (61).

C. BIOSYNTHETIC STUDIES Although feeding studies of [8-3Hlnorpluviine(14) to Narcissus pseudonarcissus L. (King Alfred daffodils) afforded primarily labeled alkaloids of the lycorenine-type including lycorenine (184) and homolycorine (181), there was also some incorporation of 14 into pluviine (15), galanthine (16), and methylpseudolycorine (137). Thus, 14 was converted much more readily by oxidation and rearrangement to the lycorenine-type nucleus than it was simply rnethylated or oxidized to give other alkaloids of the lycorine-type. In related feeding experiments in Narcissus poeticus, [8-3H]pluviine(15) was incorporated into lycorine

3. THE AMARnLIDACEAE ALKALOIDS

293

(l),galanthine (16), methylpseudolycorine, and narcissidine (31), but there was no incorporation of label found in lycorenine (137). As a result of incorporation studies in Inglescombe and Tresamble daffodil using doubly labeled norpluviine (14), which had been prepared by feeding (1 'R)-O-[1'-3H, l-14C]methylnorbelladine to the Texas daffodil, it was established that during the oxidation of 14 to give lycorenine (184), a pro-R hydrogen atom was removed from C-7 of 14 (138). Feeding experiments with doubly labeled 3-hydroxy-4-[14C]methoxy-N-methY~-(R-[~H]and -(S)-[3H]N-benzylamines in King Alfred daffodils produced oduline (186) with high (82-85%) tritium retention (139). This observation suggested that the incorporation of N-methylisovanillamineinto 186 occurred by a nonstereospecific process in which hydrogen removal from the benzylic position was governed by a kinetic isotope effect. D. SYNTHETIC STUDIES In support of an hypothesis that clivacetine (188) might be a possible biosynthetic precursor of the unusual alkaloid clivimine (192), a biogenetic-type, partial synthesis of 192 from 188 has been completed, exploiting a classic Hantzsch pyridine synthesis (136). Thus, treatment of 188 with 35% formalin and 25% ammonium hydroxide gave dihydroclivimine, which underwent facile oxidation to clivimine (192) on dehydrogenation with sodium nitrite and acetic acid. Synthetic approaches to the alkaloids of the lycorenine type developed thus far have adopted a strategy for the construction of the skeleton according to the sequence A * CD + B . In one such approach, the cyclic imide 200, which was prepared in a straightforward fashion in two steps from the urethane ester 61, served as a key intermediate in the total syntheses of clivonine (187) and the diastereomer clividine (206) (Scheme 19) (110). Thus, 200 was converted to the aryl-substituted amine 201 by chloromethylation of the aromatic ring followed by reaction of the intermediate chloromethyl compound with silver acetate in acetic acid/acetic anhydride and then treatment with LiAlH,. Subsequent oxidation of 201 with osmium tetraoxide in pyridine furnished a separable mixture (1 : 1) of the diastereomeric triols 202 and 203. Acid-catalyzed cyclization of 202 and 203 gave the corresponding ethers 204 and 205, which were converted to (I+-)-clivonine(187) and (+-)-chidine (206) by benzylic oxidation with manganese dioxide. A simple variant of this strategy has been applied to the successful synthesis of (-+)-hippeastrine(180) (Scheme 20) (140). In the event, vigorous hydrolysis of the urethane ester 61 followed by the carbodiimide-induced cyclization of the resulting amino acid and N-methylation with sodium hydride in methyl iodide furnished the lactam 207. Conversion of 207 to 208 was achieved by chloromethylation followed by reaction of the intermediate chloromethyl compound

d”

294

STEPHEN F. MARTIN

\

200 201

.

P -Ha

204:

X = H2:

205: 187: 206:

X = H2: a -Ha

X = O P-Ha X=O; a-Ha

SCHEME19

with silver acetate in acetic acid/acetic anhydride. When 208 was treated with MCPBA, the P-epoxide 209 was isolated as the sole product. This result might be contrasted with the lack of stereoselectivity that had been previously observed for the osmium tetraoxide-induced vicinal hydroxylation of 201 (110). The reaction of 209 with acetic acid and acetic anhydride in the presence of boron trifluoride etherate proceeded with selective nucleophilic opening of the epoxide at C-5 to afford an intermediate triacetate, and subsequent saponification and manganese dioxide oxidation delivered dihydrohippeastrine lactam (210). The selective reduction of the lactam moiety of 210 to give (+)-dihydrohippeastrine (211) was smoothly effected by 0-ethylation with Meerwein reagent followed by treatment of the resulting imidate with sodium borohydride. Alternatively, dehydration of the hydroxy lactam 210 was achieved by the

295


207: 208:

R=H R=CH,OAc

8 209

0

(o

- 0-

\

0

210

x=o

211:

X=H2

212

(0,

\ 0

213:

X=O

180:

X=H2

SCHEME 20

296

STEPHEN F. MARTIN

elimination of the derived mesylate on heating with LiCl/LiCO, in dimethylformamide (DMF) to furnish 212. Stereoselectiveepoxidation of 212 with MCPBA proceeded from the CL face, and a sequence of nucleophilic opening of the epoxide ring using phenylselenide ion followed by oxidative elimination provided the allylic alcohol 213. Although the direct reduction of the lactam carbony1 of 213 to yield (?)-hippeastrine (180) proved troublesome, success was achieved by employing a sequence of reactions involving O-acetylation of the C-5 hydroxyl group of 213, O-methylation of the lactam with Meerwein reagent, zinc borohydride reduction of the imidate ester, and final saponification of the C-5 allylic acetate (140).

IV. Narciclasine-Type Alkaloids A. ISOLATION AND STRUCTURAL STUDIES Kalbreclasine (216), representing another member of a growing family of glucosyloxy alkaloids, has been identified as the 2-O-p-~-glucopyranosideof narciclasine (215) based on spectroscopic studies coupled with the fact that enzymatic hydrolysis of 216 with emulsin produced narciclasine and D-glucose (46). The phenanthridones 219 and crinasiatine (220) have been isolated from Crinurn usiuticum (22). The structure of pancratistatin (221) has been established by the X-ray crystal structure determination of its monomethyl ether 222 (72). Based primarily on a mass spectral analysis, the gross structure 223 has been suggested for the new phenolic alkaloid narcicrinine (39). Whereas narciclasine (215) had been previously shown to be identical with lycoricidinol, the mutual identity of lycoricidine (214) and margetine has now also been established by a comparison of the 'H-NMR spectra of the derived triacetates (141). Although the names narciclasine and margetine have chronological priority, common usage appears to have. established narciclasine and lycoricidine as the preferred names. In agreement with a previous recommendation (141), and to avoid any further confusion in the literature, this nomenclature should be maintained.

B . BIOLOGICAL ACTIVITY Narciclasine (215) is an antitumor agent which exerts an antimitotic effect during metaphase by immediately terminating protein synthesis in eukaryotic cells at the step of peptide bond formation (97,101,141,142), apparently by interaction with the ansiomycin area of the ribosomal peptidyl transferase center (142). The alkaloid has also been found to inhibit HeLa cell growth and to stabilize HeLa cell polysomes in vivo (97). Although DNA synthesis was retarded by narciclasine, RNA synthesis was practically unaffected (97,142). Sev-

297

3. THE AMARYLLIDACEAE ALKALOIDS OR

* OH

OH

0 NH

R'

0

OH

220

221:

R=H

222:

R=Me

223

era1 narciclasine analogs such as compounds 224, 225, and 229 also exhibited strong cytostatic activity, but 226 and 231 had no antitumor activity while 230 exhibited diminished activity (141). Kalbreclasine (216) caused the significant mitogenic activation of splenic lymphocytes that is characteristic of immunostimulants (46). Both of the phenanthridones 219 and 220 exhibited notewor-

298

STEPHEN F. MARTIN

thy bacteriostatic and tumor-inhibiting activity (22). Pancratistatin (221) also exhibited anticancer activity in the murine P388 lymphocytic leukemia, PS system, and against the murine M5076 ovary sarcoma (72). Lycoricidine (214) and narciclasine (215) showed antifeedant activity against the larvae of the yellow butterfly, Eurema hecabe mandarina, and 215 also exhibited potent insecticidal action (61). C. BIOSYNTHETIC STUDIES

Feeding experiments with specifically labeled 11-hydroxyvittatine have provided evidence of its intermediacy in the biosynthesis of narciclasine (215) (143).

D. SYNTHETIC STUDIES A number of potentially useful chemical transformations of narciclasine (215) have been reported (141). For example, 215 may be converted to its monomethyl

226: 2273 228:

R'=OH;R~=H R',R~=o R' = H;R~ =OH OH

231


299

ether 224 by reaction with diazomethane and to its triacetate 225 by brief treatment with acetic anhydride in pyridine. Reaction of 215 with acetone in the presence of copper sulfate and a catalytic amount of p-toluenesulfonic acid gave the acetonide 226,which was oxidized with MnO, to provide the acid- and basesensitive enone 227. Reduction of 227 with sodium borohydride gave a mixture (2 : 1) of 226 and 228, whereas reduction with aluminum amalgam furnished 226. Catalytic hydrogenation of 215 with Pd/CaCO, in ethanol gave a trandcis mixture (1 : 2) of 229 and 230, whereas hydrogenation over Adams catalyst (PtO,) proceeded with a higher degree of stereoselectivity yielding a mixture ( 1 : 11) of 229 and 230. In these catalytic reductions, lesser amounts (1 3- 14% with Pd and 25% with Pt) of the isomerization product isonarciclasine (231)were always obtained. The majority of the approaches that have been adopted for the synthesis of narciclasine (215),lycoricidine (214), and related alkaloids have involved the strategy of constructing the ring system in the order A + C -+B. There have also been examples of the A -+BC and C -+ A + B type.

1. A + B C An efficient entry to the cis-dihydrolycoricidinenucleus (Scheme 2 I) featured the intramolecular [4 + 21 cycloaddition of the trimethylsilyloxydienamide 234 (144). Thus, alkylation of the sodium salt of the secondary amide 232, which was prepared from 153 via a mixed anhydride, with cis- l-chloro-2-butene-4tetrahydropyranyl ether provided 233. Acid-catalyzed removal of the tetrahydropyranyl protecting group followed by oxidation of the resulting alcohol with pyridinium chlorochromate afforded an intermediate aldehyde, which on exposure to excess triethylamine and trimethylchlorosilane in dry DMF at reflux gave an inseparable mixture (approximately 3 : 1) of the cis-lactams 235 and 236,respectively, via the Diels-Alder cyclization of the dienamide 234. It was presumed that 236 resulted from the acid-catalyzed isomerization of the trimethylsilyl ether derived from 235 under the conditions that were employed for the intramolecular Diels-Alder reaction of 234, although this hypothesis was tentative. Treatment of the mixture of 235 and 236 with excess acetic anhydride in pyridine followed by stereoselective, vicinal hydroxylation of the double bond using catalytic osmium tetraoxide furnished a mixture of diols that was acetylated to give the triacetates 237 and 238. Removal of the N-benzyl group proved troublesome, but it was ultimately achieved by hydrogenolysis over palladium chloride in ethyl acetate-acetic acid (4 : 1) to provide the separable triacetates 239 and 240. Modification of this route should allow facile access to naturally occumng alkaloids related to lycoricidine (214)and narciclasine (215).

300

STEPHEN F. MARTIN

OTHP

233

232

OTMS

0

0 234

Ph

235: R’ =OH; R~ = H

ns: R’=H;R‘=OH

237:

R1=OA~R2=H;R3=CH2Ph

238: R’ =H;R2 = O M R3=CH2Ph 2 3 9 R1=OAc;R2=R3=H

240: R ’ = R 3 = H R 2 = O A c

SCHEME 21

2. A - + C - , B

The Michael addition of doubly deprotonated acetyl acetaldehyde to the nitrostyrene derivative 108 yielded 241, which was converted to 242 by sequential ketalization and catalytic hydrogenation (Scheme 22) (115). Since conventional

30 1


24 1

242:

2= H

243:

Z=Br

0

244

SCHEME 22

methods for effecting the direct formation of the C ring of lycoricidine from 242 proved unsuccessful, an alternate tactic was employed. Namely, bromination of 242 gave the aryl bromide 243, which was allowed to react with benzaldehyde to give a hydroxy imine that underwent palladium-catalyzedCO insertion to furnish 244, albeit in low yield. The lactam 244 might serve as a useful intermediate for the synthesis of trans-dihydrolycoricidine, but this conversion has not yet been reported. The photocyclization of substituted benzanilides has also been explored as a concise entry to narciprimine (218) and other unsymmetrically substituted phenanthridone alkaloids of the narciclasine family (Scheme 23). Although irradiation of 245 in the presence of iodine afforded 248 in only 4% yield, photolysis of the corresponding bromo-substituted benzanilides 246 and 247 provided 248 and 249, respectively, in 24% and 15% yields (145). Removal of the 0-benzyl protecting groups from 248 and 249 by catalytic hydrogenolysis gave arolycori-

302

STEPHEN F. MARTIN

248: R’ = H; R2 =OCH2Ph 249: R’ = !$= OCH,Ph 217: R ’ = H ; R ~ = O H 218: R’ =R‘=OH

SCHEME23

cidine (217) and narciprimine (218), respectively. Despite the low yield of the photocyclization step, this approach is attractive because of its brevity. An alternate entry to the narciclasine class of alkaloids has provided access to compounds related to isonarciclasine (263) (Scheme 24). In the event, the arylation of p-benzoquinone with diazonium salts derived from the aryl mines 250 and 251 yielded the aryl-substituted benzoquinones 252 and 253, respectively (246).The selective hydroxylation of 252 and 253 with osmium tetraoxide provided the corresponding cis-diols 254 and 255. Catalytic hydrogenation of 254 and 255 using Pd/C or Raney Ni and subsequent lactonization gave the triols 256 and 257 together with small amounts of the C-2 a-epimers 258 and 259. Aminolysis of 256 and 257 afforded the corresponding racemic tetrahydrophenanthridones 260 and 261, whereas similar treatment of the a-epimers 258 and 259 led to the formation of (+)-isolycoricidine (262) and (+)-isonarcidashe (263), respectively. The Diels-Alder cycloadduct 264, which had been previously employed as an intermediate in the syntheses of the 1I-oxygenated ethanophenanthridine alkaloids (vide infia), has also been converted to the trans- and cis-(*)-dihydrolycoricidines 270 and 271 (Scheme 25) (147).Thus, N-acylation of the keto lactam 264 with methyl chloroformate followed by the chemoselective hydrolysis of the resulting imide moiety and oxidative cleavage of the intermediate keto acid with basic hydrogen peroxide afforded the urethane acid 265. Bromolactonization of 265 followed by dehydrobromination using 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) afforded the unsaturated lactone 266. The subsequent stereoselective, vicinal hydroxylation of 266 with osmium tetraoxide and 0-acetylation followed by formation of the B ring using a modified Bischler-Napieralski reaction provided 267. Saponification of the lactone and acetate functions proceeded smoothly, but irradiation of the hydrolysate to effect the photochemical decarboxylation and acetylation of the resulting products afforded an


(0 0

250: R‘=H

252:

R’=H

251: R1=OCH2Ph

253:

R’=OCH-$‘h

&: \

c0,m

254: R ’ = H

256: R’ = R3 = H; R2 =OH

255: R1=OCH2Ph

257: R’ = $ =OH; R3 = H 258: R‘ = R2 =H: R3 =OH 259: R’ =R3=OH;R2=H

260: R’=R3=H;R2=OH 261: R’=$=OH;R3=H 262: R’ = R2=H;R3 =OH 263: R’ = R3 =OH: R2= H

SCHEME 24

303

304

STEPHEN F. MARTIN

264

265

-

OAc

0

266

267

a-H,;R=Ac

269 2703 271:

p-H,;R=Ac a-H,:R=H P-H,;R=H

SCHEME 25

approximately 1 : 1 mixture of the trans- and cis-lactams 268 and 269. The lack of stereoselectivity in the photochemical decarboxylation step stands in contrast to results obtained in model systems in which only the trans-fused isomers were observed. Removal of the acetates from 268 and 269 using methanolic ammonia produced the corresponding trans- and cis-( k )-dihydrolycoricidines (270 and 271). The total synthesis of (*)-lycoricidine (214) from the aryl cyclohexene 272, which was accessed by a Diels-Alder reaction of the carbinol 46, has been

305


recorded (Scheme 26) (148).The isocyanate 273 was prepared from the acid 272 by a Curtius reaction, and 273 was cyclized through the agency of BF,/EhO, a reagent that may be of general utility for effecting the cyclizations of substituted phenethyl isocycanates, to deliver the unsaturated lactam 274. Allylic bromination of 274 with pyridinium hydrobromide perbromide in acetic acid followed by

0

0 272:

R=C02H

273:

R=NCO

274:

R=H

275:

R=Ac

276

277 OR'

278

281

SCHEME 26

282:

R=Ac

214:

R=H

306

STEPHEN F. MARTIN

the base-induced dehydrobrominationwith DBU and subsequent aerial oxidation gave the phenanthridone 219 (148a,b). In a different sequence of reactions, N-acetylation of 274 and exposure of the intermediate imide 275 to ethanolic KOH gave a mixture (about 2 : 1) of the desired carboxylic acid 276 together with the starting lactam 274 via the nonselective hydrolysis of the imide moiety of 275 (148a,c).When 276 was treated with N-bromosuccinimide (NBS), an intermediate bromolactone was produced which was heated at reflux in pyridine in the presence of DBU to give 277. The conversion of the lactone 277 to the lactam 278 was effected by heating 277 in aqueous NaOH followed by protection of the resulting allylic alcohol function as a tetrahydropyranyl ether. Epoxidation of 278 with MCPBA proceeded stereoselectively from the less hindered (Y face to give an epoxide, which underwent preferential nucleophilic opening at C-3 with phenylselenide anion, and oxidative elimination of the intermediate hydroxy phenylselenide afforded 279. Acetylation of 279 followed by acid-catalyzed deprotection of the C-1 hydroxyl function gave 280, and the subsequent elaboration of 280 to 281 was achieved by vicinal hydroxylation with stoichiometric osmium tetraoxide followed by formation of the acetonide moiety using 2,2-dimethoxypropane and catalytic p-toluenesulfonic acid in DMF. Installation of the double bond at C-lOb,C-1 was effected by dehydration with thionyl chloride in pyridine, and removal of the acetonide protecting group with trifluoroacetic acid and subsequent acetylation then gave (+)-lycoricidine triacetate (282). Treatment of 282 with methanolic ammonia completed the total synthesis of (5)-lycoricidine (214). Arolycoricidine (217) could also be prepared from 281 by sequential dehydration, using first thionyl chloride in pyridine and then concentrated hydrochloric acid in hot methanol ( 1 4 8 ~ ) . 3. C + A + B A relatively concise, asymmetric total synthesis of (+)-lycoricidine (214) (Scheme 27) has also been reported commencing with the aldehyde 283, which was readily available from D-glucose (149). Thus, 283 was converted to the nitro olefin 284 by condensation with nitromethane followed by elimination. The conjugate addition of the unstable aryllithium reagent 285 to 284 at -110°C afforded a mixture (4 : 5) of D-gluco and L-ido components, and since it was not possible to separate these intermediates by chromatography, the mixture was heated with 50% aqueous acetic acid to remove the acetonide protecting group. The resulting cyclitol derivative was then lactonized with methanolic NaHCO, to give 286 as the only crystalline product. Reduction of the nitro function of 286 by catalytic hydrogenation over Pd/C proceeded with concomitant O-debenzylation to provide 287, which underwent rearrangement to the lactam 288 on heating with K,CO, in methanol. Reaction of the tetra01 288 with benzoyl chloride in

307


283

284

288:

R=H

289

R=COPh

OR

0

290:

R=COPh

214:

R=H

SCHEME

27

pyridine in the presence of 4-dimethylaminopyridine(DMAP) gave the tribenzoate 289, and subsequent dehydration of 289 with thionyl chloride in toluene and pyridine delivered 290. Removal of the benzoate protecting groups with methanolic ammonia then completed the first total synthesis of optically pure (+)lycoricidine (214).

