The Alkaloids: Chemistry and Pharmacology, Volume 31

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THE ALKALOIDS Chemistry and Pharmacology

Volume 31

THE ALKALOIDS Chemistry and Pharmacology

A list of contents of volumes in this treatise is available from the publisher on request

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

VOLUME 31

ACADEMIC PRESS, INC. Harcourt Brace Jovanovich, Publishers

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COPYRIGHT 0 1987 BY ACADEMIC PRESS, INC. ALL RIGHTS RESERVED. NO PART OF THIS PUBLICATION MAY BE REPRODUCED OR TRANSMITTED IN ANY FORM OR BY ANY MEANS, ELECTRONIC OR MECHANICAL, INCLUDING PHOTOCOPY, RECORDING, OR ANY INFORMATION STORAGE AND RETRIEVAL SYSTEM, WITHOUT PERMISSION IN WRITING FROM THE PUBLISHER.

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(alk. paper)

PRINTED IN THE UNITED STATES OF AMERICA

87 88 89 YO

9 8 7 6 5 4 3 2 I

CONTENTS PREFACE. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

....

ix

Chapter 1 . Reissert Synthesis of Isoquinoline and Indole Alkaloids GABORBLASKO.PETER KEREKES.AND SANDORMAKLEIT I. I1. 111. IV .

Introduction Synthesis of Synthesis of Conclusion References

....................................................... Isoquinoline Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Indole Alkaloid Analogs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

........................................................ ........................................................

1 5 24 21 27

Chapter 2 . Aristolochia Alkaloids ZHONG-LIANG CHENAND DA-YUAN ZHU

I. I1. I11. IV . V. VI . VII .

Introduction . . . . . ............................................... Structural Relations and Biosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Spectroscopic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Chemical Reactions and Structural Determination . . . . . . . . . . . . . . . . . . . . . . . . . Chemical Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pharmacology and Clinical Use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Summary of Physical Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References ........................................................

29 30 36 43 47

54 62 62

Chapter 3 . Chromone Alkaloids PETERJ . HOUGHTON

I. I1. I11. IV .

Introduction . . . . . . . . . . Botanical Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Flavonoidal Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Noreugenin-Related Alkaloids ......................................... References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

V

67 68

15 87

99

vi

CONTENTS

Chapter 4 . Dibenzopyrrocoline Alkaloids I . W . ELLIOTT I . Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

I1. History . . . . . . .

111. Cryptaustoline and Cryptowoline . . . . . . . . . . . . . ............ IV . Synthesis and Reactions of Dibenzopyrrocolines .......................... ........................................ V . Pharmacology . . References ...................................

i01 103 106 108 114 115

Chapter 5 . Lupine Alkaloids KH. A . ASLANOV,Yu . K . KUSHMURADOV, AND A . S . SADYKOV

I . Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I1. 13C-NMR Spectroscopy of Quinolizidine Alkaloids ....................... 111. X-Ray Structural Investigation of Quinolizidine Alkaloids . . . . . . . . . . . . . . . . . . IV . Bicyclic Quinolizidine Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . V . Tricyclic Quinolizidine Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . VI . Tetracyclic Quinolizidine Alkaloids of the Sparteine Group . . . . . . . . . . . . . . . . . VII . Tetracyclic Alkaloids of the Leontidine Group (Quinolizidine-Indolizidine Alkaloids) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . VIII . Tetracyclic Alkaloids of the Aloperine Group ............................ IX . Tetracyclic Alkaloids of the Matrine Group .............................. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..........

118 132 134 140 146 155 164 167 169 184

Chapter 6 . Alkaloids from Ants and Other Insects ATSUSHINUMATAAND TOSHIROIBUKA I . Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

I1. Occurrence and Function ................................... 111. Structure and Synthesis

....................................

References ..............................................

........ ........ ........ .. . . . . . . . .

194 194 238 302

........ ........ ........ ........ ..........

317 319 330 356 362

Chapter 7. Pavine and Isopavine Alkaloids

BELKISGOZLER I . Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I1. Occurrence and Structure Elucidation ......................... 111. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IV . Unnatural Pavines and Isopavines ............................ V . Spectral Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

CONTENTS

VI. VII. VIII. IX. X.

Biosynthesis ............................. Chemotaxonomic Considerations . . . . . . . . . . . . Homopavines and Homoisopavines . . . . . . . . . . . Aporphine-Pavine Dimers . . . . . . . . . . . . . . . . . . Pharmacology ............................ References ..............................

INDEX ...................................

......................... ......................... ......................... ......................... ......................... .........................

312 316 378 381 383 384

.........................

39 1

This Page Intentionally Left Blank

PREFACE Discussion of the Reissert synthesis in connection with isoquinoline and indole alkaloid synthesis follows a suggestion that important methods in alkaloid chemistry be reviewed. “Aristolochia Alkaloids” refers to a group of alkaloids casually discussed under “Aporphine Alkaloids,” now taken out of this context and presented here for the first time as an independent group of alkaloids. Also for the first time ‘‘Chromone Alkaloids” and ‘‘DibenzopyrrocolineAlkaloids” are presented, many of them having interesting pharmacological properties, The “Lupine Alkaloids” were discussed in Vols. 3, 7, and 9 of this treatise. This classical group of alkaloids is updated here and presented by experts in the field. “Alkaloids from Ants and Other Insects” presents compounds discussed earlier under ‘‘Piperidine Alkaloids,’’ ‘‘Pyrrolizidine Alkaloids ,” “Simple Indolizidine and Quinolizidine Alkaloids, ’’ and “Pyrrolidine Alkaloids,’ ’ now condensed in one chapter summarizing these interesting natural products. “Pavine and Isopavine Alkaloids, discussed under the heading ‘‘Isoquinoline Alkaloids” in Vols. 12 and 17 of this treatise, now comprises more than two dozen alkaloids, justifying their presentation as a separate group of isoquinoline alkaloids. Occurrence, spectral properties, structures, and synthesis and biosynthesis are professionally covered, and pharmacological properties included whenever known. ”

Arnold Brossi

ix


-CHAPTER1 REISSERT SYNTHESIS OF ISOQUINOLINE AND INDOLE ALKALOIDS* GABORBLASKO Central Research Institute for Chemistry The Hungarian Academy of Sciences Budapest, H-1525 Hungary ~ T E R KEREKESI. AND

SANDORMAKLEIT Department of Organic Chemistry Kossuth Lajos University of Debrecen Debrecen, H-4010 Hungary

I. Introduction A. Preparation of Reissert Compounds B. Reaction of Reissert Compounds 11. Synthesis of Isoquinoline Alkaloids A. Synthesis of 1-Benzylisoquinolines B. Synthesis of Cularines and Quettamines C. Synthesis of Pavinanes D. Synthesis of Aporphines and Oxoaporphines E. Synthesis of Protoberberines F. Synthesis of Phthalideisoquipoline Alkaloids G. Synthesis of Emetine Analogs 111. Synthesis of Indole Alkaloid Analogs A. Synthesis and Reactions of 3,4-Dihydro-P-carboline Reissert Compounds B . Synthesis of Ellipticine Analogs IV. Conclusion References

I. Introduction In 1905 Arnold Reissert discovered ( I , 2) that quinoline (1) or isoquinoline (2) could react with benzoyl chloride in the presence of aqueous potassium cyanide,

* This chapter is dedicated to the memory of Dr. Wter Kerekes, who died in Bethesda, Maryland, on August 1, 1984. t Deceased. 1

THE ALKALOIDS, VOL. 31 Copyright 0 1987 by Academic Press, Inc. All rights of reproduction in any fonn reserved.