308

STEPHEN F. MARTIN

V. Galanthamine-Type Alkaloids A. ISOLATION AND STRUCTURAL STUDIES Galanthamine (291) (91,92) and lycoramine (299) (150)have been the subject of several spectroscopic studies, and a partial assignment of the 13C-NMRspectrum of 291 has been made although there were some ambiguities for some of the resonances (132).There have also been chromatographic studies of both 291 and 299 (151). The X-ray analysis of (+)-N-demethylgalanthamine (292) has been completed ( 3 4 , and this report corrected a previous one in which the structure had been erroneously assigned as galanthamine (291) (35). The structure of sanguinine (295) was initially based on spectroscopic comparisons with galanthamine (291) and related alkaloids, but this assignment was subsequently verified by its conversion to 291 by methylation with diazomethane in DMSO (62).Thus, 295 represented the second example of a phenolic base among the galanthamine-type alkaloids. The two novel alkaloids leucotamine (296) and 0-methylleucotamine (297) were shown to be the (3R)-hydroxybutyryl esters of galanthamine (291) (59) as deduced by analyses of their 'H-NMR spectra coupled with spectral comparisons with 291. Moreover, chemical support for this assignment was obtained by methylation of 2% with diazomethane to afford 297, which was then converted by saponification to galanthamine. Optically impure 0-methylleucotamine acetate was prepared by the acylation of galanthamine with optically impure ( 3 0 acetoxybutyroyl chloride in the presence of boron trifluoride etherate. The alkaloids 296 and 297 were the f i s t galanthamine-type alkaloids reported to possess a (3R)-hydroxybutyryl group, which is of some interest from a biosynthetic point of view (see Refs. 8 and 136) as these alkaloids may be the biosynthetic precursors of sanguinine (295) and galanthamine (291). The structure of another phenolic base 0-demethyllycoramine (300) was deduced from spectroscopic evidence, and this assignment was confirmed by its preparation from lycoramine (299) by demethylation on heating with dry pyridine hydrochloride (63). Other new alkaloids of this family include 2-epilycoramine (302) and N-allylnorgalanthamine (293) (60).

B . BIOLOGICAL ACTIVITY There has been considerable interest in evaluating the biological activity of galanthamine (291) and related compounds. For example, it has been claimed that (-)-galanthamine and (&)-galanthamine exhibit analgesic activity in mice comparable to that of morphine (152), and anhydro-0-demethylgalanthamine (303) showed similar analgesic activity (153).Moreover, galanthamine has also been shown (a) to inhibit reversibly cholinesterases (154); (b) to reverse nondepolarizing, neuromuscular block and restore synaptic transmission (155); (c) to

3.

309

THE AMARYLLIDACEAE ALKALOIDS

291:

R’ =H;R2=R3=Me

Galanthamine

292:

R’=R2=HR3=Me

Norgalanthamine

293

R’ =H;R2=C3H,;R3=Me

294:

R’=R2=AC;R3~Me

N-Aliyinwgalantha~ne 0.N-DicalyCNdemelhylgalant~mine

295

R’=R3=HR2=Me

Sanguinine

296:

R‘ = CG€H&H(OH)CY R2=Me; R3= H

297:

R’ = COCIY;H(OH)CH;

R2= R3= Me

Leuoolamine O-Methylleucolamine

RO

Me0

-Me

N-Me

299:

298

R=Me

300: R = H

Me0

HO

N -Me

N-Me

301: A33.4 302 3,4dihydro

303

inhibit traumatic shock (156); (d) to cause bradycardia or atrioventricular conduction disturbances (157); and (e) to exhibit potent insecticidal action against the yellow butterfly, Eurema hecabe mandQrina (61). The related alkaloid narwedine (298) has been found (a) to increase the amplitude and frequency of respiratory movements; (b) to increase the amplitude and decrease the frequency

3 10

STEPHEN F. MARTIN

of cardiac contractions; (c) to potentiate the analgesic effects of morphine; and (d) to exhibit hypotensive activity (158). C. BJOSYNTHETIC STUDIES Feeding experiments with doubly labeled 3-hydroxy-4-[14C]methoxy-N-methYI-(R)-[~H]-and -(S)-[3H]N-benzylaminesin King Alfred daffodils yielded galanthamine (291) with high (82-85%) tritium retention (139). This observation suggested that the incorporationof N-methylisovanillamine into 291 occurred via a nonstereospecific process in which hydrogen removal from the benzylic position was governed by a kinetic isotope effect.

D. SYNTHETIC STUDIES A variety of entries to the galanthamine-type alkaloids have been devised, but the single most widely investigated strategy, which has been successfully applied to the total synthesis of galanthamine (291), has involved a biomimetic approach of the type A --., B + C + D. The principal synthetic challenge posed by these substances is the construction of the quaternary carbon atom, and several other ingenious solutions to this problem have resulted in efficient approaches to lycoramine (299), although it seems likely that appropriate modification of the tactics should allow access to galanthamine (291) itself. 1. A - + B + C - + D Early efforts directed toward the total syntheses of galanthamine (291) and related alkaloids were based on their biogenesis, and this general approach has resulted in the most concise syntheses of these natural bases. For example, the phenolic oxidation of norbelladine derivatives of the general type 304 led to the formation of the narwedine-type compounds 306 via the intermediate dienones 305 (Scheme 28) (159). One of the problems encountered in early work in this area was the formation of the desired product in low yields. Furthermore, complex product mixtures typically arose from intermolecular coupling reactions of the electron-deficient intermediate, which was presumably a radical cation, and/or of the cyclized product. In this regard it should be recognized that the products were sometimes more easily oxidized than the reactants. Another major difficulty lay in the development of tactics and methods to control the ortho-para regioselectivity in the carbon-carbon bond forming step, and various blocking groups Z, which must be later removed, have been strategically positioned on the A ring to direct the regiochemical course of these oxidative cyclizations. Considerable effort has also been expended in discovering new reaction conditions and oxidizing agents to replace the classical oxidants K,Fe(CN),, FeCI,, MnO,, and

31 1


OH

I

Meo+ -

Y

Y 304

305

H

306 X, Y = H,, 0; Z = H. Br

SCHEME28

Ag,O. Protection of the basic nitrogen as an amide moiety was also found to decrease the side reactions involving oxidation at nitrogen. By combining these various tactics, it is now possible to obtain good yields of compounds related to 306 via oxidative cyclizations of phenols and their derivatives. In addition to the aforementioned oxidative methods for effecting the aryl coupling required for the creation of the quaternary carbon center, photochemically induced cyclizations have proved to be of modest utility. As an example, irradiation of the bromo amides 307 (160) and 308 (161) afforded the corresponding tetracyclic lactams 309 and 310, albeit in rather low yield. The lactam 309 had previously been converted to (?)-galanthamine (291) together with a small amount of (+)-epigalanthamine (301) by reduction with LiAIH, (162). An oxidative cyclization has been exploited as the key step in the elegant asymmetric syntheses of both (+)- and (-)-galanthamine (291)(Scheme 29) (163). This biomimetic synthesis commenced with the secondary amine 311, which was readily prepared by the reductive amination of 3,5-dibenzyloxy-4-

312

STEPHEN F. MARTIN

OH

I

308: R = M e R=H

310:

methoxybenzaldehyde with L-tyrosine methyl ester. Conversion of 31 1 to 312 was effected by N-acylation with trifluoroacetic anhydride in pyridine followed by catalytic hydrogenolysis of the O-benzyl groups; subsequent oxidative cyclization of 312 with an excess of manganic tris(acety1acetonate)in acetonitrile gave the narwedine-type enone 313 in good yield. Since both aromatic rings of 312 possessed C , symmetry, there was no problem with the production of isomers during this process. In preparation for the eventual removal of the undesired oxygen function at C-10 of 313 via a Birch reduction, the phenol 313 was phosphorylated with diethyl phosphorochloridate in the presence of triethylamine to give 314, which underwent stereoselective reduction with sodium borohydride with concomitant N-deacylation to deliver the amino alcohol 315. N-Methylation of 315 by the Eschweiler-Clarke protocol using formaldehyde and formic acid followed by ammonolysis of the ester group and acetylation of the C-2 hydroxyl function afforded 316. Dehydration of the amide moiety in 316 with phosphorus oxychloride and subsequent reaction of the resulting amino nitrile 317 with LiAlH, furnished 318, which underwent reduction with sodium in liquid ammonia to provide unnatural (+)-galanthamine. Although in principle naturally occurring (-)-galanthamine could have been prepared by an identical sequence of reactions commencing with D-tyrosine, an alternate route to 319, the enantiomer of 314, was developed. Thus, epimerization of the methyl ester group at C-6 of the N-trifluoroacetamide derived from 315 followed by oxidation of the allylic alcohol with pyridinium chlorochromate furnished 319 in 78% optical purity, albeit in low chemical yield. Since 319 could be converted to (-)-galanthamine (291) by the same sequence of reactions outlined for the transformation of 314 to (+)-galanthamine, its preparation may be considered to represent a formal total synthesis of 291 from L-tyrosine (163).

313

3. THE AMARYLLIDACEAE ALKAWIDS

311:

312:

R’=CH2Ph; R 2 = H R’ = H; R’ =CCCF3

R=H R=(EIO),PO

3 1 6 R=CONHz 317: R=CN

315

R

313: 314:

N-Me

318: 291:

R=(ElO),PO

R=n

SCHEME29

Electrochemical methods have also been exploited to advantage for effecting the critical para-ortho coupling of certain diarylethers as exemplified by the anodic oxidation of 320 to provide 321 (164). Although the conversion of 321 to galanthamine (291) remains to be reported, it is already evident that this entry to this family of alkaloids has considerable potential and merits further investigation.

3 14

STEPHEN F. MARTIN OMe

I

320

321

2. A + B - , D - , C A general methodology for the construction of quaternary carbon atoms at the carbonyl carbon of ketones has been successfully exploited for the facile synthesis of (2)-lycoramine (299)(Scheme 30) (165). Thus, the 0-allylated ovanillin 322 was allowed to react with vinyl magnesium bromide followed by Jones oxidation, and the acid-catalyzed addition of benzyl N-methylcarbarnate to the intermediate a$-unsaturated ketone furnished 323. Wadsworth-Emmons olefination of 323 with the anion derived from diethyl[(benzylideneamino)methyl]phosphonate (BAMP) provided the 2-azadiene 324. The subsequent regioselective addition of n-butyllithium to 324 delivered a metalloenamine that suffered alkylation with 2-(2-bromoethyl)-2-methyl- 1,3-dioxolane to give, after acid-catalyzed hydrolysis of the imine and ketal moieties, the 6-keto aldehyde 325. Base-catalyzed cycloaldolization and dehydration of 325 then provided the 4,4-disubstituted cyclohexenone 326. The entire sequence of reactions involved in the conversion of 323 to 326 proceeded in very good overall yield and in one pot. An improved route to the key intermediate 326 was also developed (165). Namely, 322 was converted to the monoprotected 1,Cdione 327 by sequential addition of the Gngnard reagent derived from 2-(2-bromoethyl)-2-methyl-1,3dioxolane followed by oxidation of the resulting benzylic alcohol with pyridinium dichromate (PDC). The ketone 327 was then smoothly transformed to the 2azadiene 328 by olefination with BAMP. The regioselective addition of nbutyllithium to 328 as before followed by alkylation of the resulting metalloenamine with benzyl N-(2-bromoethyl)-N-methylcarbamateand acid-catalyzed hydrolysis furnished 325, which was converted to the cyclohexenone 326 by base-induced cycloaldolization and dehydration. The removal of the 0-ally1 group from 326 was readily effected with catalytic rhodium trichloride in refluxing ethanol and was accompanied by the spontaneous cyclization of the intermediate phenol to provide the cis-hydrodibenzo-

315


___)

N-Me

1

322 323: R’,R*=o 324: R’. R* = CHN=CHP~ 325: R’ =cm,R*=CYCH,COCH,

Me0

____, N-Me

I

Cbz

Cbz

329

326

Me0

R

330: R = H

327:

331: R=CHO

328: X = CHNSHPh

X=O

SCHEME30

furan 329 as the sole product. Although reaction of the ketone 329 with NaBH, or LiAIH, in ether or tetrahydrofuran (THF) proceeded to give a mixture of epimeric alcohols, the reduction of 329 with L-Selectride in THF was highly stereoselective (>40 : l), and subsequent removal of the N-protecting group by catalytic hydrogenolysis afforded the amino alcohol 330. Several attempts to

3 16

STEPHEN F. MARTIN

effect the direct conversion of 330 to (t)-lycoramine (299) via a Pictet-Spengler reaction were unsuccessful. However, formylation of 330 with acetic formic anhydride in pyridine gave 331, and subjection of 331 to a Bischler-Napieralski cyclization (POCI,) followed by reduction of the intermediate iminium salt with methanolic sodium borohydride proceeded with concomitant saponification of the formate ester to provide (t)-lycoramine (299). A more direct and comparably efficient route to 331 simply involved the catalytic hydrogenation of 329 and subsequent formylation of the amino alcohol 330 thereby produced. 3. A + C + B + D

Another useful entry to alkaloids of the galanthamine type proceeded via the intermediacy of 5-substituted tetrahydrobenzazepines such as 336, which was employed as a precursor of (?)-lycoramine (299) (Scheme 31) (166). Triton Bcatalyzed conjugate addition of nitromethane to the cinnamonitrile derivative 332 was followed by hydrolysis of the nitro function using a modified Nef reaction which led to the dimethylacetal 333. The dimethylacetal 333 was converted to the more stable dithioacetal 334, and reduction of the nitrile function with LAH/AICl, followed by acylation of the resulting amine with ethyl chloroformate produced the urethane 335. Reaction of 335 with aqueous formaldehyde and subsequent acid-catalyzed cyclization of the intermediate N-hydroxymethyl compound via a modified Tscherniac-Einhorn aromatic amidoalkylation furnished 336. When the dithioacetal moiety of 336 was hydrolyzed using red mercuric oxide and boron trifluoride, an intermediate aldehyde was obtained that was subjected to a base-catalyzed Robinson annelation protocol to deliver the cyclohexenone 337. Interestingly, treatment of 337 with AlCl, and ethyl sulfide directly provided the keto urethane 338 by a process that presumably entailed the Lewis acid-catalyzed cyclization of the oxygen of the methoxy group at C-6 onto the enone moiety followed by the selective, nucleophilic cleavage of the then activated, yet more hindered, methyl ether at C-6 by ethyl sulfide. The elaboration of the keto urethane 338 into (2)-lycoramine (299) was conveniently achieved in one step by stereoselectivereduction (see Ref. 165b) with LiAlH, in dimethoxyethane. 4. B - - , A - - , D + C

A novel process for the construction of benzodihydrofurans via a procedure involving a heteroatom-directed photoarylation provided the basis for another total synthesis of (5)-lycoramine (299) (Scheme 32) (167). Thus, 339, which was obtained from 1,3-~yclohexanedionein two straightforward steps, was converted to 340 by sequential treatment with LiAlH,, methyl chloroformate, and aqueous acid. Epoxidation of 340 with alkaline hydrogen peroxide followed by


3 17

333: R,R=OMe 334: R. R = S(CH,),S

332

336

335

Me0

Me0 __3

337

SCHEME31

reaction of the resulting epoxide with 5-carbomethoxy-2-methoxyphenolin the presence of 1 equivalent of potassium hydride and 18-crown-6 at reflux gave the aryloxy enone 341 as the major product together with lesser amounts of the isomeric enone. Irradiation of 341 using a Pyrex filter gave the cis-fused dibenzohydrofuran 342 via a process that entailed the initial conrotatory cycliza-

318

STEPHEN F. MARTIN

P 339 340

342: x=o 343: X=(OMe),

34 1

2

MeO ___t

N-Me

344:

R=n

345:

R=SPh

N-Me

346 347:

Z=OM!3

z=n

SCHEME32

tion of 341 to give an intermediate carbonyl ylid, which underwent sequential protonation and deprotonation to provide the observed product 342. The derived dimethyl ketal 343 was reduced with LiAlH,, and the resulting amino alcohol was treated with thionyl chloride-triethylamine to induce cyclization and then aqueous acid to effect deketalization and afford the tricyclic ketone 344. The requisite 1,2-carbonyl transposition was then initiated by the conversion of 344

3. THE AMARKLIDACEAE ALKALOIDS

319

to the a-keto thioketal345 using excess lithium tetramethylpiperidideand phenyl phenylthiosulfonate. After hydride reduction of the ketone function of 345, the alcohol thus produced was converted to the corresponding mesylate, and the thioketal moiety was hydrolyzed with mercuric chloride/mercuric oxide in aqueous acetonitrile to give the keto mesylate 346. Reductive scission of the mesylate group from 346 with chromous chloride in aqueous acetone returned 347, which was transformed to (-t)-lycoramine (299) by stereoselective reduction with LiAIH,. 5. Other Synthetic Studies

Several other synthetic sequences have been developed that lead to the production of potentially useful intermediates for the total synthesis of galanthaminetype alkaloids. For example, the 4-arylbutyric acid 348 has been converted to the tetrahydrobenzazepine 349 by a modified Curtius reaction followed by cyclization of the intermediate isocyanate with polyphosphoric acid (168). N-Methylation of 349 and photooxidation of the resulting tertiary lactam in the presence of NBS gave 350.

34 8

An alternate route to substituted tetrahydrobenzazepines (Scheme 33) commenced with the Michael addition of the ester 351 to acrylonitrile in the presence of Triton B, and the intermediate cyanoester was converted to 352 by reduction of the ester function with lithium borohydride and 0-benzylation (168). Baseinduced hydrolysis of the nitrile group of 352 delivered the corresponding acid, which was transformed to 353 via a Curtius rearrangement. Subjection of 353 to a modified two-step Tscherniac-Einhorn reaction involving N-hydroxymethylation and subsequent acid-catalyzed cyclization gave 354. Finally, reaction of the aryl lead compound 356, which was prepared from 355 by tin-lead exchange, with 357 led to the production of 358 in good yield (Scheme 34) (169).