2

GABOR BLASKO, PETER KEREKES, AND SANDOR MAKLEIT

F-0

I

!a 3

H‘ ’CN

SCHEME1

resulting in 1,2-dihydro-1-benzoyl-2-cyanoquinoline(3) or 1,2-dihydr0-2-benzoyl-1-cyanoisoquinoline(4), respectively (Scheme 1). The latter type of compounds, later named “Reissert compounds,’’ became versatile tools for different synthetic applications. The chemistry of Reissert compounds has been the subject of numerous general reviews (3-10). In 1973 Popp gave a summary on the use of Reissert compounds in the synthesis of isoquinoline alkaloids and related compounds (3.We now wish to summarize new results that have appeared from 1973 to the end of 1985 for the application of Reissert compounds in the synthesis of isoquinoline as well as indole alkaloids. A. PREPARATION OF REISERT COMPOUNDS The most frequently used method for the preparation of isoquinoline Reissert compounds is treatment of an isoquinoline with acyl chloride and potassium cyanide in water or in a dichloromethane-water solvent system. Though this method could be successfully applied in a great number of syntheses, it has also some disadvantages. First, the starting isoquinoline and the Reissert compound formed in the reaction are usually insoluble in water. Second, in the case of reactive acyl halides the hydrolysis of this reaction partner may became dominant. Third, the hydroxide ion present could compete with the cyanide ion as a nucleophile to produce a pseudobase instead of Reissert compound. To decrease the pseudobase formation phase-transfer catalysts have been used successfully in the case of the dichloromethane-water solvent system, resulting in considerably increased yields of the Reissert compound. To avoid the hydrolysis of reactive acid halides in some cases nonaqueous media have been applied, e.g., acetonitrile, acetone, dioxane, benzene, while utilizing hydrogen cyanide or trimethylsilyl cyanide as reactants instead of potassium cyanide.

I . REISSERT SYNTHESIS OF ISOQUINOLINE AND INDOLE ALKALOIDS

3

II

10

SCHEME2

B. REACTION OF REISSERT COMPOUNDS Acid-catalyzed hydrolysis of Reissert compounds results in an aldehyde, a formal reduction product of the acyl halide utilized in the Reissert compound formation (11).The mechanism of the reaction according to McEwen and Cobb (3),is shown in Scheme 2. Isoquinoline Reissert compounds of type 12 could be easily converted to the corresponding 1 -cyanoisoquinolines (13) by simple base treatment ( 4 3 (Scheme 3 ) . This transformation also takes place with high yields when type 12 compounds are oxidized with molecular oxygen in a two-phase system in the presence of phase-transfer catalysts (12-14). It should be mentioned that similar oxidation of dihydro Reissert compounds of type 14 afforded the corresponding dihydroisocarbostyril derivatives (15) (12-14). Base treatment of isoquinoline Reissert compounds followed by intramolecular rearrangement, due to the absence of a proper intermolecular reaction partner, results in 1 -acylisoquinoline derivatives (18) (3). The formation of a “Reissert anion” (intermediate of type 16) is usually the introductory step in a great number of synthetic routes leading to isoquinoline as well as indole alkaloids and related compounds. On the one hand, the alkylation of a Reissert anion with alkyl halide followed by alkaline hydrolysis is the most frequently used method for the synthesis of 1-alkyl- or 1 -arylalkylisoquinolines (20) (Scheme 4). On the other hand, Reissert anions react with aldehydes to form

4


I

CN 13

12

1

2

5 R W N $ $ ,

-

R

q

c

C N d

CN

t

G-

-

$=O

R’

17

16

R W N

18

R’

SCHEME 3

29

H

RW 8

R q N _ e _ f i . R”-X

CN

CN R” 19

12

k“

16

21

‘

W

N 0 CH-OC-R’

R 22

23

SCHEME 4

KOH

N-C-R’ E ~ O H

1. REISSERT SYNTHESIS OF ISOQUINOLINE AND INDOLE ALKALOIDS

5

first an alkoxide intermediate (21), in which the negatively charged oxygen could attack the amide carbonyl to yield oxazolidine 22, and this on rearomatization affords the final product, a secondary alcohol ester (23).In the following section we discuss the utilization of the above reactions of Reissert compounds for the purpose of alkaloid synthesis.

11. Synthesis of Isoquinoline Alkaloids A. SYNTHESIS OF ~-BENZYLISOQUINOLINES The synthesis of the basic skeleton of 1-benzylisoquinolinealkaloids has been reported by Uff et al. (15) starting from isoquinoline and benzyl chloride (Scheme 5). The preparation of Reissert compound N-benzyl- 1-cyano-1,2-dihydroisoquinoline (4) was performed in a dichloromethane-water two-phase system with potassium cyanide and benzoyl chloride in about 64-69% yield. The deprotonation of 4 with sodium hydride in dimethylformamide solution, the subsequent alkylation with benzyl chloride, and the final alkaline hydrolysis could be performed as a one-pot reaction sequence to supply l-benzylisoquinoline (25) in an overall yield of 75-84%. Skiles and Cava have investigated the alkylation method of isoquinoline Reissert compounds (16), performing a comparative study on the alkylation of

R'

$QN&

H CN 4

R1=R2=R3=H

26

R1=H, R2=R3=OCH3

27

R~=R~=R'=oc%

28 R1=H, R2+R3=OCH20

SCHEME 5

6


TABLE I Comparison of Yields of Alkylation Reactions ~

Method, % yield Reissert compound

Product

A

B

C

4

24 29

46 38 52 51

95 92 94 93

91 94 96 92

26 27 28

30 31

compounds 4, 26,27, and 28 with both benzyl chloride and o-nitrobenzyl chloride, using three different reaction conditions: A. Lithium diisopropylamide in THF/HMPA B. Potassium hydroxide with benzene in the presence of dicyclohexyl- 18crown-6 C . 50% aqueous sodium hydroxide with benzene or acetonitrile in the presence of phase-transfer catalyst (cetrimonium bromide) According to measured yields, conditions B and C have been found to be much more advantageous than method A (see Table I). Several 1-benzylisoquinoline alkaloids have been synthesized utilizing the above reaction sequence. For example, takatonine (34) has been obtained from Reissert compound 27 via alkylation with p-methoxybenzyl chloride and subsequent hydrolysis and quatemarization with methyl iodide (17). Similarly, escholamine (37) has been prepared from N-benzoyl- l-cyano-6,7-methylenedioxy- 1,2-dihydroisoquinoline (28) and 3,4-methylenedioxybenzylchloride (17) as shown in Scheme 6. Reticuline (38), one of the most important intermediates in the biosynthesis of opium alkaloids, has been synthesized in racemic form (Scheme 7 ) (18). 6Methoxy-7-benzyloxyisoquinoline(39), prepared from 0-benzylisovanillin via a modified Pomeranz-Fritsch isoquinoline synthesis, was treated with benzoyl chloride and potassium cyanide to obtain Reissert compound 40. Alkylation of the anion generated from 40 with 3-benzyloxy-4-methoxybenzylchloride gave the corresponding 1-substituted Reissert compound 41 which was hydrolyzed in alkaline medium to 1-benzylisoquinoline derivative 42. Quatemarization of 42 with methyl iodide followed by sodium borohydride reduction and debenzylation led to (*)-reticuline (38) in about 25% overall yield from 39. Two similar pathways have been reported (19) for the total synthesis of a pseudobenzylisoquinoline-typealkaloid, rugosinone (43), isolated as a minor component of Thalictrum rugosum. As shown in Scheme 8 the anion of Nbenzoyl- l-cyano-6,7-methylenedioxy-l,2-dihydroisoquinoline (28) was reacted

1 . REISSERT SYNTHESIS OF ISOQUINOLINE AND INDOLE ALKALOIDS

H CN 27

+

CH,CI

-

CH$ c H 3 0 3 c NN-C-g Q

7

__

/

CH,O OCH,

\

32

33

34

O V \-0

lakatonine

35

37 Escholamine

36

SCHEME 6

with either 2-benzyloxy-3,4-dimethoxybenzaldehyde or 2,3,4-trimethoxybenzaldehyde to produce the corresponding 1 -alkylated Reissert compound 44 or 45, respectively. Alkaline hydrolysis of these intermediates followed by oxidation of the benzylic alcohol moiety resulted in 1-acylisoquinolines 48 and 49, respectively. Removal of the benzyl protecting group of 48 with trimethylsilyl iodide gave rugosinone (43).The final step of the other pathway is a regioselective demethylation at position 2 ' , which could be achieved with boron trichloride, and the participation of the neighboring carbonyl group is regarded to ensure the high selectivity in supplying rugosinone (43).