320

STEPHEN F. MARTIN

("d C0,Me

0

0

352: 353:

351

R=CN R = NHC0,Me

OCH,Ph

___)

i d , 0

CO, Me

354

SCHEME 33

Me0

357

355:

M=SnBu3

356

M=Pb(OAc),

Me0

358

SCHEME 34


32 1

VI. Crinine-Type Alkaloids A. ISOLATIONAND STRUCTURAL STUDIES The 13C-NMR spectra of crinine (359), powelline (364),undulatine (371), and haemanthamine (381) have been studied although the assignments for some carbons having nearly the same chemical shifts remain ambiguous (132). The fluorescence spectral characteristics of vittatine (385), pretazettine (395), and tazettine (397) have been compared with those of other Amaryllidaceae alkaloids (92). The structures of maritidine (387) (170), hippeastidine (392) (171), and haemanthamine (381) (172) have been confirmed by X-ray analyses. When crinamine (376) was irradiated with a high-pressure mercury lamp, it underwent rearrangement to give photocrinamine (406), the structure of which was established by single crystal X-ray analysis (173). Extensive high-resolution mass spectral studies of alkaloids of the crinine (174) and 11-hydroxycrinine (175) series have been conducted, and the fragmentation patterns of the two classes of alkaloids have been compared. The most striking feature of the mass spectra of the crinine-type alkaloids that lacked the hydroxyl group at C- 11 was the stability of the molecular ion, which was usually the base peak. Subsequent decompositions of these molecular ions resulted only in relatively small peaks, but these fragments were indeed characteristic of certain structural features of the carbon skeleton. Furthermore, the aromatic ring was retained in all fragments of high mass, whereas the nitrogen atom was frequently lost as a neutral molecule or a radical species (174). This observation stands in contrast with the mass spectra of a myriad of other nitrogen-containing molecules in which nitrogen strongly influences the fragmentation pattern by the formation of stable iminium ions. Although the precise course of the fragmentation of the molecular ions of the crinine-type alkaloids was a function of the substitution pattern in the C ring, the C - 1 l - C - 12 bond in the strained D ring was the first bond to undergo rupture. In the 11-hydroxylated crinine series, the hydroxyl substituent at C-11 was responsible for dramatic changes in the fragmentation process, presumably owing to the ability of the hydroxylic hydrogen atom of the intermediate radical cations to rearrange (175). Although the stereochemistry of the C-11 hydroxyl group was found to play a relatively minor role in affecting the fragmentation processes, the stereochemistry of the oxygen substituent at C-3 was important. For example, in those alkaloids in which the two-carbon bridge of the D ring was syn to a methoxy group at C-3, loss of methanol by transfer of the hydroxylic hydrogen gave rise to the base peaks, whereas the molecular ion was the base peak in the corresponding C-3 epimeric series. Once again, in all cases it appeared that the majority of the ions in the mass spectrum of these alkaloids arose by initial rupture of one of the bonds of the D ring, presumably driven by the

322

STEPHEN F. MARTIN

Crinine OAcetylainine Buphankine BHydmxycrinine BHydroxybuphanisine

359

360: 361: 362

363:

Powelline BHydroxypowelline Buphanidnne

364: 365:

366: 367: 368:

6-Hydmxjbuphanidnne Ambelline

I

R3

369 370: 371: 372:

R ’ = Me; R = ‘ R 3= H

’=

R R L H ; u3=OMe R ’=Me; R2=H; R3 =Om R’ = Me; R ‘=OH: R3 = OMe

Augusiine Cnnamidine Undulaline Cavinine

373

376: 3TI: 378: 379 380:

R’=M~;R~=F?=H R’ = R2= R3 =H R’ = Ac; R 2 = R3 = H

Meb 374: R = H

Deacetylbowdensine

375: R = Ac

Bowdensine

R’ =Me; R2=H: d =OH R’ =Me; R2= H; R3 =OMe

Crinamine Hamayne M Bulbispernine 3-0-Acetylhamayne 6-Hydmxycrinamine E-Melhoxycrinamine

323


=H 382 R =OH

381: R

Haemanthamine Haemanthidine

MeO&I

Me0

"lIR2

\

N 'I

I

R3

385: R ' = R ~ = H 386: R' =Me; R2 =OC!+CH(OH)C,H

392 R' =H;R2=OMe

387: R' = W ; R 2 = R 3 = H 388: R' =OMe;R2=R3=H 389 R' = R 3 = H ; d = O H 390: m:~ 2 H;= R3= OH 391: Ri = H; R* = OM; R3= OH

Maritidine 0-Methylmaritidine Epimaritidine Papyramine Epipapyramine

394

393: R',R2=OH,H

release of strain in the 11,lZethano bridge (175). Other fragmentations varied depending on the presence and location of other substitutents or functionality. In contrast to these results, the mass spectral fragmentation of cavinine (372) was suggested to be governed by the epoxide ring at C-1 and C-2 rather than by the hydroxyl group at C-1 1 on the ethano bridge. This conjecture was based on the observation that the base peak corresponded to the loss of the CHO of the

324

STEPHEN F. MARTIN

OH ~1 = OMe, R 2 = H Pretazertine 3%: R ~ = H : R ~ = o M ~ prec“welline

395:

397: R’ = OMe; R2= H; R3=O H A’ 398: R‘ =H;R2=OMe;R3=OH:A’“

Tazettine

399. R’ = OMe; R 2= H F? = We; 1,Zdihydro

Ungvedine

0

0 400

R’ =OMe;R2=H;

401:

R’ = H; R2=OMe;

Criwelline

A’s2

Epimacronine

402

Macronine

oxirane ring from the molecular ion (51). However, in the mass spectrum of the related epoxy alkaloid augustine (369), which lacks a hydroxyl at C-11, the molecular ion was the base peak, and it seems plausible that the loss of CHO from 372 may have been primarily from the two-carbon bridge of the D ring rather than from the oxirane moiety as originally proposed (25). Further investigations should resolve this issue. The alkaloid (+)-epimaritidine (389), which constitutes a missing link in the C-3 epimeric pairs of 5 , lob-ethanophenanthridine alkaloids of the vittatine-

406


325

haemanthamine type, has been isolated and its structure deduced by spectroscopic analyses and chemical correlation. That epimaritidine (389) bearing a C-3 quasi-equatorial hydroxyl group is thermodynamically more stable than its C-3 epimer maritidine (387) in which the hydroxyl group at C-3 resides in a quasi-axial orientation has been established by equilibration studies. Namely, when maritidine was heated for 4 hr under reflux in 10% aqueous HC1, a mixture of 389 and 387 was obtained in a ratio of approximately 8.5 : 1 (87). This observation may be contrasted with other reports (176,196b) in which heating a solution of epimaritidine (389) in 10% HC1 for 1 hr led to a mixture (1 : 1.1-1 -7) of maritidine (387) together with recovered 389, but it should be recognized that the intermediate cyclohexenyl cation obtained by solvolysis of either 387 or 389 would be expected to exhibit a tendency to undergo reaction with nucleophiles kinetically in a quasi-axial fashion to give preferentially 387. The structure of (+)-0-methylmaritidine (388) was assigned based on spectral comparisons with closely related alkaloids (69). The quasi-axial orientation of the methoxy group at C-3 was deduced from the diagnostic vicinal coupling constant of 5 Hz between the olefinic proton at C-2 and the quasi-equatorial proton at C-3 compared with an expected value of of about 0-2 Hz if the oxygen substituent at C-3 was quasi-equatorial. The related alkaloid 393 has been isolated from Hippeastrum ananuca (48). A number of alkaloids oxygenated at C-6 of the crinane skeleton have been isolated, including 6-hydroxycrinine (362) (24), 6-hydroxybuphanisine (363) (24), papyramine (390) (65,I77),3-epipapyramine (391) (60),and 6-methoxycnnamine (380) (44). As judged by examination of the 'H-NMR spectra, the two epimeric diastereomers of each of the 6-hydroxylated alkaloids 362, 363, 390, and 391 were in equilibrium, but 380 appeared to be stereochemically homogeneous although the relative stereochemistry was not established. The structures of these compounds were deduced principally from a combination of NMR and mass spectral studies and comparisons with known alkaloids. The structure 377 was originally assigned to the alkaloid (+)-hamayne based on spectroscopic considerations together with the fact that it could be converted to apohaemanthamine(407) on treatment with 6 N hydrochloric acid (20). Independent support for this structure was obtained from the internuclear double resonance (INDOR) and NOE studies of the related alkaloid 3-0-acetylhamayne

407

326

STEPHEN F. MARTIN

(378) coupled with the fact that both 377 and 378 afford the same diacetyl derivative (32). However, based on extensive spectral investigations, the structure 377 has also been assigned to the alkaloid (+)-bulbispermine, a substance that was clearly not identical with (+)-hamayne as judged by differences in the reported melting points and specific rotations (31).The structure 383 was therefore suggested for (+)-hamayne (31), although this would not appear to be consistent with the previous observation that (+)-hamayne underwent acid-catalyzed cyclization to give 407. While this discrepancy in structural assignments remains to be resolved, it should be noted that the differences in melting points and specific rotations reported for (+)-hamayne and (+)-bulbispermine might be due to the fact that these alkaloids were recrystallized from different solvents, and that the specific rotations were measured at different concentrations in different solvents. Two alkaloids tentatively identified as hamayne (377)and 3-acetylhamayne (378)have also been reported to be components of Crinum zeylunicum L. (44). Although certain physical properties for the alkaloid assigned to be 377 and its diacetate were not identical with those previously reported for hamayne and hamayne diacetate, the 'H-NMR spectrum at 100 MHz of the base alleged to be hamayne was superimposablewith that of an authentic sample of 377,and partial hydrolysis of its diacetate furnished a substance that was identical with 3-acetylhamayne (378)(44). While the discrepancies in the physical data for the alkaloid isolated from Crinum zeylanicum L. and hamayne might be due to polymorphic crystals, this was not established, and further structural work on these compounds should resolve the differences. The gross structure and stereochemistryof havanine (373)were deduced from spectroscopic analysis ( 5 3 , whereas the structure of narcimarkine (386)was based primarily on its high-resolution mass spectral fragmentation pattern (67). The structure of the epoxy alkaloid augustine (369)was deduced from a combination of its high-resolution mass spectral fragmentation pattern and extensive analysis of the 'H- and 13C-NMR spectra, which were completely assigned, coupled with comparisons of these spectra with those of the related alkaloids 361, 371, and 372 (25). The stereochemical features of cavinine (372)(1,2-pepoxyambelline), which had been previously deduced from its mass spectral fragmentation pattern (vide supra) (51), have been confirmed by extensive NMR studies in which the complete 'H- and 13C-NMRspectra were assigned (38).The structure of oliganine (394)was determined by spectroscopic studies and represents a new alkaloid of the crinane group; however, no relative stereochemical assignments were made (40). Reinvestigation of the alkaloid extracts of Lycoris radium Herb. (62) and Narcissus tuzettu L. (68) has revealed that tazettine (397),which had been previously isolated from these plants, was an artifact of the isolation procedure, and pretazettine (395)was in fact the naturally occurring alkaloid. In view of


327

these discoveries coupled with the known facility with which pretazettine undergoes base-catalyzed rearrangement to tazettine, previous accounts in which tazettine was reported as a natural product should be carefully regarded. As a result of mass spectral studies of alkaloid extracts of Crinum ornuturn, the new alkaloids ornazamine, and ornazidine were identified, and the tentative structure assignments of 403-405, respectively, were made (42). The stereochemistry depicted is based on the obvious relationship between these alkaloids and pretazettine (395), but no stereochemical details were given in the original report (42). The structures of ungvedine (399) (83) and varadine (402) (54, the latter of which represented a new structural type in the Amaryllidaceae alkaloids, were determined by spectroscopic studies. Further chemical support for the proposed structure of ungvedine (399) was obtained by hydrogenation of 0-methyltazettine to give 399 (83).

B . BIOLOGICAL ACTIVITY 1,2-P-Epoxyambelline (cavinine) (372) has been found to be an immunostimulant, and it produces moderate activation of mouse spleen lymphocytes (38).Although the epoxy alkaloid undulatine (371) was inactive in 9 PS and 3 PS screens, ambelline (368) did exhibit in vitro activity in the 9 PS bioassay (5). Pretazettine (395) has been the subject of numerous biological studies, and it has been shown to exhibit a number of interesting activities (96,97,101,178187). For example, 395 was found to inhibit HeLa cell growth as well as protein synthesis in eukaryotic cells by interfering with the peptide bond formation step (97,101). Furthermore, pretazettine inhibited the purified RNA-dependent DNA polymerase (reverse transcriptase) from avian myeloblastosis virus, a typical C type virus (178), in an unusual fashion since it physically combined with the polymerase enzyme itself rather than interacted with the nucleic acid template. Pretazettine also exhibited antiviral activity against the Rauscher leukemia virus in mouse embryo cell cultures by suppressing viral replication (179). Further studies revealed that pretazettine was therapeutically effective against advanced Rauscher leukemia (I 79-182,184), Ehrlich ascites carcinoma (180,186),spontaneous AKR lymphocytic leukemia (183), and Lewis lung carcinoma (185,187). Although pretazettine inhibits both the growth of Rauscher virus and cellular protein synthesis, it does not have any inhibitory effect on cellular DNA and RNA synthesis (182). Precriwelline (396), the C-3 epimer of pretazettine, has also been tested against Rauscher leukemia virus, and it has been found to be as therapeutically active (184). Although it has now been convincingly demonstrated that pretazettine is an effective agent against the Rauscher leukemia system, other studies in a number of tumor systems at the U.S. National Cancer Institute appear to suggest that this activity does not carry over to other tumor models in which pretazettine exhibited only marginal activity (188).

328

STEPHEN F. MARTIN

C. BIOSYNTHETIC STUDIES Feeding experiments with doubly labeled 3-hydroxy-4-[14C]methoxy-N-methY~-(R)-[~H]and -(S)-[3H]N-benzylamines in King Alfred daffodils resulted in the obtention of haemanthamine (381) with high (8245%) tritium retention (239).This observation suggested that N-methylisovanilimine was incorporated into the aromatic unit of haemanthamine by a process involving the nonstereospecific removal of hydrogen from the benzylic methylene of the secondary amine by the amine oxidase that generates the known biosynthetic intermediate 3-hydroxy-4-methoxybenzaldehyde. Two tracer studies involving the feeding of tritium-labeled (-)-crinine (359) and tritium-labeled oxovittatine, which was prepared by manganese dioxide oxidation of tritium-labeled vittatine (385), in Nerine bowdenii provided evidence that crinine (359) and its optical antipode vittatine (385) were not interconvertible in the plant (289).In other related feeding experiments with tritiumlabeled vittatine in Rhodophiulu bijidu, 385 has been shown to be a biosynthetic precursor of both haemanthamine (381) and montanine (584). The specific activity of the vittatine-derived haemanthamine was substantially higher than that of the montanine isolated from the same experiment. Not surprisingly, it would thus appear that 11-hydroxyvittatine was converted more efficiently to haemanthamine, which only required the methylation of the hydroxyl function at C-3, whereas the formation of montanine involved a rearrangement of the vittatine ring system in addition to the methylation of the oxygen function at C-2.

STUDIES D. SYNTHETIC The alkaloids related to crinine (359), which possess the 5 , lob-ethanophenanthridine nucleus, have been the subject of extensive synthetic investigations (190). Alkaloids of this family bearing oxygen functionality at C-11 occupy a special position since they are possible biosynthetic and chemical precursors of the subgroups that incorporate a 2-benzopyrano[3,4-c]indolering such as those alkaloids related to pretazettine (395), tazettine (397), and macronine (401) and the methanomorphanthridines such as montanine (584). A variety of approaches, which may be divided broadly into catagories based on the carbon-nitrogen bond forming step employed as the final step of skeletal construction, to this class of alkaloids have been designed. However, the most common and generally useful ones developed thus far fall into four principal types based on the sequence of ring construction: AC --$ BD (biogenetic), A + C + B -+ D, A + C + D -+ B, and A + D + C -+ B. In the biosynthetic approach, amino spirodienones are the key intermediates, and an internal Michael cyclization serves as the step for the construction of the skeleton by simultaneous creation of the B and D rings. Nonbiogenetic entries to synthetic


329

equivalents of such spirodienones have also been devised. The entry involving the sequence A 4 C -+ B +. D requires the construction of an angularly substituted phenanthridine, and the elaboration of the pyrrolidine D ring is achieved by the formation of a carbon-nitrogen bond via alkylation. The key intermediates in the approaches of the type A +. C -+ D -+ B and A + D -+ C + B are 3a-arylhydroindoles, and the formation of the B ring is generally achieved through the agency of a Pictet-Spengler reaction. 1 . A C - + BD Previous experimentation in the biosynthetic arena had established that the biogenesis of the crinine ring system, like the galanthamine ring system, involved the intramolecular oxidative phenolic coupling of norbelladine derivatives, and a number of chemical entries to the crinane skeleton by oxidative cyclization of substrates such as 408-411 have been inspired to mimic this transformation. As noted previously for the application of the biomimetic approach to the construction of the galanthamine skeleton, early work in this area was also plagued by low yields and the obtention of complex product mixtures. However, since para-para coupling is more straightforward than ortho-para coupling, no problems have been encountered in controlling the regiochemical sense of carbon-carbon bond construction. Consequently, the major effort has gone into the discovery of improved reaction conditions as well as superior oxidizing agents to replace the classic oxidants K,Fe(CN),, FeCl,, MnO,, and Ag,O, and the successful applications of several of these new advances in the redox coupling approach to the elaboration of the crinane ring system have been recorded. The norbelladine derivative 408, which served as the starting material for the synthesis of (2)-oxocrinine (415) (Scheme 3 9 , may be readily prepared from the reductive amination of piperonal with tyramine followed by acylation with trifluoroacetic anhydride ( I 91,192). When the N-acylated monophenol 408 was treated with excess thallium tris(trifluoroacetate) in methylene chloride, the dienone 412 was obtained in 19% yield (191), whereas use of the oxidant vanadium oxyfluoride in trifluoroacetic acid/trifluoroacetic anhydride afforded 412 in 88% yield (192). Base-induced N-deacylation of 412 was accompanied by spontaneouscyclization to furnish racemic oxocrinine (415). Attempts to oxidize the free amine derived from 408 led to the formation of a number of products, some of which resulted from oxidation at nitrogen. In a related study, the diphenolic substrate 409 was oxidized with a large excess of the iron complex [Fe(DMF),Cl,][FeCl,] to give the spirodienone 413 in 35%yield (193).The oxidative phenolic coupling of 409 to furnish 413 using vanadium oxytrichloride had been previously reported, but the yield was slightly lower (176). Alkaline hydrolysis of 413 to cleave the N-trifluoroacetamide pro-

330

STEPHEN F. MARTIN

408: 409: 410: 411:

R' , R '= CHz: R 3= H R'=Me:R'=R'=H R', R 2 = CHI; R 3 = W R'=R2=R3=W

tecting group proceeded with concomitant cyclization via Michael addition to complete the skeletal construction, and the subsequent 0-methylation of the phenolic hydroxyl group, which was somewhat inefficient, then finished this biomimetic synthesis of (4)-oxomaritidine (416) ( I 76,193). A promising alternate technique for effecting the oxidative coupling of nonphenolic precursors involving electrochemical oxidation has been developed. For example, the anodic oxidation of the norbelladine derivatives 410 and 411 at 1.10-1.20 V (SCE) using platinum electrodes and fluoroboric acid as the supporting electrolyte proceeded in good yields to give the dienones 412 and 414, respectively. Base-induced removal of the N-trifluoroacetyl group from 412 and 414 as described before then provided (*)-oxocrinine (415) and (+-)-oxomaritidine (416), respectively (194). Another approach for effecting the construction of the crinane ring system involved the photocyclization of bromophenolic compounds. For example, irradiation of 418 in 50% aqueous ethanol in the presence of sodium hydroxide followed by 0-acetylation produced directly the tetracyclic intermediate 417, albeit in less than 4% yield (195).Saponification of the acetate function afforded an intermediate in a previous synthesis (276) of (+)-oxornaritidine (416). The biogenetic total syntheses of both natural (+)-maritidine (387) and (+)epimaritidine (389) from L-tyrosine has been reported (Scheme 36) in which a


423:

R=CONH,

424:

R=CN

33 1

SCHEME 36

highly stereoselective, asymmetric oxidative cyclization served as the key carbon-carbon bond construction (196a,b).Initial efforts were focused on the phenolic coupling of the diphenol419, which was readily prepared by the reductive amination of isovanillin with L-tyrosine methyl ester followed by N-acylation with trifluoroacetic anhydride in pyridine. Reaction of 419 with femc chloridedimethylformamide complex afforded the para-para coupled spirodienone 421, although the best yield was 14%. Oxidations with other chemical reagents including femc chloride, iron(II1) acetylacetonate, potassium ferricyanide, vanadium oxytrichloride, manganese(II1) acetylacetonate, or thallium(II1) trifluoroacetate proceeded in even lower yields. Since the subsequent methylation of 421 also provided 422 in only low yield, a monophenolic substrate was then examined as an alternate for the oxidative coupling step. In the event, oxidation of the monophenol 420 with thallium(II1) trifluoroacetate in trifluoroacetic acid/acetonitrile gave 422 in 67% yield, but it should be noted that the yield in this critical cyclization was highly dependent on the molar ratios of oxidant to substrate as well as the solvent (196b). Ammonolysis of 422 followed by the hydroxide-induced removal of the N-trifluoroacetyl protecting group and spontaneous Michael-type cyclization of the intermediate amino dienone furnished the tetracyclic enone 423 in good yield. This crucial cyclization was highly diastereoselective, and the other possible diastereomer was not isolated from this reaction. Dehydration of the amide 423 by treatment with phosphorus oxychloride gave the aminonitrile 424, and although the reductive decyanation of 424 with sodium borohydride led solely to the reduction of the ketone function at C-3, reduction with sodium in liquid ammonia afforded optically pure (+)-epimaritidine (389) in good yield. Partial epimerization at C-3 of

332

STEPHEN F. MARTIN

389 was accomplished by heating in 10%hydrochloric acid for 1 hr (1 76) to give optically pure (+)-maritidine (387) (17%) together with recovered 389 (29%).

2. A C i . B - , D A novel application of an intramolecular, oxidative coupling of a substituted monophenol has led to a concise synthesis of 6a-epipretazettine (431) (Scheme 37) (197). In the event, condensation of piperonal and (2)-synephrine (425) followed by reaction of the intermediate oxazolidine with 2,2,2-trichloroethyl chloroformate provided the urethane 426. The subsequent treatment of 426 with [bis-(trifluoroacetoxy)iodo]benzene in the presence of propylene oxide as an acid scavenger led to the formation of the spirocyclic dienone 427, albeit in low yield. It is interesting to note that this oxidative cyclization, which was induced with hypervalent iodine(II1) in a presumably heterolytic process, represents an intriguing departure from the conventional methodology using organometallic reagents, many of which appear to function as one-electron oxidants. The construction of OH

I

OH

HO

426

425

427

SCHEME37


333

the D ring was then completed by exposure of 427 to zinc reduction to liberate the secondary amino function, which underwent subsequent cyclization by 1,4addition to the dienone moiety to furnish 428. No trace of the corresponding trans-BID diastereomer of 428 was isolated, underlining the powerful driving force for the formation of the more thermodynamically stable cis-B/D ring fusion. The reduction of 428 with DIBAL proceeded in a stereoselective fashion to afford a single allylic alcohol 429 accompanied by a small amount of the corresponding saturated alcohol, which resulted from conjugate reduction. The requisite inversion of the stereocenter at C-3 was achieved by methanolysis of the mesylate derived from 429 to give solely the allylic ether 430, which was converted to (?)-6a-epipretazettine (431) by acid hydrolysis. Thus, although the yields in the oxidative cyclizations of diphenolic substances and their derivatives may sometimes be lower than might be desired, this biomimetic approach constitutes a rapid and concise entry to the crinine family of alkaloids. Continued research in this area should lead to the development of improved synthetic methodology and tactics for effecting this important conversion, resulting thereby in highly useful syntheses of members of this class of naturally occumng bases. 3. A + C - - , B D

An improved route to the carboxylic acid 436 and the lactam 438, which were intermediates in a previous synthesis of elwesine (dihydrocrinine) (439) (198), has been reported (199). Thus, as shown in Scheme 38, piperonylnitrile (432) was converted to the keto nitrile 433 by a base-induced, double Michael reaction with ethyl acrylate followed by a Dieckman condensation and decarboxylation of the resulting P-keto ester with sodium chloride in wet DMSO. Reduction of 433 with DIBAL under carefully controlled conditions proceeded in a highly stereoselective fashion, and subsequent acetylation of the intermediate syn-hydroxy aldehyde furnished 434 in very good overall yield from 432. Wadsworth-Emmom olefination of 434 with the sodium salt of diethyl cyanomethylphosphonate and subsequent hydrogenation over a borohydride-reduced palladium catalyst afforded the saturated nitrile 435, which was converted to the acetoxy acid 436 by hydrolysis with 40% aqueous potassium hydroxide/diethylene glycol followed by reacetylation of the hydroxyl group at C-3. Subjection of the acid 436 to a classic Curtius rearrangement produced the isocyanate 437, which underwent cyclization on treatment with excess polyphosphoric at room temperature to form the acetoxy lactam 438 (199). A somewhat improved procedure for effecting the conversion of the acid 436 to the lactam 438 involved the cyclization of the isocyanate 437 with phosphorus oxychloride followed by stannic chloride ( 1 9 8 ~ )The . conversion of 438 to (5)-elwisine (dihydrocrinine) (439) had been previously reported (198b).

334

STEPHEN F. MARTIN

432

433

R 434

435:

R=CN

436:

R=C%H

437:

R=NCO

( O d

(O

0+OAC

0

0 439

438

SCHEME 38

A variant of the preceding strategy was applied to the total syntheses of (2)elwesine (439), (-+)-epielwesine (449), and (t)-oxocrinine (415) (Scheme 39) (200). This approach featured a new methodology for the construction of substituted tetrahydrobenzazepinering systems that was based on a two-step Tscherniac-Einhorn-like aromatic amidoalkylation as exemplified by the conversion of 443 to 444. To this end, the unsaturated nitrile 440 was allowed to react with nitromethane in the presence of Triton B, and the intermediate nitro compound was converted to the acetal 441 by reaction with methanolic sodium methoxide followed by concentrated sulfuric acid in dry methanol. Transketalizationof 441

335


440

441:

R=OMe

442:

R. R = S(CH,),S

n

n 0

N

0

#-Cbz

\

Cbz

443

444

445: X = H 446 X=&

449:

R' =H:R~=OH

439:

R' = O H ; R ~ = H

SCHEME39

447:

X=H

448:

x=Br

336

STEPHEN F. MARTIN

with 1,3-propanedithioland boron trifluoride etherate gave the dithioacetal442, which on reduction with LiAlH,-AlCl, (1 : 1) followed by acylation of the intermediate primary amine with benzyl chloroformate gave the urethane 443. In a useful modification of the Tscherniac-Einhorn reaction, 443 was converted to 444by the initial base-catalyzed condensation of 443 with aqueous formaldehyde followed by cyclization of the resulting N-(hydroxymethyl) intermediate with p toluenesulfonic acid in refluxing benzene. Removal of the dithiane protecting group with red mercuric oxide and boron trifluoride etherate afforded an aldehyde that was readily converted to the key intermediate spirocyclic enone 445 via a Robinson annelation. In order to transform the spirocyclic enone 445 to (*)-elwesine (439) and (2)epielwesine (449), it was treated with boron trifluoride and dimethylsulfide to cleave the N-carbobenzyloxy protecting group, and cyclization of the resulting amino enone spontaneously ensued to produce (&)-dihydrooxocrinine (447). Reduction of carbonyl function of 447 with sodium borohydride afforded (-t)-3epielwesine (449), which was converted to (&)-elwesine (439) by inversion of the hydroxyl function at C-3 via a Mitsunobu protocol using diethyl azodicarboxylate, triphenylphosphine, and formic acid. Attempted reduction of 447 directly to 439 by a Meerwein-Ponndorf-Verley reduction or with bulky hydride reagents gave only mixtures of 449 and 439 that were difficult to separate. The enone 445 was then converted to (?)-oxocrinine (415) by a sequence that commenced with the bromination of 445 using excess 5,5-dibromo-2,2-dimethyl-4,6-dioxo-1,3-dioxane to provide a mixture of bromo ketones 446. Removal of the N-carbobenzyloxy protecting group according to the protocol previously detailed gave 448 as a mixture (a-Br : p-Br = 3 : 1) of diastereomers, but only the a-bromo isomer underwent dehydrobrominationon heating with lithium bromide and lithium carbonate in dry DMF to furnish 415. Interestingly, treatment of the @-bromoderivative of 448 under similar conditions afforded the debrominated product 447 (ZOO). 4. A - + C - + B - - + D Another approach for the elaboration of the crinane skeleton featured the formation of the D ring through the agency of an intramolecular alkylation to construct the final carbon-nitrogen bond. A simple illustration of this approach may be found in the synthesis of (f)-crinane (453) (Scheme 40) (201). Thus, acylation of the imine derived from 2-allylcylcohexanoneand benzylamine with piperonoyl chloride followed by the thermal or photochemical isomerization of the resulting mixture of enamides afforded 450 as a homogeneous substance in good overall yield. Irradiation of 450 induced an electrocyclizationto provide the lactam 451 in fair yield, and subsequent ozonation of 451 and reduction of the

337


____c

0

0

Ph

451

450

Ph 453

452

SCHEME40

intermediate aldehyde with LiAlH, furnished 452. Catalytic N-debenzylation of 452 and treatment of the intermediate amino alcohol with thionyl chloride resulted in the formation of (-+)-crinane (453). Although this photochemical approach to the crinane skeleton could be modified to allow access to other enamides having functionality in the C ring, no such extensions have been reported. Another example involving the construction of an ACB ring precursor that then was elaborated to the crinane skeleton via the formation of a carbonnitrogen bond to effect closure of the D ring may be found in the first total synthesis of haemanthidine (382) (Scheme 41) (202). Thus, arylation of maleic acid with the diazonium salt derived from the amine 454, which was prepared in five steps from piperonal, followed by dehydration of the intermediate aryl maleic acid with acetic anhydride gave the anhydride 455. Diels-Alder reaction of 455 with butadiene and subsequent treatment of the resulting cycloadduct with sodium methoxide afforded as the sole product the half acid-ester 456, which arose from the exclusive attack by methoxide ion at the more hindered carbonyl group. Conversion of the carboxylic acid 456 to the isocyanate 457 was achieved by sequential reaction of 456 with oxalyl chloride and sodium azide followed by a thermal Curtius rearrangement of the intermediate acyl azide. Cyclization of 457 to the lactam 458 was promoted by a variety of acids; however, use of polyphosphoric acid gave the best results. At this juncture, two basic strategies were envisioned for completing the

338

STEPHEN F. MARTIN

qy"' 0

455

454

456:

R=COZH

457:

R=NCO

458

&

OMS

,llJ

B

0

0

459 X=l

461 : R = CCH2COC6H,Br

460: X=OMe

462: R=CHNz

OMS

382: R'=H;R2=OH

463: R'.R'=Z=O

466: R'=OH:R'=H

464: R' = H; Rz = OAC; Z = H, OAC 465: R'=OAc;R'=H;Z=H.OAC

SCHEME 41


339

synthesis of haemanthidine (382). The first involved the initial functionalization of the C ring followed by formation of the D ring, whereas the second entailed the construction of the D ring prior to the introduction of functionality onto the C ring. However, when the D ring was in place, a high degree of stereochemical control in the functionalization of the C ring could not be achieved (vide infru), and the former approach was therefore implemented. In the event, iodolactonization of the carboxylate salt derived from the ester 458 afforded 459, and subsequent warming of the iodo lactone 459 with aqueous alkali generated an intermediate epoxy acid salt, which suffered sequential nucleophilic opening of the epoxide moiety followed by relactonization on treatment with methanol and boron trifluoride to deliver the methoxy lactone 460. Saponification of the lactone function in 460 followed by esterification of the resulting carboxylate salt with p-bromophenacylbromidein DMF and subsequent mesylation with methanesulfonyl chloride in pyridine provided 461. The diazoketone 462 was prepared from 461 by careful saponification of the ester moiety using powdered potassium hydroxide in THF followed by reaction with thionyl chloride and then excess diazomethane. Completion of the D ring by cyclization of 462 to the keto lactam 463 occurred spontaneously on treatment of 462 with dry hydrogen chloride. Although the remaining steps required for the conversion of 463 to haemanthidine (382) were conceptionally straightforward, it was an experimentally difficult task owing to the poor stereoselectivityencountered in the reduction of the neopentyl ketone function at C-1 1. Moreover, the more forcing conditions required in some experiments to effect the reduction of the sterically hindered carbonyl function at C-11 resulted in an internal Cannizzaro hydride transfer process that produced nortazettine (467). The best results were eventually obOMe

1

467

tained by the reduction of 463 with disiamylborane followel by acetylation of I ie crude product mixture with acetic anhydride and boron trifluoride to furnish both 464 and 465. After this mixture of 464 and 465 was heated with DBN to effect the elimination of the mesylate, removal of the acetyl functions with LiAlH, furnished a mixture (3.6 : 1) of (*)-haemanthidine (382) and (-+)-11-epihaemanthidine (466) (202).

340

STEPHEN F. MARTIN

In the alternate and unsuccessful approach to haemanthidine (382), which entailed the construction of the D ring prior to the functionalizationof the C ring, the ester 458 was converted to the unsaturated keto lactam 468 by a straightforward route analogous with the one discussed above for the transformation of 461 to 463. The carbonyl group at C-6 was then reduced with sodium borohydride to alleviate concern over its reactivity, but epoxidation of the double bond at C-2 and C-3 of 469 afforded a mixture of diastereomeric a-and (3-epoxides. Owing to the lack of stereoselectivity in this crucial step, this route was abandoned (202).

X

468:

X=O

469:

X=H.OH

5. A - - , C + D + B A process involving a cationic aza-Cope reaction coupled with a Mannich reaction has been devised for construction of cis-3a-aryloctahydroindoles from 2-amino cyclopentanol derivatives, and it constitutes a general and attractive entry to the alkaloids of the crinine family (203). For example, the addition of [ 1-(3,4-methylenedioxyphenyl)ethenyl]lithium to the imino ketone 470, which was readily prepared from truns-2-amino cyclopentanol by condensation with benzophenone and then Swern oxidation, and subsequent reduction of the intermediate hydroxy imines with sodium cyanoborohydride gave the epimenc amino alcohols 471 and 472 in an approximately 3.7 : 1 ratio (Scheme 42). The stereochemical preference for the addition of the vinyllithium reagent from the face syn to the imine substituent was a noteworthy phenomenon that was also observed in other related cases ( 2 0 3 , ~ )The . amino alcohols 471 and 472 underwent facile reaction with paraformaldehyde (1 equiv) in the presence of camphorsulfonic acid (0.9 equiv) upon heating in DMSO to give cleanly the cis3aaryloctahydroindolone 473 as the sole product. Removal of the N-diphenylmethyl protecting group from 473 by transfer hydrogenation gave 474, which had previously been converted via racemic 477 to (+)-crinine (359) (204). Although the acid-catalyzed reaction of the cis-amino alcohol 472 with paraformaldehyde proceeded smoothly to give the cis-3a-aryloctahydroindolone473

341


470

471: 472:

a -OH

P-OH

k 473: 474:

477

R=CHPII, R=H

475:

R=CH,Ph

476

R = (R )CHMePh

SCHEME42

irrespective of solvent, the corresponding reaction of the trans-amino alcohol 471 was markedly solvent dependent; a mixture of cis- and trans-3a-aryloctahydroindolones, the cis being the major product, was obtained when solvents other than DMSO were employed. Apparently, the ratio of cis- and cruns-octahydroindolones obtained from 471 was kinetically controlled, and the solvents presumably influenced the preferred conformational topology for the initial cationic aza-Cope rearrangement (478 -+ 479) (Scheme 43), which established the stereochemistry of the ring fusion produced in the subsequent Mannich cyclization (479 -+480 or 479 -+ 481) (203~). 0

k 478

479

480:

B -Ar

461:

a-Ar

342

STEPHEN F. MARTIN

A related approach exploited a N-cyanomethyl group to serve in the dual role of a nitrogen protecting group and a latent precursor of the formaldehyde iminium ion (e.g., 478), and this innovative modification in tactics resulted in a simplified route to the cis-3a-aryloctahydroindole474 (203a,c).To this end, the amino ketone 482 was readily prepared in one step by the reaction of 1,2bis(trimethylsily1oxy)cyclopentene with N-benzyl-N-cyanomethyl amine . When 482 was exposed to [ 1-(3,4-methylenedioxyphenyl)ethenyl]lithium,a mixture (1 : 14) of 483 and 484 was obtained. It is noteworthy that the stereochemical sense

0 NCH2Ph

I

CHpCN

CH,CN

482

483:

a-OH

484:

P -OH

of the nucleophilic addition of the vinyllithium reagent to the amino ketone 482 was opposite to that observed in the nucleophilic additions of organometallic reagents to the imino ketone 470. It is plausible that the stereochemical outcome of the addition to the amino ketone 482 was the result of a chelation-controlled process in which a transition state involving a cis-[3.3.0] system was preferred, whereas the addition to the imino ketone 470 was subject to stereoelectronic control proceedkg via a transition state in which the imino group was approximately perpendicular to the carbonyl group (i.e., a Felkin-Anh transition state). Heating 484 in ethanol containing silver nitrate then presumably generated an intermediate iminium salt that suffered a tandem aza-Cope/Mannich sequence to produce the cis-3a-aryloctahydroindolone475, which was readily transformed to 474 under transfer-hydrogenation conditions. The use of a cationic aza-Cope rearrangement in concert with a Mannich cyclization has also been applied to the total synthesis of enantiomerically pure (-)-crinine (359) (205).In the event, nucleophilic opening of cyclopentenoxide with the aluminum amide that was formed on reaction of (R)-a-methylbenzylamine and trimethylaluminum gave the amino alcohol 485 together with its (1S,2S) diastereomer. Although there was essentially no asymmetric induction in this process, the diastereomeric amino alcohols were readily separated by chromatography, and the overall procedure therefore constitutes an efficient means for the preparation of enantiomerically pure 2-amino alcohols from epoxides. When the hydrochloride salt derived from 485 was treated with paraformaldehyde and potassium cyanide, the amino nitrile 486 was formed. Subsequent Swern oxida-

343


Me

A Ph

487

tion of 486 followed by reaction of the intermediate amino ketone with [l-(3,4methylenedioxyphenyl)ethenyl]lithium gave the cis-amino alcohol 487 in high yield, and no trace of the epimeric alcohol was detected. Exposure of 487 to silver nitrate resulted in the formation of the cis-3a-octahydroindolone476, which was then converted to optically pure 474 by transfer-hydrogenation. The PictetSpengler cyclization of 474 afforded 477, which was elaborated in four steps and 26% overall yield into (-)-crinine (359) following precisely the protocol previously described in the racemic series [(a) Br,/HOAC; (b) LiClIDMFlreflux; (c) LiAIH,/THF; (d) BuLi, TsCl, 2% aq NaHCO,/rt] (204,205). A strategy for the construction of alkaloids of the crinine-type via a novel procedure for annelating a pyrrolidine ring onto an unsaturated six-membered carbocycle featured the intramolecular ene reaction of unsaturated acyl nitroso compounds such as 492 and 501 to provide the cyclic hydroxamic acids 493 and 502, respectively (206,207). The application of this methodology to the synthesis of (+)-crinane (453) commenced with the addition of 4-lithiobenzodioxole to 3-methoxycyclohexenone to afford the enone 488 (Scheme 44) (206). The 1,2-reduction of 488 with sodium borohydride followed by acetylation provided the acetate 489, which was subjected to the Ireland modification of the Claisen rearrangement. Thus, sequential deprotonation of 489 with lithium diisopropylamide in THF containing 5% HMPA followed by addition of tert-butyldimethylchlorosilane produced an intermediate ketene acetal, which underwent a [3,3]sigmatropic rearrangement on heating to give 490. The transformation of 490 to the hydroxamic acid 491 was then accomplished by treatment with thionyl chloride and then hydroxylamine hydrochloride. Although all attempts to effect the direct conversion of 491 to the acyl nitroso compound 492 and thence into the desired ene product 493 were unsuccessful, this problem was expeditiously resolved by oxidizing 491 with tetrapropylammonium periodate in the presence of 9,lO-dimethylanthracene to afford the Diels-Alder adduct 496 in high yield. Thermolysis of 496 in refluxing toluene then generated the requisite acyl nitroso compound 492 in situ, and the subsequent ene reaction that ensued spontaneously delivered the cyclic hydroxamic

344

STEPHEN F. MARTlN

488: 489:

490:

R',R'=o R' = OAC;R' = H

X=OH

491: X=NHOH 4 9 2 X=NO

493

494:

x=o

495:

X=H2

n

453

496

SCHEME 44

acid 493. 0-Acetylation of 493 followed by catalytic hydrogenation over Pd/C and then nitrogen-oxygen bond cleavage induced by TiC1, yielded the lactam 494, which was reduced with LiAlH, to give the secondary amine 495. Subjection of 495 to the standard conditions of the Pictet-Spengler cyclization with aqueous formalin in the presence of hydrochloric acid gave (%)-crinane (453). Alternatively, heating the arnine 495 with N,N-dimethylrnethyleneamonium iodide (Eschenmoser's salt) also afforded 453 in high yield, and this mild modification of the classic Pictet-Spengler cyclization should prove advantageous in more highly functionalized systems (206).