8

GABOR BLASKO, PI~TERKEREKES, AND SANDOR MAKLEIT

CH,O 38 Reticuline

SCHEME7

CH,OVOR CH,O OCH,

46

R=CH20

48

R=CH2@

47

R=CHJ

49

R=CH3

SCHEME 8

44

R=CH2$?

45

R=CH3

43 Rugosincne


R'

9

R'

-

NaH, DMF

O'COCl KCN

R'

R'

1, NaOCH3 2,

CH,OH HC1

CHO , 57 R ~ = H , R ~ = O H 58 R ~ = O H , R ~ = H

59

RLH,$=OH

60 R~=CH, R ~ = H

CH,O

CHO ,

51 R ~ = H , $=OH 52

50 Trlmethoqulnol

FAOH, R~=H SCHEME9

In work aimed at developing a long-acting bronchodilator agent, analogs of trimethoquinol (50), containing a saligenine moiety (compounds 51 and 52) instead of the catechol nucleus, have been synthesized via a Reissert route (20), as shown in Scheme 9. Experiments have been made (21) for the synthesis of bisbenzylisoquinoline-typealkaloids by alkylation of the anion of isoquinoline Reissert compounds (4, 26, and 28) with bifunctional diaryl ethers such as 61, 62, and 63. 0-Methyldauricine (64) has been prepared by this route (Scheme lo), via condensation of Reissert compound 26 with diaryl ether 62 to give dialkylated product 65 followed by alkaline hydrolysis to afford bisbenzylisoquinoline 66. Quaternarization of 66 with methyl iodide and subsequent sodium borohydride reduction gave 0-methyldauricine (64) in racemic form (21). B. SYNTHESIS OF CULARINES AND QUETTAMINES

Cularine (67) and related alkaloids constitute a small group of l-benzylisoquinoline-related alkaloids, which are distinguished from the main group by

10

GABOR BLASKO, PETER KEREKES, AND SANDOR MAKLEJT

B r-

C H z o o

-02

CHJL

CH,- Br

Q o y H 2 C I OCH,

61

62

OCH,

CH,-Br

@

CH30QO CH,-Br

OCH,

63

66

64

O-Methyldauricine

SCHEME10

possession of an intramolecular ether linkage between the isoquinoline nucleus and the l-benzyl portion. Cularines might be formed in nature by phenolic oxidative coupling of the corresponding 1-benzylisoquinolines; therefore, their biomimetic total synthesis involves the construction of a 1-benzylisoquinoline system with proper substitution pattern. Jackson et al. (22) reported the biomimetic total synthesis of (+)-cularine (67) itself (Scheme 11). Benzyolation of isoquinoline 68 in the presence of potassium cyanide gave Reissert compound 69, the anion of which was alkylated with 3benzyloxy-4-methoxybenzyl chloride, resulting in intermediate 70. After al-


CH,O ,0-CH20

CH,O $-CH,O 68

11

H CN

69

OCH,

72

67

R=CX3

73

R=H

Cularine

SCHEME11

kaline hydrolysis the required 1-benzylisoquinoline 71 was obtained. N-Methylation of 71 followed by sodium borohydride reduction and acidic cleavage of the benzyl ether groups supplied 1,2,3,4,-tetrahydro- 1-(3-hydroxy-4-methoxybenzyl)-7-methoxy-2-methylisoquinolin-8-ol(72). Compound 72 was oxidized with potassium ferricyanide in an aqueous ammonium acetate-chloroform twophase system to 0-demethylcularine (73), which could be converted to (?)cularine (67) by methylation with diazomethane. Oxocularine (74) and oxocompostelline (75) have also been synthesized (Scheme 12), with a novel cyclization in the key reaction step which leads to the cularine skeleton. 2’-Bromo-1-benzylisoquinolines 78 and 79, obtained by the Reissert method from 69, were dehydrohalogenated with dimsyl sodium, giving rise to a benzyne intermediate which could be attacked by either the nitrogen or oxygen nucleophile present in the molecule. The nitrogen attack generates dibenzopyrrocoline derivatives 80 and 81, respectively. At the same time, the intramolecular reaction of the phenoxide with the benzyne system resulted in cularines 82 and 83. The last two compounds could be oxidized in air or by Fremy’s salt to the target natural products oxocularine (74jand oxocompostelline (75), respectively (23).

12


CHO , @-CH,O H CN 69

R'O OR' 76

R~=Z=CH~

77 R1tRz=CH2

4

74

R ~ = R ~ = c HOxocularine ~

75

R I + R ~ = c H ~Oxocompostelline

SCHEME12

Quettamine (84) is an isoquinoline alkaloid incorporating a furan moiety condensed with both rings of the isoquinoline nucleus (24), and it is closely related biogenetically to cularine-type alkaloids. The total synthesis of quettamine (84) (Scheme 13) has been performed by the utilization of the known Reissert compound 69. Treatment of the anion generated from 69 with 4-benzyloxybenzaldehyde yielded benzoate ester 85, which was hydrolyzed to the corresponding alcohol 86. N-Methylation of 86 followed by sodium borohydride reduction resulted in 1-benzylisoquinoline derivative 87 in high yield. Cyclization of the dihydrofuran ring was carried out with trifluoroacetic acid through a


13

1, C R j I

CH30 0-CH20 H C N

2, NaBH4

69

@-CH,O

-

R=CO#

86

R=H

-

cplH-CH,O 3030:H3

pl-CH,O

85

TFA

' 87

u lOH

uOH 84

88

Buettairine

SCHEME 13

benzylic cation derived from 87 to produce stereoselectively tetracycle 88 with a trans relationship between H-1 and H-a.Finally, quaternarization of 88 with methyl iodide gave (*I-quettamine (84) iodide (25).

C. SYNTHESIS OF PAVINANES The total synthesis of pavinane alkaloid platycerine (89) (Scheme 14) has been accomplished successfully (26) via 1-benzylisoquinolinederivative 91 obtained from Reissert intermediate 90. Quaternarization of 91 with methyl iodide followed by lithium aluminum hydride reduction supplied 1,2-dihydroisoquinoline 92, which on treatment with a 7 : 5 mixture of formic acid and phosphorous acid gave (*)-platycerine (89) in 60-70% yield.

D. SYNTHESIS OF APORPHINES AND OXOAPORPHINES The aporphines constitute one of the largest groups of isoquinoline alkaloids and have a wide range of physiological activity. For example, bulbocapinine (93) (see Scheme 15) affects the central nervous system and causes catatonia, boldine

14

G ~ O BLASKO, R PETER KEREKES, AND SANDOR MAKLEIT

89

Platycerine

SCHEME14

(94) has a mild sedative and diuretic activity, and glaucine (95) has covulsive as well as antitussive properties. Apomorphine (96), a.semisynthetic derivative of morphine, proved to be a promising drug for the treatment of Parkinson's and related neurological diseases, owing to its ability to stimulate the central dopamine receptors. Isothebaine (97) depresses the central nervous system, apocodeine (98) has emetic activity, and the quaternary laurifoline chloride (99) has hypotensive activity. Neumeyer and co-workers have performed a thorough investigation (27) on structure-activity relationships of aporphines closely related to the dopaminergic apomorphine (96), which contains a virtually conformationally fixed dopamine moiety. Working toward the synthesis of a great number of mono-, di-, and trihydroxyaporphine derivatives, they frequently utilized the Reissert alkylation method (Scheme 16). For example, in the case of the syntheses of racemic apomorphine (96) (28), 8-hydroxyaporphine (100) (29), 10-hydroxyaporphine (101) (30), and 11-hydroxyaporphine (102) (31), the N-benzoyl-l-cyano-l,2dihydroisoquinoline (4) was used as starting material together with a properly substituted 2-nitrobenzyl chloride. Reissert alkylation followed by alkaline hydrolysis gave l-(2-nitrobenzyl)isoquinoline derivatives 107, 108, 109, and 110, respectively. Quaternarization of these compounds with methyl iodide followed by potassium borohydride and catalytic reduction resulted in N-methyl- 1,2,3,4-