3. THE AMARYJMDACEAE ALKALQIDS

345

The further application of this strategy to the total synthesis of (k)-dihydromaritidine (506) was initiated with the addition of 4-lithioveratrole to 3methoxycyclohexenone to afford the enone 497 (Scheme 45) (207). Hydride reduction of 497 and acetylation gave the allylic acetate 498, which underwent an ester enolate Claisen rearrangement according to the method of Ireland as previously described above to give the carboxylic acid 499. Reaction of the acid chloride derived from 499 with hydroxylamine furnished the hydroxamic acid 500. Subsequent oxidation of 500 with tetrapropylammonium periodate in the presence of 9,lO-dimethylanthracene and thennolysis of the Diels-Alder adduct of the acyl nitroso compound 501 thus obtained afforded the cyclic hydroxamic acid 502. The cleavage of the nitrogen-oxygen bond present in 502 was effected with TiCl, to provide the lactam 503, which underwent reaction with NBS in

497:

R',R'=o

498:

R'=oA~;R'=H

499 500: 501:

x=oH X=NHOH X=NO

OH

k 502:

R=OH

504:

x=o

503:

R=H

505:

X=Hz

506

SCHEME45

346

STEPHEN F. MARTIN

aqueous dimethoxyethane (DME) to furnish a single bromohydnn. After removal of the bromide by radical reduction with tri-n-butyltin hydnde to furnish the lactam alcohol 504, reaction with LiAlH, followed by Pictet-Spengler cyclization of the resulting m i n e 505 yielded (2)-dihydromaritidine (506) (207). Another concise strategy for the synthesis of alkaloids related to crinine features the application of a general and useful procedure for the elaboration at a carbonyl center of a quaternary carbon atom bearing differentially functionalized alkyl substituents. The application of this methodology to the total syntheses of (+-)-crinine (359) and (a)-buphanisine (361) (Scheme 46) commenced with the

Ph 507: 508:

509

x=o

51 0

X = CH-N=CHPh X = CH-NLiCHPhBu

511

359 361:

R=H R=Me

SCHEME46


347

monoprotected 1,Cdione 507, which was readily available in two steps from piperonal by sequential reaction with the Grignard reagent derived from 2-methyl-2-(2-bromoethyl)- 1,3-dioxolane followed by oxidation of the intermediate benzylic alcohol with pyridinium dichromate (208). Reaction of 507 with diethyl N-benzylideneaminolithiomethylphosphonateproduced the 2-azadiene 508, which underwent regioselective addition of n-butyllithium to generate the metalloenamine 509 in situ. Subsequent alkylation of 509 with ally1 N-benzyl-N-(2bromoethy1)carbamate followed by the addition of aqueous acid provided an intermediate 6-ketoaldehyde, which suffered cycloaldolization and dehydration on treatment with pyrrolidine in 33% aqueous AcOH-MeOH to furnish the key 4,4-disubstituted cyclohexenone 510 in very good overall yield from 507. The conversion of 510 to the cyclohexadienone 511 was most effectively accomplished by sequential bromination with PhNMe,Br, in EtOAc in the presence of catalytic H,SO, followed by dehydrobromination with diazobicycloundecene (DBU) in refluxing benzene. The palladium(0)-catalyzedremoval of the N-ally1 carbamate protecting group was accompanied by the spontaneous cyclization of the resulting secondary amine via Michael addition to give an intermediate cis-3a-arylhydroindolenone,which was reduced with alane to provide a mixture (1 : 1.3-1.5) of the epimeric allylic alcohols 512 and 513. The inversion of configuration at C-3 of 512 to give 513 was easily effected by sequential mesylation followed by nucleophilic displacement with cesium acetate in DMF and saponification. Somewhat surprisingly, the solvolysis of the mesylate derived from 512 in aqueous NaHCO, led to a mixture (1.2 : 1) of the allylic alcohols 512 and 513. After removal of the N-benzyl protecting group from 513 through the agency of a-chloroethyl chloroformate, a Pictet-Spengler cyclization of the intermediate secondary amine furnished (2)-crinine (359) (208). On another front, the mixture of allylic alcohols 512 and 513 was converted by reaction with methanesulfonic acid anhydride in the presence of triethylamine to a mixture of the corresponding mesylates, which were subjected collectively to methanolysis to afford 514, and none of the allylic ether epimeric at C-3 was isolated. N Debenzylation of 514 followed by a classic Pictet-Spengler cyclization then afforded (*)-buphanisine (361) (208). A closely related variant of this novel strategy has also been applied to the efficacious total syntheses of (+)-haemanthidine (382) and (+)-pretazettine (395) (209). In the event (Scheme 47), sequential reaction of the zinc derivative of the metalloenamine 509 with the protected amino acetaldehyde 516, pivaloyl chloride, and then 3 N HCl provided an intermediate S-keto aldehyde, which underwent cycloaldolization and dehydration on treatment with pyrrolidine in 33% aqueous AcOH-MeOH to furnish 517 as a mixture (1.5 : 1) of diastereomers. The a’-bromination of 517 with PhNMe,Br, in EtOAc followed by dehydrobromination with DBU in refluxing benzene then provided the racemic cyclohexadienone 518. Palladium(0)-catalyzed removal of the N-allyloxycar-

348

STEPHEN F. MARTIN

c02c3

H5

516

517

518

519

520:

R' =OH; R2 = H R'=H;R'=OH

OMe

1

bH

521: a-OCO&rt: R = M e

522: p0COBut: R = M e 382

523: u ~ C O B U ' ; R = C H O

SCHEME

47


349

bony1 protecting group from 518 occurred with concomitant cyclization via 1,4addition to form an inseparable mixture of cis-3a-arylhydroindolenones,which underwent selective 1,Zreduction from the exo face with DIBAL in THF to give the diastereomeric allylic alcohols 519 and 520 in an approximately 1 : 2 ratio. When this mixture of the four diastereomeric alcohols 519 and 520 was subjected to sequential mesylation and methanolysis, the allylic methyl ethers 521 and 522 were produced in a 1 : 1.5 ratio. Unfortunately, despite a number of efforts, no completely satisfactory method for effecting the inversion of the undesired neopentyl alcohol 522 to give 521 could be devised. Sequential reaction of 521 with molecular oxygen in the presence of metallic platinum in aqueous dioxane and then with acetic formic anhydnde furnished the N-formyl derivative 523. On heating with POCl,, the formamide 523 underwent a Bischler-Napieralski cyclization, and the remaining pivaloate ester was then removed by careful saponification with lithium hydroxide in methanol to afford (+)-haemanthidine (382). Subsequent N-methylation of 382 followed by mild basic workup then afforded the unstable base (2)-pretazettine (395) in accord with literature precedent (211). A bimolecular Diels-Alder reaction has been exploited as a key step for the construction of the C ring in a synthesis of (2)-tazettine (397) and (?)-6aepipretazettine (431) (Scheme 48) (210). The reaction of the piperonyl ketone 524 with N,N-dimethylformamide dimethylacetal to give a vinylogous amide followed by treatment with thiophenol in the presence of p-toluenesulfonic acid afforded the vinyl sulfide 525 together with its geometric isomer as a 5 : 1 mixture. Direct bromination of 525 was effected with PhNMe,Br, to provide an intermediate a-bromoketone which underwent S-oxidation with MCPBA to give, according to the reaction conditions, either the sulfoxide 526 or the sulfone 527, each as a mixture (5 : 1) of geometric isomers. The major geometric isomer in each of the compounds 525-527 was tentatively assigned the 2 configuration as shown. Based on earlier model studies, it was concluded that the sulfone 527 was a more satisfactory dienophilic partner than the corresponding sulfoxide 526 since the cycloadducts derived from sulfoxides related to 526 and 1-methoxy-3trimethylsilyloxybutadiene (528) underwent facile deacylation and aromatization. Consequently, thermal reaction of the sulfone 527 with the diene 528 followed by chromatography on silica gel furnished a mixture of (4 : 1) of the epimeric cyclohexenones 529, and the subsequent treatment of 529 with aqueous methylamine followed by chromatography on alumina afforded the cis-hydroindolenedione 530 (210). Selective reduction of 530 with DIBAL gave a mixture (1 : 3) of the allylic alcohols 531 and 532 via preferential delivery of hydride to the unsaturated carbonyl function from the exo face. The allylic alcohol 531 was then converted to the allylic ether 533 by reaction with diazomethane in the presence of anhydrous aluminum chloride, whereas the major allylic alcohol 532 was converted to

350

STEPHEN F. MARTIN

525: X=H;n=O 5 2 6 X=Br,n=l 527: X=Br.n=2

524

0

529

530

OMe

I

531: 532 533:

R'=OH:R'=H R'=H;R*=OH R' =OM; R ~ K=

SCHEME 48

533 by sequential treatment with methanesulfonic acid anhydride and triethylamine in THF followed by solvolysis of the intermediate mesylate in methanol. Unfortunately, the reduction of the hindered neopentyl ketone group present in 533 did not proceed with a high degree of stereoselectivity to give 534. For example, when the reduction of 533 was camed out with sodium borohydride, the alcohols 534 and 535 were obtained as a mixture (3 : l), whereas reduction of 533 with K-Selectride afforded a mixture (1 : 8) of 534 and 535. All attempts to convert 534 directly to (2)-pretazettine (395)by interpolation of a

35 1


one-carbon unit between the hydroxyl function at C-6a and the aromatic ring through the use of some electrophile at the oxidation level of formic acid were uniformly unsuccessful. On the other hand, heating 535 with trimethylorthoformate in 115% polyphosphoric acid followed by the acid-catalyzed hydrolysis of the intermediate methoxyacetal 430 delivered (+)-6a-epipretazettine (431)

(210). Although repeated efforts to reproduce the previous claim in the literature

(211) that (-+)-6a-epipretazettine(431) suffered base-induced conversion to ( 2 ) tazettine (397) resulted in failure, an alternate route to 397 from 431 proved fruitful (2IOb).Thus, reduction of 431 with LiAlH, afforded the diol536, which was converted to 538 by selective 0-silylation of the primary benzylic hydroxyl group with tert-butyldimethylsilylchloride in the presence of triethylamine and 4pyrrolidinopyridine followed by oxidation of the remaining hydroxyl group at C-6a according to the Moffat-Pfitzner protocol. Fluoride-induced cleavage of the silyl protecting group and spontaneous cyclization afforded (5)-tazettine (397). Hydride reduction of the neopentyl carbonyl function in 538, which bore an ortho substituent on the adjacent aromatic ring, proceeded predominantly (3 : 1) from the endo rather than the exo face to give 539 as the major product together with the epimeric alcohol 540. OMe

OMe

536:

I

I

OH

OTBS

R'=OH;R2=H

537: R1=H;R2=OH

538: 539:

R1,R2=0 R1=Cti;R2=H

540:

R'=H;R~=OH

A procedure for the transformation of (+)-tazettine (397) to (+)-pretazettine (395) has been developed (212). The reaction of 397 with LiAIH, provided a mixture of the diols 536 and 537 in an approximately 9 : 2 ratio. Thus, it is again apparent that the preferred stereochemicalpathway for the delivery of hydride to the neopentyl carbonyl function is from the endo face of the cis-3a-arylhydroindole whenever the angular aryl group possesses an ortho substituent. Oxidation of 537 with manganese dioxide gave a mixture (approximately 3 : 2 : 1) of (+)pretazettine (399, (+)-3-epimacronine (400), and (+)-tazettine (397). In a sim-

352

STEPHEN F. MARTIN

ilar fashion, oxidation of the diol 536 gave a mixture (approximately 7 : 4) of (+)-6a-epipretazettine (431) and (+)-6a-epi-3-epimacronine(541) (212). In related studies', the diol 537 was cyclized with 3% H,SO, to give deoxypretazettine (542), which was converted in four steps to deoxypretazettine neomethine (543) (212,213).

400:

X=OpH

541:

X=Oa-H X=Hz;BH

542:

543

6. A + D + C + B A Diels-Alder reaction played a key role in the design of a general strategy, which has been successfully applied to the total syntheses of a number of alkaloids including (+)-haemanthamine (381) (214), (?)-haemanthidine (382) (215), (*)-tazettine (397) (215), (2)-crinamine (376) (2Z6),(*)-6-hydroxycrinamine (379) (216), (*)-criwelline (398) (216), and ('-)-macronine (401) (216). The pivotal intermediate in these syntheses was the hydroindolene 546 that was prepared by the thermal [4 + 21 cycloaddition of butadiene with the latent dienophile 545, which was accessible from 544 by catalytic hydrogenation and cyclization (Scheme 49) (214). Reaction of 546 with NBS in dioxane containing a catalytic amount of HC10, followed by treatment of the resulting mixture with methanolic sodium methoxide afforded the epoxide 547, and the subsequent nucleophilic opening of the epoxide moiety with boron trifluoride etherate in methanol afforded an intermediate methoxy hemiacetal that was reduced with LiAlH, to furnish a single amino diol 548. Pictet-Spengler cyclization of 548 according to the standard protocol gave 550, which was readily converted to (2)haemanthamine (381) by selective tosylation of the less hindered secondary hydroxyl group and base-induced elimination on heating with DBU in DMSO (214). The hydroindole 548 was also converted to (+)-haemanthidine (382) and (?)tazettine (397) (215). The transformation of 548 to 549 was achieved by sequential N- and 0-formylation, selective hydrolysis of the formate ester, and then 0acetylation. The elaboration of 549 to 551 was then effected via Bischler-


544

353

545

54 6

547

Napieralski cyclization by heating with POCI, in xylene followed by methanolic workup and saponification of the acetate groups. After selective tosylation of the hydroxyl group at C-2 on 551 using p-toluenesulfonyl chloride in pyridine, baseinduced elimination with DBU in DMSO and hydrolysis of the N,O-acetal with 50% aqueous acetic acid then produced (-+)-haemanthidine (382)(215). In a related sequence of reactions, cyclization of 549 with POCI, and then aqueous workup produced the carbinolamine 552. N-Methylation of 552 with methyl iodide followed by treatment with strong base resulted in an intramolecular Cannizzaro process to deliver the intermediate 553, which was converted to (+)-tazettine (397) by tosylation and base-induced elimination (215).

354

STEPHEN F. MARTIN

OMe

553

The conversion of the cycloadduct 546 to (t)-crinamine (376), (*)-6-hydroxycrinamine (379), (+)-criwelline (398), and (+)-macronine (401) commenced by reduction of 546 with NaBH, followed by acetylation to produce solely the acetate 554, which arose by hydride attack on the hindered neopentyl ketone exclusively from the convex face syn to the aryl substituent (Scheme 50) (216). The stereo- and regioselective addition of the elements of PhSeOMe to the carbon-carbon double bond of 554 followed by oxidation of the intermediate methoxy selenide and elimination of phenylselenous acid gave the allylic ether

554

376

X=H;R=H

379 558:

X=OH;R=H X=OH;R=Ac

SCHEME50


355

555 as the sole product. Subsequent reduction of 555 with LiAlH, furnished the amine 556, which underwent a Pictet-Spengler cyclization to produce (+-)crinamine (376). On the other front, the reaction of the lactam 555 with triethyloxonium fluoroborate and chemoselective reduction of the intermediate imino ether with NaBH,/SnCl, 2Et,O complex gave the amine 557. N-Formylation of 557 with acetic formic anhydride in pyridine and subsequent Bischler-Napieralski cyclization using POCl, in refluxing toluene gave the carbinolamine 558,which afforded (+)-6-hydroxycrinamine (379)on saponification of the acetate group at C-11 (216). Alternatively, N-methylation of the acetate 558 with methyl iodide in methanol succeeded by treatment with aqueous KOH led to the formation of (?)-criwelline (398)(226). However, oxidation of 558 with manganese dioxide afforded an intermediate lactam, which was converted to (+-)-macronine (401) by base-induced hydrolysis of the lactam moiety followed by acid-catalyzed lactonization and finally reductive N-methylation with HCHO-NaBH, (216). An elegant and general strategy for the synthesis of alkaloids possessing annelated pyrrolidines as a structural subunit has been developed (217), and it features the acid-catalyzed, thermally induced rearrangement of cyclopropyl imines to produce A2-pyrrolines, which may then be subjected to reaction with methyl vinyl ketone to give a hydroindole (2176). The application of this methodology to the total synthesis of (+)-elwesine (439)(Scheme 51) commenced with the aryl cyclopropylnitrile 559, which was conveniently available from piperonyl cyanide (432)by the lithium amide-induced cyclopropanation of 432 with ethylene dibromide ( 2 1 7 ~ ) Reduction . of 559 with DIBAL followed by condensation of the resultant aldehyde with benzylamine afforded the aldimine 560, and subsequent thermolysis of 560 in the presence of ammonium chloride led to the formation of the p-aryl endocyclic enamine 561. It should be noted that the molecular reorganization of 560 to 561 was not purely a thermal process, but the reaction required the presence of an acid catalyst having a nucleophilic gegenion. Conversion of 561 to its hydrochloride salt and subsequent reaction with methyl vinyl ketone in acetonitrile delivered the cis-3a-arylhydroindolone562. The annelations of endocyclic enamines related to 561 with methyl vinyl ketone were also found to be acid catalyzed (2176). Attempts to effect the N-debenzylation of 562 using protocols based on cyanogen bromide or alkyl chloroformateswere unsuccessful owing to complications involving thz facile p-elimination of the acyl-substituted nitrogen group. Consequently, the carbonyl function of 562 was first reduced catalytically to return a mixture (8 : 1) of the alcohols 563 and 564, and subsequent removal of the N-benzyl group from the hydrochloride salt of 563 was effected by catalytic hydrogenolysis to give 565, which provided (*)-elwesine (439)on PictetSpengler cyclization. On the other hand, reduction of the ketone 562 with sodium borohydride yielded a mixture (1 : 3) of the alcohols 563 and 564, and

356

STEPHEN F. MARTIN

559: 560:

561

R=CN R=CH=N-CHzPh

Ph

562:

R’,RZ=O

563: 564:

R’ =OH; R’= H R’=H;RZ=OH

SCHEME 51

when 564 was subjected to the sequence of catalytic N-debenzylation to give 566 followed by Pictet-Spengler cyclization, (+)-3-epielwesine (449) was obtained in good overall yield ( 2 1 7 ~ ) . A related entry to the natural bases 439 and 449 has been reported that commenced with the a-phenylsulfenylated nitrile 567 (Scheme 52) (218). Thus, Michael reaction of 567 with ethyl acrylate in the presence of a catalytic amount of Triton B and then desulfurization of the intermediate sulfide using Urushibara’s nickel afforded the cyano ester 568. Base-induced saponification of the ester moiety afforded the corresponding acid, .which was subjected to a modified Curtius rearrangement, and the intermediate isocyanate was trapped with benzyl alcohol to provide the urethane 569. Selective reduction of the nitrile function of 569 with DIBAL followed by acid-catalyzed cyclization of the intermediate urethane aldehyde afforded the hemi-amidal 570, which was converted to the cis-3a-arylhydroindolone571 by sequential reaction with methyl vinyl ketone in the presence of Triton B and heating in 20% methanolic HCl. When 570 was simply dehydrated, the resulting endocyclic enamide was found to be unreactive toward methyl vinyl ketone. Reduction of the carbonyl function of 571 with DIBAL gave a mixture (1 : 3.5) of the epimeric alcohols 572 and 573, and

351


569

567: R = S R 568: R = CH,CH,CO, Et

570

571

572: R1 =OH; R2= H; R3 = Cbz 573: R1 = H; R2 =OH; R3 = Cbz

SCHEME 52

subsequent removal of the N-carbobenzyloxy protecting group from 572 and 573 via palladium-catalyzed hydrogenolysis afforded the corresponding secondary amino alcohols 565 and 566, which had previously been converted to 0)elwesine (439) and (?)-3-epielwesine (449), respectively (217). A final approach to the cis-3a-arylhydroindole skeleton that has resulted in a concise total synthesis of (*)-epielwesine (449)featured the acid-promoted cyclization of (2)-vinylsilane imines such as 575 (Scheme 53) (219). Thus, sequential alkylation of 3,4-(methylenedioxyphenyl)acetonitrile (432) with (a-4-brorno- 1-butenyltrimethylsilane and 1-bromo-2-chloroethane provided

358

STEPHEN F. MARTIN

P

SiMe

/J

SiMe,

574

575

576

SCHEME53

574, which underwent hydride reduction with DIBAL to afford the A'-pyrroline 575. Cyclization of 575 was readily induced on treatment with trifluoroacetic acid to give the cis-hydroindolene 576. Although attempts to convert 576 to the known secondary amino alcohol 566 via the agency of hydroboration were unsuccessful, the allylic secondary amine 576 was cleanly hydrated to yield 566

by sequential treatment with Hg(OAc), (2 equiv) in aqueous THF followed by reduction of the intermediate organomercurial with NaBH,. When 566 was subjected to the usual conditions of the Pictet-Spengler reaction as before, (*)epielwesine (449) was obtained in very good overall yield (219). It is interesting to note that (I?)-vinylsilane imines related to 575 did not cyclize under conditions required to effect the cyclization of 575 since u-IT hyperconjugative or vertical stabilization of the developing p-silyl cation in the transition state for cyclization of these substrates was presumably less effective.

VII. Other Structural Types A. NORBELLADINE DERIVATIVES Latisoline (577) is a novel glucosyl alkaloid that was isolated from Crinum latifolium (36), and the structural assignment was based on its hydrolysis with emulsin to provide the aglycone latisodine (578) and D-glucose. Further support

359

3. THE AMARnLIDACEAJ? ALKALOIDS

for the structure of 577 was derived from the complete analysis of its 13C-NMR spectrum coupled with comparisons with the 13C-NMR spectra of latisodine (578) and belladine. Unequivocal chemical proof of the structure of the aglycone latisodine (578) was obtained by its synthesis by the reductive amination of veratraldehyde and tyramine . X

577: R=P-Dglu;X=H 578: R = X = H 579: R=Me;X=OMe

The isolation of ryllistine (579) represented the first time that a 4-oxygenated norbelladine alkaloid had been isolated from the plants of the family Amaryllidaceae. The structural assignment was based on spectroscopic methods including a complete assignment of the 13C NMR spectrum combined with its chemical synthesis by reductive amination of veratraldehyde and homoveratrylamine (6).

B. MESEMBRANE TYPE Although the alkaloids of the mesembrane type are structurally similar to certain alkaloids of the family Amaryllidaceae, they are generally found in the plants of the family Aizoaceae, but there have been several exceptions to this generalization. For example, amisine (580) has been isolated from Hymenocallis arenicola Northrop ( 5 3 , and mesembrenol(581) has been isolated from Crinum oliganthum (41). The isolation of 580 and 581 represented the first instances in OMe

NMe,

I

580

Me 581

360

STEPHEN F. MARTIN

which alkaloids of these structural types have been isolated from plants of the family Amaryllidaceae.

C. AUGUSTAMINE Augustamine (582), which was isolated from Crinum uugustum Rox., represents a new structural type of alkaloid in the family Amaryllidaceae (26), and its structure was deduced by extensive 'H- and 13C-NMR studies, which resulted in the complete assignments of the 'H- and 13C-NMR spectra, together with an analysis of its mass spectrum. The assignment of the cis ring fusions were based on analysis of vicinal coupling constants of the relevant protons. Me

582

D. MONTANINE TYPE The structure of brunsvigine (583) has been established by the X-ray analysis of the corresponding 0,O'-di-p-bromobenzoate (7u). Furthermore, the 'H-NMR spectra of brunsvigine together with several of its derivatives have been completely assigned, and the ORD and CD spectra of these compounds have been measured. The structure of 583 was related to other 5,l lb-methanomorphanthridine alkaloids by methylation and other chemical transformations including a series of Hoffmann degradations (7b). Although the alkaloids of the montanine type have not stimulated a high degree of synthetic interest, several approaches to montanine (584) have been

583: R'=R2=H;R3=OH 584: R'=Me; R2=OH;R3= H


36 1

585

recently developed. These have involved the design of different tactics for the construction of 3-aryloctahydroindoles that could be cyclized under PictetSpengler conditions to provide access to the complete skeletal framework of the target alkaloid (220). Thus, kinetic addition of the anion derived from 3,4-(methylenedioxypheny1)acetonitrile (432) to l-nitrocyclohexene (585) delivered 586 as the major product, and subsequent hydrolysis of the nitro function of 586 via a modified Nef reaction followed by reductive cyclization of the resulting mixture of keto nitriles gave a mixture (1 : 1) of the trans- and cis-octahydroindoles 589 and 590, respectively (Scheme 54) (220). Alternatively, reduction of 586 with DIBAL afforded a mixture (1 : 1) of the nitro aldehydes 587 and 588. Although the reductive cyclization of 587 proceeded smoothly to give 591, the attempted reductive cyclization of the trans isomer 588 furnished only acyclic andlor polymeric materials (220). Another approach to the 3-aryloctahydroindolering system commenced with the reaction of 592, which was readily available from the condensation of

592

593

362

STEPHEN F. MARTIN

piperonal with cyclohexanone, with nitromethane using a supported tetrabutylammonium fluoride catalyst to give the nitro ketone 593. Reductive cyclization of 593 then furnished the truns-fused octahydroindole 589 (220).

E.

4-ARYLTETRAHYDROISOQUINOLINETYPE

Latifine (594) is a new phenolic base isomeric with cherylline (595) that has been isolated from Crinurn lutifoliurn L. (221). The (S) configuration at C-4 of 594 was deduced from an observed negative Cotton effect in the ORD curve of 594 and 595, and this assignment was confirmed by an X-ray analysis of the Nbromobenzamide derivative of 594.

PH

594: R ' = O H ; R ~ = H 1 2 595: R = H R =OH

The total syntheses of both ( 2 ) -and (+)-latifine (594) have been completed employing a Claisen rearrangement as the key step (Scheme 55) (222). Access to racemic 594 required the allylic ether 596, which was readily prepared albeit in only fair yield, by the Mitsunobu reaction of 4-benzyloxycinnamyl alcohol with 2-methoxyphenol in the presence of diethyl azodicarboxylate and triphenylphosphine. On thermolysis in refluxing N,N-dimethylaniline, 596 underwent facile molecular reorganization, and subsequent alkylation of the intermediate monophenol with benzylbromide in DMF in the presence of K,CO, returned 597. Ozonolysis of 597 followed by hydride reduction of the resulting aldehyde then afforded the primary alcohol 598. The Mitsunobu reaction of 598 with phthalimide followed by hydrazinolysis gave a primary amine, which was formylated with acetic formic anhydride in pyridine to produce the formamide 599. Since the secondary amide 599 afforded only intractable tars on attempted cyclization under Bischler-Napieralski conditions, it was first converted to the homologous N-methylformamide 600 by sequential reaction with LiAlH, and acetic formic anhydride. On reaction with POCl, in refluxing benzene, cyclization onto the more highly activated ring of 600 ensued, and the intermediate

363


OBn

I

597

596

p"

OBn

I

598: 599: 600:

Z=OH Z=NHCHO Z=NMeCHO

601: 594:

R=Bfl R=H

SCHEME 55

iminium salt was reduced with sodium borohydride to elaborate the 4-arylhydroisoquinoline 601. The conversion of 601 to (+)-latifine (594) was readily accomplished by removal of the 0-benzyl protecting groups by catalytic hydrogenolysis . The asymmetric synthesis of unnatural (+)-latifine commenced with the reaction of the (S)-epoxide 602 with sodium benzenethiolate followed by oxidation of the intermediate sulfide with hydrogen peroxide to give 603 as a mixture (1 : 1) of diastereomeric sulfoxides (Scheme 56). Alkylation of the dianion derived from 603 with 4-benzyloxybenzyl chloride and thermolysis of the resulting sulfoxide in refluxing toluene in the presence of CaCO, afforded the (R)-allylic alcohol 604 as a single product. The Mitsunobu reaction of 604 with 2-methoxyphenol using diisopropyl azodicarboxylate then gave 605, and subsequent thermolysis of 605 induced a Claisen rearrangement that proceeded via a chair

364

STEPHEN F. MARTIN OBn

OBn

604

OBn

OMe

606

605

Me0

OH

607

608

SCHEME56

365


transition state to deliver the (@-olefin 606 in which the stereocenter at C-4 is (R) rather than (S) as in the natural product. Benzylation of the phenolic hydroxyl group in 606 followed by ozonization and hydride reduction afforded the optically active alcohol 607, which was converted to optically active, unnatural (+)-latifine (608) in eight steps according to the sequence of reactions outlined above for the preparation of the racemic material. Unfortunately, the optical purity of the 608 thus obtained was rather low, indicating that partial racemization had occurred at some stage during the conversion of 603 to 606 (222). Several efficient syntheses of (?)-cherylline (595) have been reported, and the common strategic feature of these entries is the cyclization of p-quinonemethides or functional equivalents thereof (223-225). For example, reaction of 609, which was readily accessible from 4-benzyloxystyrene by sequential reaction with bromine and methanol, with 3-benzyloxy-4-methoxy-N-methylbenzylamine gave the tertiary amine 611 (223). In related work, 611 was obtained via aminolysis of the mesylate 610 that was prepared in two straightforward steps from 4-benzyloxystyrene oxide (224). When 611 was heated in strong acid, cycliza-

9

OBn

1

Me0

2

61 1

609: Z=Br 610: Z=OMs

tion with concomitant 0-debenzylation ensued to produce (+)-cherylline (595) (223,224).Presumably, a cation which may be formulated as a quinonemethide such as 612 (X = H2) was the key intermediate in this cyclization reaction. A general approach to precursors of p-quinonemethides has been developed that involved the olefinations of p-quinoneketals as 615 with suitable nucleophiles. For example, the reaction of 615 with the anion derived from 613 led directly to the p-quinonemethide ketal 616 via a Peterson reaction (Scheme 57) (225). Alternatively, 616 was prepared by the initial reaction of 615 with the anion of 614 followed by mild dehydration of the intermediate tertiary alcohol

366

STEPHEN F. MARTIN

X

612:

X=H2,0

Me0

OMe

COCH,R N-Me

+

BnO

0 61 5

613: R=SiMea 614: R = H

Me0

___, BnO

616

SCHEME 51

-

367


with the sulfurane Ph,S[OC(CF,),Ph],. When 616 was stirred with boron trifluoride etherate in dichloromethane at room temperature, the lactam 617 was produced, presumably via an intermediatep-quinonemethide related to 612 (X = 0).Removal of the 0-benzyl protecting group by catalytic hydrogenolysis and subsequent reduction of the lactam moiety with LiAlH, afforded the tetrahydroisoquinoline 618. Selective cleavage of the methyl ether group at C-4’, which was not deactivated toward nucleophilic cleavage by phenoxide formation under the reaction conditions as would be anticipated for the methoxy group at C-6, was achieved with sodium ethyl mercaptide in DMF to give (+)-cherylline (595) (225). A more concise route to (2)-cherylline was also devised and commenced with the reductive amination of isovanillin with methylamine followed by reaction of the intermediate benzylamine with vinyl triphenylphosphonium bromide to provide the aminophosphonium salt 619. Sequential treatment of 619 with nbutyllithium and the quinone ketal 615 followed by reaction of the resulting crude allylic amine 620 with boron trifluoride etherate gave the phenolic amine 618 in good overall yield (225).

N-Me HO

619

620

A novel approach to the synthesis of alkaloids bearing a 4-arylisoquinoline ring subunit has been developed that exploits the nitrogen analog of a pinacol rearrangement (226). As shown in Scheme 58, condensation of the homophthalic anhydride 621 with the imine 622 provided a mixture of the lactams 623 and 624. The kinetic product 623 was converted to the thermodynamically more stable trans product 624 on refluxing in acetic acid, and oxidative decarboxylation of 624 with lead tetraacetate in the presence of cupric acetate then proceeded with retention of configuration to deliver the acetate 625. Conversion of 625 to the phenolic amino alcohol 626 was achieved via sequential reduction with LiAlH, and removal of the 0-benzyl group by catalytic hydrogenolysis over PdiC in

368

STEPHEN F. MARTIN

M

@

q

+

O

-

OMe

” BOJ$

Me0

Me NN 621 622

Me0

/

-

Me0

\

N-Me

M

OMe

Me0

/e

o

\

\

w

N-Me

4

0

-

623:

a-H

625: X = 0 R’ = Ac: R Z =Bn

624:

B-H

626: x=H,; R ’ = R * = H

b

OH

Meov I

Me0A

Y

-

M CI -e

M Me0 e

\ o

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\

+

627

F

O

M

g

CI 628

SCHEME58

glacial acetic acid. When 626 was heated in refluxing acetic acid with palladium on charcoal, a mixture ( 1 : 2) of the positional isomers 627 and 628, respectively, was obtained.

Acknowledgments I wish to thank the Robert A. Welch Foundation and the National Institutes of Health for the support of our work that is described herein. I also thank Ms. Susie F’ruett for her invaluable


369

assistance in preparing the manuscript, Ms. Jill Duprk for conducting a thorough search of the literature, and Drs. Carlton L. Campbell and Thomas H. Cheavens for their help in proofreading the final version of this chapter.

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149. (a) H. Paulsen and M. Stubbe, Tetrahedron Lett. 23, 3171 (1982). (b) H. Paulsen and M. Stubbe, Liebigs. Ann. Chem., 535 (1983). 150. M. R. Yagudaev, A. Abdusamatov, and S. Yu. Yunusov, Khim. Prir. Soedin. 10, 183 (1974); Chem. Abstr. 81, 63819s (1974). 151. S. H. Hong, J. F. Li, and R. X. Xu, Chih Wu Hsueh Pao 23, 334 (1981); Chem. Abstr. 95, 209453f (1981). 152. T. Kametani, C. Seino, K. Yamaki, S. Shibuya, K. Fukumoto, K. Kigasawa, F. Satoh, M. Hiiragi, and T. Hayasaka, J. Chem. Soc., 1043 (1971). 153. T. Kametani, K. Yamaki, S. Shibuya, K. Fukumoto, K. Kigasawa, F. Satoh, M. Hiiragi, and T. Hayasaka, J. Chem. SOC.,590 (1971). 154. (a) V. D. Tonkopii, V. B. Prozorovskii, and M. G. Konstorum, Byull. Eksp. Biol. Med. 80, 120 (1975); Chem. Abstr. 83, 189728W (1975). (b) E. T. Vasilenko and V. D. Tonkopii, Biolkhimiya 39, 701 (1974); Chem. Absrr. 82, 129132 (1975). 155. (a) V. P. Fisenko and V. Mitsov, F a r m . Toksikol (Moscow) 38, 34 (1975); Chem. Abstr. 82, 132979d (1975). (b) A. Baraka and D. Cozanitis, Anesth. Anulg. 52,832 (1973); Chem. Abstr. 81, 22842e (1974). 156. A. T. Dolgushina, Povysh. Rezistentnosti Organiztnu, 182 (1973); Chem. Abstr. 81, 72709h (1974). 157. D. A. Cozanitis, K. Nuuttila, P. Karhunen, and A. Baraka, Anaesthesist 22, 457 (1973). 158. E. D. Bazhenova, Kh. U. Aliev, and U. B. Zakirov, Farmkol. Alkaloidov Ikh. Proizvod., 74 (1972); Chem. Abstr. 80, 103864r (1974). 159. For a review see T. Kametani and K. Fukumoto, Synthesis, 669 (1972). 160. T. Kametani, K. Yarnaki, T. Terui, S. Shibuya, and K. Fukumoto, J. Chem. SOC. Perkin Trans. 1 , 1513 (1972). 161. T. Kametani, K. Yamaki, and T. Terui, J. Heterocyclic Chem. 10, 35 (1973). 162. T. Kametani, K. Shishido, E. Hayashi, C. Seino, T. Kohno, S. Shibuya, and K. Fukumoto, J. Org. Chem. 36, 1295 (1971). 163. (a) K. Shimizu, K. Tomioka, S.-I. Yamada, and K. Koga, Heterocycles 8,277 (1977). (b) K. Shimizu, K. Tomioka, S . 4 . Yamada, and K. Koga, Chem. Phurm. Bull. 26, 3765 (1978). 164. D. Krikorian, R. Vlahov, S. Parushev, M. Chinova, I. Vlahov, H.-J. Schafer, H. Duddeck, and G. Snatzke, Tetrahedron Lett. 25, 2969 (1984). 165. (a) S. F. Martin, and P. J. Garrison, J. Org. Chem. 46,3567 (1981). (b) S. F. Martin, and P. J. Garrison, J. Org. Chem. 47, 1513 (1982). 166. I. H. Sanchez, J. J. Soria, F. J. Lopez, M. I. Larraza, andH. J. Flores, J. Org. Chem. 49, 157 (1984). 167. A. G. Schultz, Y. K. Yee, and M. H. Berger, J. Am. Chem. Soc. 99, 24 (1977). 168. I. G. Sanchez, M. I. Larraza, H. J. Flores, E. A. Martell, I. Linzaga, and A. A. Carter, Heterocycles 23, 251 (1985). 169. D. J. Ackland, and J. T. Pinhey, Tetrahedron Lett. 24, 5331 (1985). 170. V. Zabel, W. H. Watson, P. Pacheco, and M. Silva, Cryst. Struct. Commun. 8, 371 (1979). 171. W. H. Watson, V. Zabel, M. Silva, and P. Pacheco, Cryst. Struct. Commun. 11, 157 (1982). 172. W. H. Watson, J. Galby, and M. Silva, Acta Crystallogr. Sect. C , Cryst. Struct. Commun. 40, 156 (1984). 173. Y. Tsuda, M. Kaneda, S. Takagi, M. Yamaki, andY. Iitaka, TetrahedronLett. 1199 (1978). 174. P. Longevialle, D. H. Smith, A. L. Burlingame, H. M. Fales, and R. J. Highet, Org. Mass Spectrorn. 7, 401 (1973). 175. P. Longevialle, H. M. Fales, R. J. Highet, and A. L. Burlingame, Org. Mass Spectrom. 7,417 (1973). 176. M. A. Schwartz and R. A. Holton, J . Am. Chem. SOC.92, 1090 (1970). 177. G. Song, Fenxi Huuxue 9, 520 (1981); Chem. Abstr. 96, 162994m (1982).