15

CH,

OR 93 Bulbocapnine

HO F

X

C

H

94

R=H

95

R=CX3

Boldine Glaucine

3

RO 96

R=H

98

R=CH3

Apomorphine

97

Isothebaine

Apocodeine

r ,

99

Iaurifoline

SCHEME 15

tetrahydro- l-(2-aminobenzyl)isoquinolines 111, 112, 113, and 114. Pschorr cyclization of these latter compounds followed by methoxy cleavage with hydroiodic acid yielded racemic apomorphine (96), or 8-hydroxy-, 10-hydroxy-, and 11-hydroxyaporphines (100, 101, and 102), respectively. Similarly to the above reaction sequence N-alkyl analogs of bulbocapnine (93) have been prepared via the above Reissert alkylation-Pschorr cyclization route (32). A novel and efficient synthesis of aporphinic alkaloids has been developed by Kupchan and O'Brien (33) via oxidative photocyclization of I-(or-hydroxy-2iodobenzyl)d-hydroxy-7-rnethoxyisoquinolinessuch as 120, 121, or 122, all prepared by the Reissert method shown in Scheme 17. N-Methylation of oxoaporphines 124 and 125 yielded corunnine (127) and nandazurine (128), respectively. Reduction of 124 with Zn-AcOH resulted in thalicmidine (130), and similar reduction of 125 gave domesticine (131) in racemic form. Caaverine (129) has also been prepared by this route (33). Reissert alkylation and Pschorr cyclization have frequently been utilized for the synthesis of oxoaporphine alkaloids by Cava and co-workers. Their synthetic

16

GABOR BLASKO, PETER KEREKES, AND S h O R MAKLEIT

111

R1=R2=OH,

112

R~=R'=H,

113

R1=R3=H,

114

R1=OH,

96

R3=H $=OH

R2=OH R2=R3=H

R~=R'=oH,

R~=H

100 R~=R'=H, $=OH

101 R ~ = R ~ = H$=OH , I02

$=OH,

R2=R3=H

SCHEME 16

work comprising the synthesis of phenolic oxoaporphine alkaloid antheroline (132) ( 3 4 , the structure revision and synthesis of subsessiline (133) ( 3 3 , as well as the total synthesis of imenine (134) (36) are shown in Schemes 18-20.

E. SYNTHESIS OF PROTOBERBERINES The Reissert alkylation method was also utilized for synthesizing the basic skeleton of protoberberine alkaloids (Scheme 21). Reaction of 3,4-dihydroisoquinoline derivatives 149, 150, and 151 with 2-chloromethylbenzoy1 chloride and trimethylsilyl cyanide in methylene chloride gave the corresponding 2chloromethylbenzoyl-1,2,3,4-tetrahydroisoquinaldonitriles(152, 153, and 154,


17

n

ILO

123

R~=R~=H

126

RW=H

127

R1=R2=OCH3 Oorunnine

128

R1+Rz=OCH20 Nandazurine

R~=P=H

129 R ~ = R ~ = R = H

Caaverine

130 R1=R2=OCH3, R=CH3

Thalicnidine

131

Donesticine

R1+R2=OCH20, R=C?

SCHEME 17

respectively). Reaction of these Reissert compounds with sodium hydride in dimethylformamide led directly to 8-oxoprotoberberine derivatives 158, 159, and 160 respectively, in high yields (37,38). The reaction could be extended successfully to the synthesis of 5,6-didehydro-8-oxoprotoberberinederivatives 167 and 168 as well (38,39). The synthesis of 168 has also been completed by using other reaction conditions (Scheme 22). 6,7-Dimethoxyisoquinoline(162) was reacted with potassium cyanide and 2-chloromethylbenzoy1chloride in the presence of a catalytic amount of benzyltriethylammoniumchloride, resulting in 164 which on treatment with lithium diisopropylamide in hexamethylphosphoramide-tetrahydrofuran solvent mixture afforded the cyclized product 168 in high yield (40).

18


@ :

CH30 C H 3/ 0 F I 4

P

CH,O

'

CH,O

\

OR

0 C H,-$

139 R=CH20

I38

132

R=H

Antheroline

SCHEME 18

-

cCH,OH \3 0 T

-

CCH,O H30@:

\

N H, \

OCH,-$ 142

\

OR 143 R=CH2@ 133

SCHEME19

R=H

Subsessiline


19

145

148

134 Imenine

SCHEME20

In 1981 multistep syntheses of (2)-mecambridine (169) and orientalidine (170) (Scheme 23) were accomplished by Kerekes (41), starting from a properly substituted Reissert compound. 2-Benzoyl- 1-cyano- 1,2-dihydro-8-methoxy-6,7methylenedioxyisoquinoline (171), obtained from cotarnine, was reacted with potassium cyanide and 3-benzyloxy-4-methoxybenzyl chloride; intermediate 172 was hydrolyzed to l-(3-benzyloxy-4-methoxybenzyl)-8-methoxy-6,7-methylenedioxyisoquinoline (173) without purification. 1-Benzylisoquinoline 173 on debenzylation and catalytic hydrogenation gave the corresponding 1,2,3,4tetrahydroisoquinoline derivative 174. The internal Mannich reaction of 174 in neutral medium gave the 10,ll-disubstituted protoberberine derivative 175 as major product in addition to the 9,lO-disubstituted isomer 176. Treatment of compound 175 with formaldehyde in methanolic sodium hydroxide gave 11-0demethylmecambridine (177) as a crystalline product. 11-0-Demethylmecambridine (177) was finally converted to (+-)-mecambridine (169) on methylath with diazomethane, and into (*)-orientalidhe (170) on treatment with sodium hydride and dichloromethane in dry dimethylformamide.

20


149 R~=R‘=H

150 F ? = R ~ = O C H ~ 151

-

R~+R’=OCH~O

%z:

1

SCHEME 22

152

R~=R’=H

153

R~=R~=OCR~

154

R~+R~=OCH~O

;:1$;;

1. RElSSERT SYNTHESIS OF ISOQUINOLINE AND INDOLE ALKALOIDS

21

NaOH DI@ 171’

OCH,

172

-

-

HCHo

I74

173

- c%R,

-

CH30

ECHO NaOH

\

OCH,

(:% ,

CH30

\

R‘

HO

17s

AH,OH

176

$=OH,

OCH,

OH

F2 1

R~=H

CHp2

DlIF

I69

OCH,

OCH,

Fkecambri d ine

170 Orientalidine

SCHEME 23

F. SYNTHESIS OF PHTHALIDEISOQUINOLINE ALKALOIDS Among the great number of different approaches for the synthesis of phthalideisoquinoline alkaloids the application of Reissert compounds, developed first by Kerekes et al. (42,43),proved to be one of the most efficient and suitable methods (Scheme 24). Treatment of isoquinoline Reissert compounds 26 or 28 with sodium hydride in dimethylformamide resulted in the formation of the corresponding “Reissert anions,” which were reacted with dimethoxy- or methylenedioxy-substituted o-forrnylbenzoic acid ester derivatives 178 and 179, respectively. The presumed mechanism of this reaction involves an initial reaction

22


178 R3=R4=CCHj 179 R3+R4=OCHz0

-

Q

by". CH-OC-g

Rk I82

R1+R2=R3+R4 =OCH20

186

R1+R2=R3+R4=OCHz0

187 188

R1+Rz=OCH20,

189

R1=R2 ,R3=R4 E O C S

I83

R'+R'

184

R1=R2=OCH3,

185

R1=Rz =R3=R4 =OCH3

=0CB2 0 , R3 =R4 =CCH3 R7+R4=OCHz0

R1=R2=OCH3,

R3=R4=OCH 3 R7+R4=OCHZC


198 R1+R2=R3+R4=OCH2C

20 2 R1+Rz =R3 +R4 =OC% 0

199 R1+R2=OCH20,

R3=R4=OCK,

203 R1+Rz=OCH20,

200 R1=R2=OCItj,

R3+R4=OCHz0

201

204 R1=Rz=CCHj,

205

R1=Rz=R3=R4=OC~

23

R3=R4=OCH 3 R3+R4=OCH;10

R1=Rz=R3 =R4=OCH3

SCHEME 24 (Continued)

96

NaOH

o \

o \

206

207

r

1

210

SCHEME 25

of the Reissert anion with the aldehyde carbonyl to form an alkoxide type intermediate (180), whose negatively charged oxygen attacks the amide carbonyl to yield an oxazolidine of type 181, which on rearomatization affords O-benzoyl- 1 -benzylisoquinolinederivatives 182-185. Saponification of the latter compounds with potassium hydroxide in aqueous alcoholic solution and subsequent lactonization by treatment with hydrochloric acid results in the phthalideisoquinoline skeleton with proper substitution patterns at rings A and D. The aromatic phthalideisoquinolines (186-189) obtained were hydrogenated in the presence of a PtO, catalyst to obtain a nearly 1 : 1 mixture of erythro and threo norphthalideisoquinolines (190-193 and 194-197, respectively). The mixtures of erythro and threo diastereomer pairs were separated by preparative thinlayer chromatography, and finally Eschweiler-Clark N-methylation was performed on each norphthalideisoquinoline derivative, yielding (-+)-bicuculline (198), (?)-corlumine (199), (k)-P-hydrastine (200), and (+)-cordrastine I1 (201) all with erythro relative configuration and, on the other hand, (+)adlumidine (202), (+)-adlumine (203), (+)-a-hydrastine (204), and (+-)-~ordrastine I (205) with the threo relative configuration of their C-1, C-9 stereo centers (42-44). The fact that pairs of diastereomeric N-norphthalideiso-

24

GABOR BLASKO, PETER KEREKES, AND

cHO C ,H 3 0\w CN N - HF - g

+

SANDORMAKLEIT

:

%$H

-

C .’H ,, CHO

26 212

211

SCHEME26

quinolines and phthalideisoquinolines were thus available has allowed a structure-activity relationship investigation on their y-aminobutyric acid (GABA, the inhibitory neurotransmitter agent of the mammalian central nervous system) antagonist activity (45). Reaction of 2-(o-formylbenzoyl)-1,2-dihydroisoquinaldonitrile (206) with base followed by an intramolecular acylmigration gave the unsubstituted phthalideisoquinoline skeleton 210 as shown in Scheme 25 (40).

G. SYNTHESIS OF EMETINE ANALOGS Successful attempts have been made for the preparation of different emetine analogs (46). For example, 211 has been synthesized by the reaction of Reissert compound 26 with the protoemetine analog 212 (Scheme 26).

111. Synthesis of Indole Alkaloid Analogs A. SYNTHESIS AND REACTIONS OF 3,4-DIHYDRO-P-CARBOLINE REISSERT COMPOUNDS The Reissert reaction of 3,4-dihydro-P-carboline (213) has also been studied (47,48). It has been shown that 3,Qdihydro-P-carboline (213) afforded 1cyano-2,9-dibenzoyl-l,2,3,4-tetrahydro-~-carboline (214) with a phase-transfer catalyst and trimethylsilyl cyanide (Scheme 27). However, the “normal” Reissert product 2-benzoyl-1-cyano- 1,2,3,4-tetrahydro-P-carboline(215) was obtained when a catalytic amount of anhydrous aluminum chloride was used in addition to the trimethylsilyl cyanide reagent. Reaction of 214 with sodium


25

218

SCHEME 21

219 R=CHz@

221

220 R=H

222 R=H

223

224

R=cH~!$

SCHEME 28

hydride and excess of methyl iodide gave l-cyano-2,9-dimethyl-1,2,3,4tetrahydro-P-carboline (216), while the use of 1,3-dibromopropane instead of methyl iodide led to the tetracyclic compound 217, which represents the skeleton of the canthin-6-one-type alkaloids. Similar reaction of 215 with a,a-dibromo-oxylene supplied the benzoazepino-P-carboline 218 (47). It is interesting to mention that the hydrolysis was not accompanied by the elimination of the CN group. Treatment of 4-chlorobutanoyl Reissert compounds 219 and 220 with sodium hydride in dimethylfomamide afforded indolo[2,3-a]quinolizinederivatives 221 and 222, respectively, in an intramolecular alkylation process (Scheme 28).

26


Similarly, intramolecular cyclization of the 2-chloromethylbenzoy1Reissert derivative 223 resulted in N-benzyldemethoxycarbonyl-oxogambirtannine(224) (47).

B. SYNTHESIS OF ELLIPTICINE ANALOGS The formation of Reissert derivatives of the antineoplastic agent ellipticine (225)(Scheme 29) and their reactions have been extensively studied by Popp and co-workers (39,49-51). The ellipticine Reissert compound 226 could be prepared either with benzoyl chloride and potassium cyanide in a dichloromethanewater system or, better, with benzoyl chloride and trimethylsilyl cyanide in dichloromethane. In similar manner 9-methoxyellipticine and a number of 6substituted ellipticines have also been converted to the corresponding Reissert compounds. Reaction of 2-benzoyl-6-benzyl-l-cyano-l,2-dihydroellipticine(227) with alkyl halides in dimethylfonnamide in the presence of sodium hydride gave the

225

226 RL=H

Ellipticine

227 R1=CH2g

CH R CN

M 228 X2=C$ 229 R2=CH,0

P 230 R2=CH3 231

232

R2=C%0

SCHEME29


27

alkylated Reissert derivatives 228 or 229, which could be hydrolyzed to 1alkyl-6-benzylellipticines 230 and 231, respectively. The ellipticine Reissert compound 226 has also been converted to its cyclic fluorobrate salt 232 on treatment with fluoroboric acid in glacial acetic acid.

IV. Conclusion Although a number of effective synthetic methods have been developed for the synthesis of isoquinoline as well as indole alkaloids (Bischler-Napieralski, Pictet-Spengler, Pomerantz-Fritsch syntheses, etc.), there is still a need to improve the existing methods and to develop new ones. It can be stated that the synthetic approach via Reissert compounds proved to be one of the most efficient routes to the alkaloids in question in the 1970s and 1980s. First, the preparation of 1-benzylisoquinoline alkaloids received much attention. More recently, the synthesis of aporphines, phthalideisoquinolines, and ellipticines, all of them possessing different valuable pharmacological properties, became the target of organic chemists. The Reissert approach has proved to be a good synthetic tool with general applicability to the synthesis of these type of alkaloids.

REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22.

A. Reissert, Chem. Ber. 38, 1603 (1905). A . Reissert, Chem. Ber. 38, 3415 (1905). W. E. McEwen, and R. L. Cobb, Chem. Rev. 55, 511 (1955). F. D. Popp, Adv. Heterocyclic Chem. 9, 1 (1968). F. D. Popp, Adv. Heterocyclic Chem. 24, 187 (1979). F. D. Popp, Bull. SOC.Chim. Belg. 90, 609 (1981). F. D. Popp, Heterocycles 1, 165 (1973). F. D. Popp, Heterocycles 14, 1033 (1980). F. D. Popp and B. C. Uff, Heterocycles 23, 731 (1985). J. V. Cooney, J . Heterocyclic Chem. 20, 823 (1983). E. Mosettig, Org. React. 8, 218 (1954). M. D. Rozwadowska and D. Brbzda, Tetrahedron Lett., 589 (1978). M. D. Rozwadowska, and D. Brbzda, Can. J . Chem. 58, 1239 (1980). S . Ruchirawat and M. Chuankamnerdkam, Heterocycles 9, 1345 (1978). B. C. Uff, J . R. Kershaw, and J. L. Neumeyer, Org. Synth. 54, 1892 (1974). J. W. Skiles and M. P. Cava, Heterocycles 9, 653 (1978). A. J . Birch, A. H. Jackson, and P. V. R. Shamnon, J . Chem. SOC.Perkin Trans I , 2190 (1974). P. Kerekes, S . Makleit, and R. Bognfu, Acta Chim. Hung. 98, 491 (1978). H. Y. Cheng and R. W. Doskotch, J . Nut. Prod. 43, 151 (1980). S . F. Dyke, A. W. C. White, and D. Hartley, Tetrahedron 29, 857 (1973). D. C. Smith and F. D. Popp, J . Heterocyclic Chem. 13, 573 (1976). A. H. Jackson, G . W. Stewart, G . A. Chamock, and J. A . Martin, J . Chem. SOC. Perkin Trans I , 1911 (1974).