375

178. T. S. Papas, L. Sandhaus, M. A. Chirigos, and E. Furusawa, Biochem. Biophys. Res. Commun. 52, 88 (1973). 179. N. Suzuki, S. Tani, S. Furusawa, and E. Furusawa, Proc. SOC. Expl. Biol. Med. 145, 771 (1974). 180. E. Furusawa, N. Suzuki, S. Furusawa, and J . Y. B. Lee, Proc. SOC.Expl. Biol. Med. 149,771 (1975). 181. E. Furusawa, S. Furusawa, J. Y. B. Lee, and S. Patanavanich, Proc. SOC. Expl. Biol. Med. 152, 186 (1976). 182. E. Furusawa, S. Furusawa, J. Y.B. Lee, and S. Patanavanich, Chemotherapy 24,259 (1978). 183. E. Furusawa, R. H. Lockwood, S. Furusawa, M. K. M. Lum, and J. Y. B. Lee, Chemotherapy 25, 308 (1979). 184. E. Furusawa, H. Irie, D. Combs, and W. C. Wildman, Chemotherapy 26, 36 (1980). 185. E. Furusawa and R. H. Lockwood, Proc. West. Pharmacol. SOC.24, 45 (1981). 186. E. Furusawa, M. K. M. Lum, and S. Furusawa, Chemotherapy 27, 277 (1981). 187. E. Furusawa, S. Furusawa, and L. Sokugawa, Chemotherapy 29, 294 (1983). 188. Matthew Suffness (NCI), personal communication (1982). 189. A. I. Feinstein and W. C. Wildman, J. Org. Chem. 41, 2447 (1976). 190. Y. Tsuda, Heterocycles 10, 555 (1978). 191. (a) M. A. Schwartz, B. F. Rose, and B. Vishnuvajjala, J . Am. Chem. SOC. 95,612 (1973). (b) For related work, see M. A. Schwartz, B. F. Rose, R. A. Holton, S. W. Scott, and B. Vishnuvajjala, J . Am. Chem. SOC. 99, 2571 (1977). 192. S. M. Kupchan, 0. P. Dhingra, and C.-K. Kim, J. Org. Chem. 43, 4076 (1978). 193. E. Kotani, N. Takeuchi, and S. Tobinaga, Tetrahedron Lett., 2735 (1973). 194. E. Kotani, N. Takeuchi, and S. Tobinaga, J. Chem. SOC.Chem. Commun., 550 (1973). 195. T. Kametani, T. Kohno, S. Shibuya, and K. Fukumoto, Tetrahedron 27, 5441 (1971). 196. (a) S.-I. Yamada, K. Tomioka, and K. Koga, Tetrahedron Lett., 57 (1976). (b) K. Tomioka, K. Koga, and S.-I. Yamada, Chem. Pharm. Bull. 25, 2681 (1977). 197. J. D. White, W. K. M. Chong, and K. Thimng, J . Org. Chem. 48, 2300 (1983). 198. (a) H. Irie, S. Uyeo, and A. Yoshitake, J. Chem. SOC.(C), 1802 (1968). (b) T. Fushimi, H. Ikuta, H. Irie, K. Nakadachi, and S. Uyeo, Heterocycles 12, 1311 (1979). (c) S. Uyeo, H. Irie, A. Yoshitake, and A. Ito, Chem. Pharm. Bull. (Tokyo) 13, 427 (1965). 199. I. H. Sanchez and M. T. Mendoza, Tetrahedron Lett. 21, 3651 (1980). 200. I. H. Sanchez, F. J. Lopez, J. J. Soria, M. I. Larraza, and H. J. Flores, J. Am. Chem. SOC. 105, 7640 (1983); see also reference 168. 201. I. Ninomiya, T. Naito, and T. Kiguchi, J. Chem. SOC., Perkin Trans. I , 2261 (1973). 202. J . B. Hendrickson, T. L. Bogard, M. E. Fisch, S. Grossert, and N. Yoshimura, J. Am. Chem. SOC. 96, 7781 (1974). 203. (a) L. E. Overman and E. J. Jacobsen, Tetrahedron Lett. 23,2741 (1982). (b) L. E. Overman and L. T. Mendelson, J. Am. Chem. SOC. 103, 5579 (1981). (c) L. E. Overman, L. T. Mendelson, and E. J. Jacobsen, J. Am. Chem. SOC. 105, 6629 (1983). 204. H. W. Whitlock and G. L. Smith, J. Am. Chem. SOC.89, 3600 (1967). 205. L. E. Overman and S. Sugai, Helv. Chim. Acta 68, 745 (1985). 206. G. E. Keck and R. R. Webb, 11, J . Am. Chem. SOC.103, 3173 (1981). 207. G . E. Keck and R. R. Webb, 11, J. Org. Chem. 47, 1302 (1982). 208. S. F. Martin and C. L. Campbell, Tetrahedron Lett. 28, 503 (1987). 209. S. F. Martin and S. K. Davidsen, J. Am. Chem. SOC. 106, 6431 (1984). 210. (a) S. Danishefsky, J. Moms. G. Mullen, and R. Gammill, J. Am. Chem. SOC. 102, 2838 (1980). (b) S. Danishefsky, J. Moms, G. Mullen, and R. Gammill, J . Am. Chem. SOC. 104, 7591 (1982). 211. W. C. Wildman and D. T. Bailey. J. Am. Chem. SOC. 91, 150 (1969).

376

STEPHEN F. MARTIN

212. (a) S. Kobayashi, M. Kihara, and T. Shingu, Heterocycles 12, 1547 (1979). (b) S. Kobayashi, M. Kihara, T. Shingu, and K. Shingu, Chem. Pharm. Bull. 28, 2924 (1980). 213. S. Kobayasbi, M. Kihara, T. Hashimoto, and T. Shingu, Chem. Pharm. Bull. 24,716 (1976). 214. Y. Tsuda and K. Isobe, J . Chem. SOC. Chem. Commun., 1555 (1971). 215. Y. Tsuda, A. Ukai, and K. Isobe, Tetrahedron Lett., 3153 (1972). 216. K. Isobe, J. Taga, and Y. Tsuda, Tetrahedron Lett., 2331 (1976). 217. (a) R. V. Stevens, L. E. DuPree, Jr., and P. I. Loewenstein, J. Org. Chem. 37,977 (1972). (b) For a review, see R. V. Stevens, Acc. Chem. Res. 10, 193 (1977). 218. I. H. Sanchez, F. J. Lopez, H. J. Flores, and M. I. Larraza, Heterocycles 20, 247 (1983). 219. L. E. Overman, and R. M. Burk, Tetrahedron Lett. 25, 5739 (1984). 220. 1. H. Sanchez, M. I. Larraza, I. Rojas, F. K. Brena, and H. J. Flores, Hetereocycles 23, 3033 (1985). 221. S. Kobayashi, T. Tokumoto, and 2. Taka, J . Chem. SOC., Chem. Commun., 1043 (1984). 222. S. Takano, M. Akiyama, and K. Ogasawara, J . Chem. SOC. Perkin Trans. I , 2447 (1985). 223. T. Kametani, K. Takahashi, and C. V. Loc, Tetrahedron 31, 235 (1975). 224. H. Hara, R. Shirai, 0. Hoshino, and B. Umezawa, Heterocycles 20, 1945 (1983);H. Hara, R. Shirai, 0. Hoshino, and B. Umezawa, Pharm. Bull. 33, 3107 (1985). 225. D. J. Hart, P. A. Cain, and D. A. Evans, J. Am. Chem. SOC. 100, 1548 (1978). 226. M. Cushman and P. Mohan, Tetrahedron Lett. 26, 4563 (1985). 227. The extensive collection of alkaloid samples belonging to the late Professor William C. Wildman, one of the pioneers in the elucidation of the chemistry and the structure of alkaloids of the family Amaryllidaceae, have been acquired from Mrs. Ruth Wildman by Dr. Henry M. Fales at the National Institutes of Health, National Heart, Lung, and Blood Institute, Bethesda, MD 20205. 228. J. M. Llabrks, F. Viladomat, J. Bastida, C. Codina, M. Serrano, M. Rubiralta, and M. Feliz, Phyrochemistry 25, 1453 (1986).

CUMULATIVE INDEX OF TITLES Aconitum alkaloids, 4, 275 (1954)

diterpenoid, 7, 473 (1960) C,g diterpenes, 12, 2 (1970) C20 diterpenes, 12, 136 (1970) Acridine alkaloids, 2, 353 (1952) Acridone alkaloids, experimental antitumor activity of acronycine, 21, 1 (1983) Actinomycetes, isoquinolinequinones, 21, 55 (1983) Ajmaline-Sarpagine alkaloids, 8, 789 (1965), 11, 41 (1968) Alkaloid structures spectral methods, study, 24, 287 (1985) unknown structure minor alkaloids, 5, 301 (1955), 7, 509 (1960) unclassified alkaloids, 10, 545 (1967), 12, 455 (1970), 13, 397 (1971), 14, 507 (1973), 15, 263 (1975), 16, 511 (1977) Alkaloids in the plant, 1, 15 (1950), 6, 1 (1960) Alkaloids from Aspergillus, 29, 185 (1986) Pnitridiantha species, 30, 223 (1987) Tabernaemontana, 27, 1 (1986) Alstonia alkaloids, 8, 159 (1965). 12, 207 (1970). 14, 157 (1973) Amaryllidaceae alkaloids, 2, 331 (1952), 6, 289 (1960), 11, 307 (1968), 15, 83 (1975), 30, 251 ( 1987) Amphibian alkaloids, 21, 139 (1983) Analgesics, 5, 1 (1955) Anesthetics, local, 5, 21 1 (1955) Anthranilic acid, related to quinoline alkaloids, 17, 105 (1979) Antimalarials, 5, 141 (1955) Antitumor alkaloids, 25, 1 (1985) Apocynaceae alkaloids, steroids, 9, 305 (1967) Aporphine alkaloids, 4, 119 (1954), 9, 1 (1967). 24, 153 (1985) Arisrotelia alkaloids, 24, 113 (1985) Aspidosperma alkaloids, 8, 336 (1965), 11, 205 (1968). 17, 199 (1979) Azafluoranthene alkaloids, 23, 301 (1984) Bases simple, 8, I (1965) simple indole, 10, 491 (1967) Benzophenanthridine alkaloids, 26, 185 (1985) Benzylisoquinoline alkaloids, 4, 29 (1954), 10, 402 (1967)

377

378

CUMULATIVE INDEX OF TITLES

Bisbenzylisoquinoline alkaloids, 4, 199 (1954), 7, 439 (1960), 9, 133 (1967), 13, 303 (1971), 30, 1 (1987) occurrence, 16, 249 (1977) structure, 16, 249 (1977) pharmacology, 16, 249 (1977) synthesis, 16, 319 (1977) Bisindole alkaloids, 20, 1 (1981) Emus alkaloids, steroids, 9, 305 (1967), 14, 1 (1973) Cactus alkaloids, 4, 23 (1954) Calabar bean alkaloids, 8, 27 (1965). 10, 383 (1967), 13, 213 (1971) Calabash curare alkaloids, 8, 515 (1965), 11, 189 (1968) Calycanthaceae alkaloids, 8, 581 (1965) Camptothecin, 21, 101 (1983) Cancentrine alkaloids, 14, 407 (1973) Capsicum species, pungent principle of, 23, 227 (1984) Carbazole alkaloids, 13, 273 (1971), 26, 1 (1985) Carboline alkaloids, 8, 47 (1965), 26, 1 (1985) P-Carboline congeners and ipecac alkaloids, 22, I (1983) Cardioactive alkaloids, 5, 79 (1955) Celestraceae alkaloids, 16, 215 (1977) Cephaloruxus alkaloids, 23, 157 (1984) Cbemotaxonomy of papaveraceae and fumaridaceae, 29, 1 (1986) Cinchona alkaloids, 14, 18 1 (1973) chemistry, 3, 1 (1953) Colchicine, 2, 261 (1952), 6, 247 (1960), 11, 407 (1968), 23, 1 (1984) Configuration and conformation, elucidation by X-ray diffraction, 22, 51 (1983) Corynantheine, yobimbine, and related alkaloids, 27, 13 I (1986) Cularine alkaloids, 4, 249 (1954), 10, 463 (1967), 29, 287 (1986) Curare-like effects, 5, 259 (1955) Cyclopeptide alkaloids, 15, 165 (1975)

Daphniphyllum alkaloids, 15, 41 (1979, 29, 265 (1986) Delphinium alkaloids, 4, 275 (1954) diterpenoid, 7, 473 (1960) Cln-diterpenes, 12, 2 (1970) C2,-diterpenes, 12, 136 (1970) Diplorrhyncus alkaloids, 8, 336 (1965) Diterpenoid alkaloids Aconirum, 7, 473 (1960), 12, 2 (1970) Delphinium, 7, 473 (1960), 12, 2 (1970) Garrya. 7, 473 (1960), 12, 2 (1960) general introduction, 12, xv (1970) Clg-diterpenes, 12, 2 (1970) C20-diterpenes, 12, 136 (1970) C19-Diterpene alkaloids Aconirum, 12, 2 (1970) Delphinium, 12, 2 (1970) Garrya, 12, 2 (1970)


structure, 17, 1 (1979) synthesis, 17, 1 (1979) C,,-Diterpene alkaloids Aconitum, 12, 136 (1970) chemistry, 18, 99 (1981) Delphinium, 12, 136 (1970) Garrya, 12, 136 (1970) Ebumamine-Vincamine alkaloids, 8, 250 (1965), 11, 125 (1968),20, 297 (1981) Elaeocarpus alkaloids, 6,325 (1960) Elucidation, by X-ray diffraction structural formula, 22, 51 (1983) configuration, 22, 51 (1983) conformation, 22, 51 (1983) Enamide cyclizations, application in alkaloid synthesis, 22, 189 (1983) Enzymatic transformation of alkaloids, microbial and In vitro, 18, 323 (1981) Ephreda bases, 3, 339 (1953) Ergot alkaloids, 8, 726 (1965),15, 1 (1975) Erythrina alkaloids, 2, 499 (1952),7, 201 (1960),9, 483 (1967), 18, 1 (1981) Erythrophleum alkaloids, 4, 265 (1954),10, 287 (1967) Eupomaria alkaloids, 24, 1 (1985) Forensic chemistry, alkaloids, 12, 514 (1970) Galbulirnima alkaloids, 9, 529 (1967). 13, 227 (1971) Garrya alkaloids diterpenoid, 7, 473 (1960) C,s-diterpenes, 12, 2 (1970) C20-diterpenes, 12, 136 (1970) Geissospermum alkaloids, 8, 679 (1965) Gelsemiurn alkaloids, 8, 93 (1965) Glycosides, monoterpene alkaloids, 17, 545 (1979) Haplopiryton cimicidum alkaloids, 8, 673 ( I 965) Hasubanan alkaloids, 16, 393 (1977) Holarrhena group, steroid alkaloids, 7, 319 (1960) Hunteria alkaloids, 8, 250 (1965) Iboga alkaloids, 8, 203 (1965), 11, 79 (1968) Imidazole alkaloids, 3, 201 (1953), 22, 281 (1983) Indole alkaloids, 2, 369 (1952), 7, 1(1960), 26, l(1985) distribution in plants, 11, 1 (1968) simple, including P-carbolines and P-carbazoles, 26, 1 (1985) Indole bases, simple, 10, 491 (1967) Indolizidine, simple, and quinolizidine alkaloids, 28, 183 (1 986) 2,2’-Indolylquinuclidinealkaloids, chemistry, 8, 238 (1965),11, 73 (1968) In v i m and microbial enzymatic transformation of alkaloids, 18, 323 (1981) Ipecac alkaloids, 3, 363 (1953), 7, 419 (1960),13, 189 (1971), 22, l(1983) P-Carboline alkaloids, 22, 1 (1983)

379

380


Isolation of alkaloids, 1, 1 (1950) Isoquinoline alkaloids, 7, 423 (1960) biosynthesis, 4, 1 (1954) I3C-NMR spectra, 18, 217 (1981) simpie isoquinoline alkaloids, 4, 7 (1954), 21, 255 (1983) lsoquinolinequinones, from actinomycetes and sponges, 21, 55 (1983) Kopsia alkaloids, 8, 336 (1965)