28

GABOR BLASKO, PETER KEREKES, AND SANDOR MAKLEF

23. I. M. Boente, L. Castedo, A. Rodriguez, J. M. Saa, R. Suau, and M. C. Vidal, Tetruhedron Lett. 24, 2295 (1983). 24. M. H. Abu Zarga, G. A. Miana, and M. Shamma, Tetrahedron Lett. 22, 541 (1981). 25. S. Chattopadhyay and M. Shamma, Heterocycles 19, 697 (1982). 26. F. R. Stermitz and D. K. Williams, J. Org. Chem. 38, 1761 (1973). 27. .I. L. Neumeyer, in “The Chemistry and Biology of Isoquinoline Alkaloids” (J. D. Phillipson, M. F. Roberts, and M. H. Zenk, eds.), pp. 146-170, and references cited therein. SpnngerVerlag, Berlin, Heidelberg, 1985. 28. 1. L. Neumeyer, B. R. Neustadt, and K. K. Weinhardt, J. Phurm. Sci. 59, 1850 (1970). 29. J. L. Neumeyer, W. P. Dafeldecker, B. Costall, and R. J. Naylor, J. Med. Chem. 20, 190 (1977). 30. J. L. Neumeyer, J. F. Reinhard, W. P. Dafeldecker, J. Guarino, D. S. Kosersky, K. Fuxe, and L. Aganati, J . Med. Chem. 19, 25 (1976). 31. J. L. Neumeyer, F. E. Granchelli, K. Fuxe, U. Ungerstedt, and H. Corrodi, J. Med. Chem. 17, 1090 (1974). 32. D. R. Elmaleh, F. E. Granchelli, and J. L. Neumeyer, J. Heterocycl. Chem. 16, 87 (1979). 33. S. M. Kupchan and P. F. O’Brien, J . Chem. SOC., Chem. Commun., 915 (1973). 34. M. P. Cava and I. Noguchi, J. Org. Chem. 37, 2936 (1972). 35. J. W. Skiles and M. P. Cava, J . Org. Chem. 44, 409 (1979). 36. M. P. Cava and I. Noguchi, J. Org. Chem. 38, 60 (1973). 37. S. Ruchirawat, N. Phadungkul, M. Chuankamnerdkam, and C. Thebtaranonth, Heterocycles 6 , 43 (1977). 38. S. Ruchirawat, W. Lertwanawatana, and P. Thepchumne, Tetrahedron Lett. 21, 189 (1980). 39. S. Veeraraghavan and F. D. Popp, J. Heterocyclic Chem. 18, 17 (1981). 40. J. A. Tyrell and W. E. McEwen, J . Org. Chem. 46, 2476 (1981). 41. P. Kerekes, Acta Chim. Hung. 106, 303 (1981). 42. P. Kerekes, G. Horvith, Gy. Gail, and R. Bognh, Actu Chim. Hung. 97, 353 (1978). 43. P. Kerekes, Gy. Gail, R. Bognhr, T. Tor6, and B. Costisella, Actu Chim. Hung. 105, 283 ( 1980). 44. P. Kerekes, unpublished results. 45. J. Kardos, G. Blask6, P. Kerekes, I. Kovics, and M. Simonyi, Biochern. Pharmucol. 33,3537 (1984). 46. R. F. Watts and F. D. Popp, J. Heterocyclic Chem. 15, 1267 (1978). 47. S. Veeraraghavan and F. D. Popp, J. Heterocyclic Chem. 18, 909 (1981). 48. F. D. Popp and S. Veeraraghavan, Heterocycles 15, 481 (1981). 49. S. Veeraraghavan and F. D. Popp, Synthesis, 384 (1980). 50. F. D. Popp and S. Veeraraghavan, J. Heterocyclic Chem. 19, 1275 (1982). 51. F. D. Popp, Heterocycles 14, 1033 (1980).

-CHAPTER2 -

ARISTOLOCHIA ALKALOIDS ZHONG-LIANG CHENAND DA-YUANZHU Shanghai Institute of Materia Medica Academia Sinica Shanghai, Peoples Republic of China

I. Introduction 11. Structural Relationships and Biosynthesis

111.

IV.

V.

VI.

VII.

A. Chemical Types B. Biosynthetic Studies Spectroscopic Properties A. Mass Spectra B. Nuclear Magnetic Resonance Chemical Reactions and Structural Determination A. Structure of Aristolochic Acid I B. Other Aristolochic Acids C. Miscellaneous Reactions Chemical Synthesis A. Synthesis of Aristolochic Acids and Aristolactams B. Synthesis of 4,s-Dioxoaprophines Pharmacology and Clinical Use A. Antitumor Activity B . Immunomodulating Activity C. Antifertility Activity D. Miscellaneous E. Clinical Use F. Toxicity Summary of Physical Properties References

I. Introduction Aristolochia is regarded as a genus of the family Aristolochiaceae; they are climbing and twining vines, distributed in the tropic and temperate zones. There are about 200 species worldwide ( I ) , and more than 40 of them have been studied chemically: A . acuminata, A . argentina, A . badamae, A . baetica, A . bambusifolia, A . bracteata, A . championii, A . chilensis, A . clematitis, A . cucurbitoides, A . debilis, A. elegans, A . esperanzae, A . fangchi, A . fimbriata, A . grifithii, A . heterophylla, A . indica, A . italica, A . kaempferi, A . kwangsiensis, A . 29

THE ALKALOIDS, VOL. 31 Copyright 0 1987 by Academic Press, Inc. All rights of reproduction in any form reserved.

30

ZHONG-LIANG CHEN AND DA-YUAN ZHU

longa, A . macedonica, A . manshuriensis, A . maurorum, A . maxima, A . mollissima, A . moupinensis, A . ornithocephala, A . pallida, A . pendurata, A . reticulata, A . rotunda, A . serpentaria, A . sipho, A . tagala, A . taliscana, A . taliscula, A . tomentosa, A . triangularis, A . tuberosa, A . watsonii, A . westandii, and A . zenkeri, etc. (see Table 11). Some species of Aristolochia plant have been extensively used in folk medicine (2-4). The purpose of this chapter is to review the chemistry, spectroscopicproperties, biosynthesis, pharmacology, and clinical use of Aristolochia N-containing substances. Early studies on the nitrophenanthrenic acids were summarizedby Pailer in 1960 (3,and more recently by Mix et al. (6) and Ding and Lou (7). In 1971, Horrisberger reviewed the chemistry, pharmacology, and medical use in chronic infections of aristolochic acid (8). Several reasons can be given for the strongly increasing interest in this group of natural products: first, the structural and biosynthetic relationships between aristolochic acids, aristolactams, 4,5-dioxoaporphines, and other isoquinoline alkaloids; second, the various biological activities of a number of compounds such as aristolochic acid I (1). Aristolochic acid I was reported as a potential tumor inhibitor. It inhibited the experimental tumor growth in animals and destroyed malignant human tumor cell growth in tissue cultures at low concentration (9-11). Aristolochic acid I has been widely used as a phagocyte stimulant in western Europe for some years. Recently, however, it has been sho.wn to be a potential carcinogen (12), and the denitro compound, aristolic acid (3,4-methylenedioxy-8-methoxyphenanthrenicacid, 70) was reported as an antifertility active substance (13,14). Aristolochic acids are very easily soluble in alkali and form sodium salts that are recovered by acidification (15). The aristolochic acids and methyl esters were separated by column chromatography as usual, and thin-layer chromatography (TLC) (16), high-performance liquid chromatography (I 7 ) , and ion-exchange chromatography (18) have been used for separation and purification. Some industrial-scale methods have been also reported (19-22). Most aristolochic acids and aristolactams in the pure state are sparingly soluble in ether, alcohol, chloroform, and acetone and readily soluble in DMSO, pyridine, and other alkaline solvents. For recrystalization of these compounds sometimes a Soxletor is used.

11. Structural Relationships and Biosynthesis

A. CHEMICAL TYPES The natural Aristolochia N-containing substances may be divided into three structural types: nitrophenanthrenic acids, phenanthrene lactams, and isoquinoline alkaloids.

31

2. ARISTOLOCHIA ALKALOIDS

1. Nitrophenanthrenic Acids Aristolochic acids, representatives of the substituted 10-nitrophenanthrene-1acids, have been known since 1943, when Rosenmund and Reichstein first isolated aristolochic acid I (1) from A. clematitis (23) [this compound was named aristolochic acid A by Tomita and Sasagawa (24)].Its structure was elucidated by Pailer et al. in 1956 by means of chemical reactions (25), and when several aristolochic acids-aristolochic acids I1 (2) (aristolochic acid B by Tomita), I11 (3) IIIa (4) (aristolochic acid C by Tomita), IV (5), and IVa (6)-were isolated from the root of A . clematitis by Pailer and his co-workers (26) and in the meantime from A . debilis and A. fangchi by Sasagawa (27).

1

1 R = H

2 R1= 3

R1=

4 R1=

,

R 2 = OCH

* OCH3,R 2 OH,

=

R1

3

H , R = H

1

7 R = OH

H

8

R2= H

9

5 R1=

OCH ,R2= OCH3 3 6 R1= OH, R2= OCH 3 10 R ~ = G ~ UR , ~ =OCH

11 R1=

R1= OCH 3 ,R2= OCH 3 R1= H , R 2 = OCH 3 C-1

OCH3,R2=

, Rz= OCH3

NH2 CH

12

~1: H

,

I 3

R*,NH-CH I COOCHg

-CH2-COOH

3

A general structural feature of these aristolochic acids is that the oxygenated functions are usually substituted at the C-6 and/or C-8 position. Chen et al. have isolated 7-hydroxy-8-methoxy-3,Cmethylenedioxy-10-nitrophenanthrenic-1-acid (7), 7,8-dimethoxy-3,Cmethylenedioxy- 10-nitrophenanthrenic-1-acid (8) (28), which are oxygenated at both C-7 and C-8. Tseng and Ku isolated an unusual species, debilic acid (9), a nitrophenanthrenyl acetic acid derivative (29). Recently, a glucoside of aristolochic acid, aristoloside (lo), was isolated from A. manshuriensis by Nakanishi et al. (30) and developed by the Otsuka Pharmaceutical Co. group as an antitumor agent (31).Aristolochic amides 11 (32) and 12 (33) have been also reported. Aristolochic acid derivatives have been found only among plants of the family Aristolochiaceae (Aristolochia spp. and Asarum canadense var. refexum (34)] and in Bragantia wallichii (35,36).In all derivatives, substitution of nitro group is present at C-10, the carboxy group is present at C-1, and a methylenedioxy is substituted at C-3 and C-4 only. This general structure will be very interesting in biosynthesis and plant biochemistry.

32

ZHONG-LIANG CHEN AND DA-YUAN ZHL

2. Phenanthrenic Lactams Aristolactam (13) (in some papers, aristololactam) was first prepared by catalytic hydrogenation or zinc reduction in acetic acid from aristolochic acid I (25). It has been isolated from several Aristolochia plants, including A . debilis and A . fangchi (24). Kupchan and Merianos isolated the first aristolactam N-glucoside (19) from A . indica (37).

Maldonado et al. isolated taliscanine (aristolactam BI, 21) from the root of A . taliscana (38). Other aristolactams were subsequently discovered in Stephania cepharantha (Menispennaceae) (39),Schefferomitra subaequalis (Annonaceae) (40), and Doryphora sassafras (Monimiaceae) (41). Priestap and co-workers systematically analyzed the aristolactams from rhizomes of A. agentina and isolated 13 aristolactams: aristolactams I (13), I1 (14), I11 (15), IV (16), Ia (17), I11 (18), A11 (24), A111 (25), AIa (26), AIIIa (27), B1(21), BII (22), and BIII (23) (42, 43).

3. Isoquinoline Alkaloids Some isoquinoline alkaloids have been isolated from Aristolochia plants. Magnoflorine (28) was first isolated from several plants of this genus: A . argentina, A . baetica, A . clematitis, A . debilis, A. fangchi, A . heterophylla, A. kaempferi, A . macedonica, and A . moupinensis. Asimilobine (29) (25), cyclanoline (30) (24),and hydrastine (31) (44) were also isolated. Priestap et al. isolated a phenanthrene amine, argentinine (32), from the root of A . argentina (45). Zhu et al. separated two new 4,5-dioxoaporphine alkaloids, tuberosinone (33) and tuberosinone-N-P-glucoside(34), from A . tuberosa (46).


33

J

CH 3

28

0

33 R = H

35

34 R=Glu

Govindachari and Viswanathan identified the aristolochine which was isolated by Krishnaswamy et al. 1935 (35)as 1-curine by 'H NMR, MS, and direct comparison with authentic sample of 1-curine to establish its identity (48,49).ElSebakhy and Waterman reported the results of an examination of the leaves of A. elegans in which a bisbenzyl isoquinoline alkaloid, (-)-(R,R)-7'-O-methyl cuspidaline ( 3 9 , was isolated. This study failed to show the presence of any other nitro compounds in the leaves of A. elegans (50).

B. BIOSYNTHETIC STUDIES The biosynthesis of aristolochic acids is considered to begin with l-benzyltetrahydroisoquinoline precursors and to proceed via aporphine intermediates (5). In radioactive labeling studies, Spenser and Tiwari infused dl-tyrosine-2-14C into the stem ofA. sipho. The 14C-labeledaristolochicacid I formed lost more than 60% of its radioactivity when it was decarboxylated to the corresponding nitro phenanthrene derivative. Administration of dl-dihydroxyphenylalanine-2-14Cre-

34


HO

\

#-

HO

OH

36

----, c HHO3

0 7 - C € 1 3

c

A

-

C

H

3 4

/

HO

\

0

CH 3

OCH3

313

37

-CH3

OCH3 39

H/ F

40

p j f C H 3 -

1

41

SCHEME 1

sulted in the formation of radioactive aristolochic acid I, which did not lose radioactivity during decarboxylation. Decarboxylation of the acid derived from dihydro~yphenylethylamine-2-'~C resulted in the formation of an inactive nitrophenanthrene derivative. The aristolochic acid I derived from dl-noradrenaline-2-14C was labeled exclusively at the carboxy C atom. These results indicated that the norlaudanosoline derivative 36 was an intermediate in biosynthesis of aristolochic acid (51). Schuette etal. confirmed this hypothesis. They found that supplying tetrahydropapaverine-4-14C hydrochloride to A . sipho gave no radioactive aristolochic acid I, but feeding norlaudanosoline-4-14CHC1yielded 14C-labeled aristolochic acid I with the carboxy group containing 60% of the radioactivity (52). Comer et al. conducted studies in which tyrosine, dopa, dopamine, or noradrenaline served as the specific precursor. Feeding of doubly labeled (3-14Cand 15N) tyrosine demonstrated that the nitro group of aristolochic acid I originates from the amino group of tyrosine (53). The incorporation of tyrosine, 3,4dihydroxyphenylalanine, orientaline (37), prestephanine (40), and stephanine (41) into aristolochic acid in A. bracteata was studied by Sharma et al. in 1982. The evidence strongly supported the sequence shown in Scheme 1 for the biosynthesis of aristolochic acid I. Oxidative coupling of orientatline (37) gives prestephanine (40), which is cyclized to stephanine (41); oxidative cleavage of stephanine funished aristolochic acid I (1) (54). Parallel feeding with (--)-(R)and (+)-(S)-orientaline showed that the sterospecificity is maintained in the biosynthesis route (54) and that the methylenedioxy group in aristolochic acid originates from an 0-methoxyphenol precursor.

35


Until relatively recently the aristolochic acids were known to occur in only the family Aristolochiaceae, but aristolactams and 4,5-dioxoaporphine alkaloids have been isolated from Menispermaceae, Annonaceae, Papaveraceae, and Piperaceae. Akasu et al. isolated cepharanone A (aristolactam 11, 14), cepharanone B (aristolactam BII, 22), cepharadione A (42), and cepharadione B (43) from Stephania cepharentha (Menispermaceae) (39). Cepharanone A has also been found in Piper saneturn (Piperaceae) (56). From the bark of SchefSerornitra subaequalis Duke and Gellert isolated alkaloid Y whose spectral properties are very similar to those reported for aristolactam BII (22) (40).Braz Fo et al. have isolated a monooxoaporphine alkaloid, fuseine (44), from another Annonaceae plant Fusea longifolia, and its structural features closely resemble reduced debilic acid (58).