Local anesthetics, alkaloids, 5 , 21 1 (1955) Localization of alkaloids in the plant, 1, 15 (1950), 6, 1 (1960) Lupine alkaloids, 3, 119 (1953), 7, 253 (1960), 9, 175 (1967) Lycopodium alkaloids, 5 , 265 (1955), 7, 505 (1960), 10, 306 (1967), 14, 347 (1973), 26, 241 (1985) Lythracae alkaloids, 18, 263 (1981) Mammalian alkaloids, 21, 329 (1983) Marine alkaloids, 24, 25 (1985) Maytansinoids, 23, 71 (1984) Melodinus alkaloids, 11, 205 (1968) Mesembrine alkaloids, 9, 467 (1967) Metabolic transformation of alkaloids, 27, 323 (1986) Microbial and in uirro enzymatic transformation of alkaloids, 18, 323 (1981) Mirragyna alkaloids, 8, 59 (1965), 10, 521 (1967), 14, 123 (1973) Monoterpene alkaloids, 16, 431 (1977) glycosides, 17, 545 (1979) Morphine alkaloids, 2, 1 (part 1, 1952). 2, 161 (part 2, 1952), 6, 219 (1960), 13, 1 (1971) Muscarine alkaloids, 23, 327 (1984) Mydriatic alkaloids, 5, 243 (1955) a-Naphthaphenanthridine alkaloids, 4, 253 (1954), 10. 485 (1967) Naphthyl isoquinoline alkaloids, 29, 141 (1986) Narcotics, 5, 1 (1955) '3C-NMR spectra of isoquinoline alkaloids, 18, 217 (1981) Nuphar alkaloids, 9, 441 (1967), 16, 181 (1977) Ochrosia alkaloids, 8, 336 (1965), 11, 205 (1968) Ourouparia alkaloids, 8, 59 (1965), 10, 521 (1967) Oxaporphine alkaloids, 14, 225 (1973) Oxindole alkaloids, 14, 83 (1973)

Papaveraceae alkaloids, 10, 467 (1967), 12, 333 (1970), 17, 385 (1979) pharmacology, 15, 207 (1975) toxicology, 15, 207 (1975) Penraceras alkaloids, 8, 250 (1965) Peptide alkaloids, 26, 299 (1985) Phenanthroindolizidine alkaloids, 19, 193 (198 I ) Phenanthroquinolizidine alkaloids, 19, 193 (1981) P-Phenethylamines, 3, 3 13 (1 953) Phenethylisoquinoline alkaloids, 14, 265 (1973)


38 1

Phthalideisoquinoline alkaloids, 4, 167 (1954), 7, 433 (1960), 9, 117 (1967), 24, 253 (1985) Picrulima alkaloids, 14, 157 (1973) Picrulima nirida alkaloids, 8, 119 (1965), 10, 501 (1967) Piperidine alkaloids, 26, 89 (1985) Plant systematics, 16, I (1977) Pleiocurpu alkaloids, 8, 336 (1965), 11, 205 (1968) Polyamine alkaloids, putrescine, spermidine, spermine, 22, 85 (1983) Pressor alkaloids, 5 , 229 (1955) Protuberberim alkaloids, 4, 77 (1954). 9, 41 (1967), 28, 95 (1986) Protopine alkaloids, 4, 147 (1954) Pseudocinchona alkaloids, 8, 694 (1965) Putrescine and related polyamine alkaloids, 22, 85 (1983) Pyridine alkaloids, 1, 165 (1950), 6, 123 (1960), 11, 459 (1968). 26, 89 (1985) Pyrrolidine alkaloids, I, 91 (1950). 6, 31 (1960), 27, 270 (1986) Pyrrolizidine alkaloids, 1, 107 (1950), 6, 35 (1960), 12, 246 (1970). 26, 327 (1985) Quinazolidine alkaloids, see Indolizidine Alkaloids Quinazoline alkaloids, 3, 101 (1953), 7, 247 (1960), 29, 99 (1986) Quinazolinocarbolines, 8, 55 (1965), 21, 29 (1983) Quinoline alkaloids other than Cinchona, 3, 65 (1953), 7, 229 (1960) related to anthranilic acid, 17, 105 (1979) Rauwolfia alkaloids, 8, 287 (1965) Reserpine, chemistry, 8, 287 (1965) Respiratory stimulants, 5 , 109 (1955) Rhoeadine alkaloids, 28, 1 (1986) Sulamandru group, steroids, 9, 427 (1967) Sceletium alkaloids, 19, 1 (1981) Senecio alkaloids, see Pyrrolizidine alkaloids Securinega alkaloids, 14, 425 (1973) Sinornenine, 2, 219 (1952) Sulunum alkaloids chemistry, 3, 247 (1953) steroids, 7, 343 (1960), 10, 1 (1967), 19, 81 (1981) Sources of alkaloids, I , 1 (1950) Spectral methods, alkaloid structures, 24, 287 (1985) Spermidine and related polyamine alkaloids, 22, 85 (1983) Spermine and related polyamine alkaloids, 22, 85 (1983) Spirobenzylisoquinoline alkaloids, 13, 165 (1971) Sponges, isoquinolinequinones, 21, 55 (1983) Stemonu alkaloids, 9, 545 (1967) Steroid alkaloids Apocynaceae, 9, 305 (1967) Buxus group, 9, 305 (1967), 14, 1 (1973) Holarrhenu group, 7 , 3 19 (I 960) Salumundru group, 9, 427 (1967) Solanum group, 7 , 343 (1960), 10, 1 (1967), 19, 81 (1981) Verurrum group, 7 , 363 (1960). 10, 193 (1967), 14, 1 (1973)


Stimulants respiratory, 5, 109 (1955) uterine, 5, 163 (1955) Structural formula, elucidation by X-ray diffraction, 22, 51 (1983) Strychnos alkaloids, 1, 375 (part 1--1950), 2, 513 (part 2-1952), 6, 179 (1960), 8, 515, 592 (1965), 11, 189 (1968) Sulfur-containing alkaloids, 26, 53 (1985)

Tarus alkaloids, 10, 597 (1967) Toxicology, Papaveraceae alkaloids, 15. 207 (1975) Transformation of alkaloids, enzymatic, microbial and in vitro, 18, 323 (1981) Tropane alkaloids, chemistry, 1, 271 (1950), 6, 145 (1960), 9, 269 (1967), 13, 351 (1971). 16, 83 (1977) Tropoloisoquinoline alkaloids, 23, 301 (1984) Tropolonic Colchicum alkaloids, 23, 1 (1984) Tylophoru alkaloids, 9, 517 (1967) Uterine stimulants, 5, 163 (1955)

Veratrum alkaloids chemistry, 3, 247 (1952) steroids, 7, 363 (1960), 10, 193 (1967), 14, 1 (1973) “Vinca” alkaloids, 8, 272 (1965), 11, 99 (1968) Voucunga alkaloids, 8, 203 (1965), 11, 79 (1968) X-Ray diffraction, elucidation of structural formula, configuration, and conformation, 22, 5 1 (1983) Yohimbe alkaloids, 8, 694 (1965) Yohimbine alkaloids, 11, 145 (1968), 27, 131 (1986), see 01x0 Coryantheine

SUBJECT INDEX A Acetylhippamine, 287 Amaryllidaceae, 25 1 Ambrimbine, 177 Amisine, 359 Anhydrocorinium chloride, 265 Anhydrolycorine-7-one, 265 Antioquine, 177 Apateline, 18, 156 Apohaemanthamine, 325 Aromoline, 139, 156 Augustamine, 360 Augustine, 324, 326

B Baluchistanamine, 108, 156 Baluchistine, 18, 156 Beccapoline, 156, 175 Beccapolydione, 178 Berbacolofflammine, 20, 156 Berbamine, 143, 156 Berbamine 0-ethers, 104 Berbibuxine, 20, 156 Bisbenzylisoquinoline alkaloids analysis of, 128 biochemical transformation of, 114 biosynthesis of, 131, 198 chromatography of, 129 ether cleavage of, 106 Hofrnann elimination of, 113 oxidation of, 107 pharmacology of, 142 reduction of, 111 synthesis of, 115, 119 spectral properties of, MS-spectra of, 123 NMR-spectra of, 124 optical properties of, 127 UV-spectra of, 127 X-ray diffraction of, 128

Brunsvigine, 360 Buphanisidine, 346 Buphanisine, 347 Bursanine, 21, 156 C

Cadambine, 233 Cadamine, 245 Calafatimine, 22, 156 Calafatine, 22, 156 Calafatine N-oxides, 23, 156 Camptoneurine, 245 Cancentrine, 7, 156 Candicusine, 178 Cantleyine, 23 1 Caribine, 263 Carnialine, 262 Catapol, 239 Cepharanthine, 156 Chenabine, 24, 156 Cheratamine, 178 Cherylline, 365 Chillanamine, 24, 156 Chitraline, 25, 156 Chondrofoline, 156, 175 Clivaceline, 291 Clivacetine, 293 Clivatine, 291 Cliviaaline, 291 Cliviahaksine, 291 Cliviamaritine, 291 Cliviasindhine, 262 Clividine, 293 Clivimine, 293 Clivojuline, 291 Clivonine, 289, 292 Cocsuline, 8, 157 Cocsuline N-oxide, 179 Cocsulinine, 8, 157 Colofflammine, 25, 157 Coyhaiquine, 26, 157 383

384

SUBJECT INDEX

Coyhaiquinine, 157, 179 Crinamine, 355 Crinane, 336 Crinine, 321, 342 Crinsiatine, 296 Criwelline, 352 Curacautine, 27, 157 Curine, 18, 157, 175 Cycleahomine, 9, 157 Cycleanine, 108, 157 Cycleanine N-oxide, 27, 157

D Daphnine, 28, 157 Dauricine, 157 Daurisoline, 28, 157 Dehydroapateline, 30, 157 Dehydrohuangshanine, 179 Dehydromaritidien, 345 Dehydromicranthine, 30, 157 Dehydrotelobine, 30, 157 Dehydrothalifaberine, 180 Dehydrothalmelatine, 180 Demethylhomolycorine, 292 Demethylisothalicberine, 31, 157 Demethylpeinamine, 31, 157 Desmethyladiantifoline, 2, 157 Desmethylcycleanine, 32, 157 Desmethylthalidasine, 32, 157 Desmethylthalidezine, 33, 157 Desmethylthalistyline, 33, 158 Desmethylthalrugosidine, 33, 158 Diacetyllycorine, 287 Dihydrocadambine, 232 Dihydrolycorine, 265 Dihydrosecocepharanthine, 34, 158, 175 Dihydrothalictrinine, 34, 158 Dihydrowarifteine, 9, 158 Dimethylcurine, 35, 158 Dimethyldihydrowarifteine, 9, 158 Dimethylwarifteine, 10, 158 Dinklacorine, 36, 158

E Efatine, 181 Elwisine, 333 Epiberbvaldine, 181 Epielwesine, 334, 336, 356, 357 Epigalanthamine, 31 1

Epimacronine, 351 Epimaritidine, 324, 330 Epipretazettine, 333, 351 Epithalfinine, 13 Epivaldiberine, 37, 158 Epivaldivianine, 181 Epoxyambelline, 327

F Faberidine, 181 Faberonine, 181 Faralaotrine, 37, 158 Funiferine, 16, 136, 158 Funiferine dimetho salt, 38, 158 Funiferine, N-oxide, 38, 158

G Galanthanmine, 308, 310, 312 Galanthine, 262, 292 Gentianine, 23 1 Gilgitine, 39, 158 Gilletine, 40, 158 Goleptine, 262 Grisabine, 40, 158 Guattegaumerine, 41, 158 Gyroamericine, 182 Gyrocarpine, 182 Gyrocarpusine, 183 Gyrolidine, 183

H Haemanthamine, 321 Haemanthidine, 339, 347, 352 Hamayne, 325, 326 Harmaline, 226 Harman, 225 Harmine, 226 Havanine, 326 Hebridamine, 183 Hernandezine N-oxide, 42, 109, 159, 175 Hippadine, 264 Hippeastidine, 321 Hippeastrine, 289, 292 Huangshanine, 42, 159, 176 Hydroxybuphanisine, 325 Hydroxycrinine, 325 Hydroxylyalidine, 226

385

SUBJECT INDEX

I Insulanoline, 159,176 Insularine, 159,176 Isochondodendrine, 159,175 Isodaurisoline, 43,159 Isogilletine N-oxide, 43,159 Isolycoricidine, 302 Isonarciclasine, 302 Isopauridianthoside, 232 Isotetrandrine, 119,159 Isothalicberine, 43, 159 Isothalidezine, 44,159 Isotrilobine, 116,159 Isotubocurarine, 122 Istanbulamine, 47,159 Iznikine, 45,159

J Jhelumine, 24,45, 159 Johnsonine, 46,159 Jolantinine, 46,159

K Kalashine, 47,159 Kalbreclasine, 296 Kalbretorine, 265 Karakoramine, 48,159 Khyberine, 37,48,159 Kohatine, 183 Krukovine, 49,159 Kurramine, 184

L Latifine, 362 Latisoidine, 358 Latisoline, 358 Leucotamine, 308 Limacine N-oxide, 184 Lirnacusine, 26,38,159 Lindoldhamine, 41,49,159 Loganine, 231 Lyadine, 226 Lyalidine, 226,244 Lyaline, 226,244 Lyaloside, 231,236,240 Lyalosidofemine, 238 Lyalosidosinapine, 238

Lycoramine, 308,314,318 Lycorane, 268,278 Lycorenine, 289,293 Lycoricidine, 296,299,304,306 Lycorine, 262,268,279,292 M Macolidine, 50, 159 Macoline, 51,159 Macronine, 354 Malekulatine, 52,159 Maritidine, 325,330 Medelline, 185 Mesembrenol, 359 Methothalistyline, 53, 160 Methyl-7-O-demethylpeinamine,56,160 Methylapteline, 53, 160 Methylberberamine, 53,160 Methylchitraline, 185 Methylcissampereine, 10 Methylcocsoline, 54,160 Methylcurine, 35, 55, 160 Methylcuspidaline, 185 Methyldauricine, 5 , 160 Methyldeoxopunjabine, 56,160 Methyldihydrowarifteine, 9, 160 Methyllimacusine, 185 Methyllindoldhamine, 57, 160 Methylnorapateline, 57, 160 Methylpachygonamine, 58,160,176 Methylpakistanine, 59, 160 Methylpunjabine, 59, 160 Methylthalibrine, 59,160 Methylthalibmnimine, 60, 160 Methylthalmine, 15,186 Methylwarifteine, 10,160 Montanine, 360

N Narcimarkine, 326 Narciprimine, 301 Narcissidine, 293 Nariclasine, 296,298 Narwedine, 309 Natalinine, 186 Nauclechine, 233,244 Nauclefoline, 228,244 Naufoline, 233,244 Neothalibrine, 60,161

386

SUBJECT INDEX

Nor-chondocurine, 186 Noradiantifoline, 61, 160 Norhemandezine, 61 Norisotetandrine, 62, 160 Norlimacusine, 187 Norpakistanine, 187 Norpanurensine, 62, 160 Norpenduline, 187 Norpluviine, 293 Nortazettine, 339 Nortenuipine, 28, 161 Northalibrine, 63, 161 Northalibrunine, 63, 161 Northalicarpine, 64, 161, 188 Northalmine, 188 Nortiliacorinine A and B, 10, 161 Nortrilobine. 188

0 Obaberine, 116, 119, 161 Obolongamine, 64, 161 Oduline, 293 Osomine, 65, 161 Oxandrine, 66, 161 Oxocancentrine, 66, 161 Oxocrinine, 329, 330, 334 Oxofangchirine, 189 Oxomaritidine, 330 Oxothalbrunimine, 67, 107, 161 Oxothalicarpine, 67, 161 Oxyisotetrandrine, 68, 161

P Pachygonamine, 58, 69, 161, 176 Pachyovatamine, 189 Pakistanamine, 11, 161 Pancratistatin, 298 Panurensine, 69, 161 Patagonine, 70, 161 Pauridiantha, 223 Pauridianthine, 226, 234, 244 Pauridianthinine, 226 Pauridianthinol, 226, 231, 234, 244 Pauridianthoside, 232, 236, 240 Peinamine, 70, 161 Pendine, 71, 161 Pendulinine, 71, 161 Phaeantharine, 4, 162

Picroside, 239 Pisopowamine, 189 Pisopowetine, 189 Pisopowiaridine, 189 Pisowiarine, 189 Pisowidine, 189 Pispowine, 189 Poetinatine, 291 Polybeccarine, 190 Porveniramine, 72, 162 Powelline, 321, 328 Pratorimine, 265 Pratosine, 265 Precriwelline, 327 Pretazettine, 321, 326, 347, 357 Pseudolycorine, 262, 265 Pseudoxandrine, 66, 162 hnjabine, 73, 162

R Repanduline, 12, 162 Revolutinone, 73, 162 Revolutopine, 74, 162 Rhynchopine, 240 Rubenine, 233 Rubescine, 240, 243 Rupancamine, 191 Ryllistine, 359 5

Sanguinine, 308 Sciadenine, 74, 162 Sciadoferine, 75, 162 Sciadoline, 75, 162 Secantioquine, 191 Seccohaberine, 191 Secocepharanthine, 76, 162 Sindamine, 77, 162 Stebisimine, 119, 162 Sternbergine, 262 Strictosidine, 228, 230, 233, 237, 243 Strictosidine lactarn, 228, 230, 243 Swertiamarin, 231

T Talcamine, 77, 162 Tazettine, 321, 326, 349, 351

387

SUBJECT INDEX

Temuconine, 78, 162 Tetandrine N-oxide, 78, 162, 175 Tetrandrine, 12, 162, 196 Thalbadenzine, 79, 163 Thalfine, 13, 163 Thalfinine, 13, 163 Thaliadanine, 79, 163 Thaliadine, 80, 163 Thalibrine, 80, 163 Thalibrunimine, 7, 81, 163 Thalibrunine, 6, 163 Thalicarpine, 163 Thalicarpine N-oxide, 192 Thalictine, 81, 163 Thalictrinine, 82, 163 Thalictropine, 106, 163 Thalidezine, 14, 163 Thalifabatine, 192 Thalifaberine, 83, 163, 176 Thalifabine, 83, 163, 176 Thalifabonine, 192 Thalifarapine, 193 Thalifasine, 193 Thaligosidine, 84, 163 Thaligosine, 84, 163 Thaligosinine, 85, 163 Thaligrisine, 193 Thalilutidine, 85, 163 Thalilutine, 86, 163 Thaliphylline, 193 Thalipine, 86, 163 Thalirabine, 87, 163 Thaliracebine, 88, 163 Thalirevoline, 88, 163 Thalirevolutine, 89, 163 Thalirugidine, 90, 163 Thalirugine, 90, 163 Thaliruginine, 91, 163 Thalisamine, 173 Thalistine, 91, 163 Thalistyline, 92, 164 Thalivarmine, 194 Thalmethine, 14, 164 Thalmine, 15, 164 Thalmirabine, 92, 164 Thalpindione, 93, 164

Thalrugosamine, 174 Thalrugosaminine, 94, 164 Thalrugosinone, 94, 164 Thalsimine, 15, 164 Thalsivasine, 194 Tiliacorine, 15, 164 Tiliacorinine, 15, 164 Tiliacorinine N-oxide, 95, 164 Tiliafunimine, 95, 164 Tiliageine, 16, 136, 164 Tiliamosine, 96, 164, 176 Tiliarine, 164, 176 Toddalidimerine, 97, 164 Trianthine, 263 Trigilletimine, 98, 164 Trilobine, 58, 116, 164 Tubocurarine, 17, 164, 197 Tubocurine, 17, 164

U Undulatine, 321 Ungeremine, 289 Ungiminorine, 287 Ungredine, 327 Ungremine, 267 Uskudaramine, 99, 164

V Valdiberine, 99, 164 Valdivianine, 100, 164 Vanuatine, 100, 165 Varadine, 327 Vateamine, 100, 165 Vilaportine, 194 Vittatine. 321

W Warifteine, 10, 165 1

Zaidine, 263 Zephyranthine, 263, 268, 272


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