The cooccurrence of aristolactams and dioxoaporphines in these families is a very interesting problem from a chemotaxonomical point of view and supports the view that the Aristolochiales is related to Magnoliales and Ranunculales (43). Castedo et al. isolated pontevedrine (46), a 4,5-dioxoaporphine from Glaucium jlavurn (Papaveraceae). The conversion of pontevedrine to the related aristolactam (48) takes place in vitro and can be regarded as a benzilic acid rearrangement followed by loss of one carbon. They proposed the 4,5-dioxoaporphines as possible intermediates and the biosynthetic pathway as shown in Scheme 2 (59). Priestap has isolated a total of 12 aristolactams from A . argentina. These compounds all show a substitution pattern similar to that of the accompanying

OH

n

-CH3

6CH3

SCHEME2

I

OCH3

36

WONG-LIANG CHEN AND DA-YUAN ZHU

aristolochic acids, and Priestap suggested that the aristolochic acids are derived from aristolactams rather than directly from quaternary aporphine alkaloids (43). The structural relationships between plants and insects have become very highly regarded (60).Euw and co-workers isolated aristolochic acid I from the swallowtail butterfly; 51 butterflies gave 5-6 mg aristolochic acid I (61). Aristolochic acid Ia has been also found by Rothschild et al. to occur in Zerynthia polyxena, a butterfly whose larvae feed on Aristolochia clematitis (62). Urzua er al. investigated the papilionoid butterfly living in Chile. The larval stages of the butterfly feed on the aboveground parts of A . chilensis, the food material contains aristolochic acid, and the insects retain these compounds after metamorphosis. Aristolochic acids I and Ia are major components of the tender stems and the leaves of A . chilensis, but aristolochic acids I and IVa appear to be the main acid components of this butterfly. The difference in composition was explained by metabolic transformation by the insect. From a biological point of view, the phenomenon has been interpreted as a result of an ancestral butterfly larva with the ability to store these poisonous metabolites, thus obtaining immediate protection from predators (63).

111. Spectroscopic Properties Spectroscopic methods are widely used for the structural determination of Aristolochia alkaloids. These compounds all show a substituted phenanthrene chromophore in UV spectra. The UV spectrum of aristolochic acid I is characterized as follows: 223 (30000), 250 (30600), 318 (11500), 390 (5700) (24).The other aristolochic acid analogs are similar, for instance, aristolochic acid IV: 220 (4.41), 242 (4.53), 253 (4.53), 292 (4.17), 330 (4.02), 402 (4.00) (26); aristolochic acid Ia: 221, 255, 283, 321, 389 (63);aristolactam: 241 (4.50), 250 (4.47), 259 (4.56), 291 (4.16), 300 (4.15) (24); tuberosinone: 228 (4.57), 277 (4.12), 286 (4.15), 318 (4.05), 330 (4.16), 372 (3.91), 390 (3.94); tuberosinone-N-D-glucoside:227 (4.59), 240 (4.63), 285 (4.08), 330 (4.09), 370 (3.72), 388 (3.72), 477 (4.14) (46). The phenolic derivatives of this series, such as aristolochic acid Ia and 4 3 dioxoaporphine, suffered considerable bathochromic shifts, and further shifts toward the longer wavelength region are observed on addition of alkali. For instance, the UV spectrum of 4,5dioxoaporphine (49), 246 (4.70), 292 (4.14), 305 (4.26), 318 (4.28), 459 (4.23), shifts to 241 (4.71), 256 (4.67), 305 (4.21), 331 (4.25), 510 (4.30) in alkaline solution (64).This bathochromic shift was also found in aristolochic acid Ia (50) (63, 65). The UV spectroscopic method has been used for the quantitative analysis of aristolochic acids from plants or pharmaceutical products (66-68,71).

37


The IR spectra are useful for detecting functional groups of Aristolochia alkaloids. Aristolochic acids show two characteristic bands at 1550 and 1350 cm- due to the absorption of nitro group, and the carboxy OH group appears at 3000-2500 .cm- as a broad continuous absorption. Hydroxy derivatives of aristolochic acids or aristolactams show OH and NH absorptions at 3300-3500 and 3200-3400 cm- l. The carboxy or lactam carbonyl is present at 1690 cm- l . In general, the aromatic ring system shows stretches at 1625-1575 and 15251475 cm- as usual, and observation of the 900-700 cm- region is often used for analysis of substitution type in aromatic derivatives (28). A. MASS SPECTRA The mass spectra of Aristolochia N-containing compounds were first reported by Pailer et al., who studied the electron impact-induced fragmentation of the esters of aristolochic acids. They found that the nitro radical is very easily split off from the molecular ion, giving the base peak (M - 46) , and then the CH,, CO, etc. were removed. Pailer et al. concluded the fragmentation was as shown in Scheme 3 (26). High-resolution mass spectroscopy is a very useful tool for the identification of Aristolochia alkaloids, for the analysis of mixtures, or for detection of trace impurities. Eckhardt et al. found that the primary clevage of aristolochic acid I occurs in the condensed aromatic system, which has a carboxy and a nitro functional group in pen position, with the elimination of NO,. This cleavage is usually observed in aristolochic acids and closely related compounds, in nitro naphthalenic compounds in general. The molecular ion of aristolochic acid, mlz 341, was determined as C,,Hl,NO,. The primary fragmentation of molecular ion consists of the elimination of a nitro group to yield the base peak at mlz 295 and then further fragments due to consecutive loss of small units, such as H, CH, CO, and CHO, at the ions C,,Hl0O5 294 (M - 47), C16H,0, 280 (M - 61), C16H1104267 (M - 74), C1&04 252 (M - 89), C15Hl10, 239 (M - 102), C14H,0, 224 (M - 117), and C,,H,O, 196 (M- 145). The main fragmentation peaks are quite similar to the aristolochic esters (69). Debilic acid (9) was the minor constituent of the Chinese medicinal plant A . +

38


cq-&cH3 \o" I 3H;o&-34c

N02

-

\

R1

I

R2

-

Z2EL

go2 \

R1

c4p

2

(M-46)

R

OCH3

0 \

R2 (M-61)

i

(M-89)

c(x&Q :*

1

c43

\

(Mi:llo R2

t.?.:

(M-59) R1 SCHEME 3

R2 (M-117)

debilis (29). Riicker and Chung recorded the mass spectrum of methyl ester of debilic acid. It showed a strong molecular peak and fragments at mlz 338 (M 31), 323 (M - 46),308 (M - 46 - 30), 293 (308 - 15); the fragmentation is shown in Scheme 4 (70). The mass spectra of 4,5-oxoaporphine alkaloids are characterized by a direct loss of CO (M- 28) from the molecular ion (base peak) leading to a prominent peak at mlz 265 (27%). Subsequent loss of a methyl group accounted for the other significant peak at mlz 250 (51%) (64). Terasa et al. have reported mass spectrum of 2-(phenanthro[3,4-6]-1,3-dioxole-6-nitro-5-carboxamido)propanoicacid methyl ester (12), a new aristolochic

m/z 308

(M-46-70) SCHEME 4

39


m/e 396 (8%)

(M-16) 380 (1%) a. 365 ( 3 % )

bH C .

d. e.

290 263 248 220

(36%) (20%)

(5%) (10%)

SCHEME 5

acid derivative which was isolated from A . longu. Compound 12 shows an amino acid joined to the main structure by means of an amido linkage, and the main fragmentation is loss of the nitro group to form a base peak at m/z 350 and/or cleavage of the side chain (Scheme 5 ) (33). B . NUCLEARMAGNETIC RESONANCE

'H-NMR spectroscopy is the most commonly used technique in the structural elucidation of Aristolochiu alkaloids. 'H-NMR spectral data of aristolochic acids, aristolactams, and other related compounds are compiled in Table I. A comparison of chemical shifts and coupling constants indicates certain correlations which may be of diagnostic value. The aristolochic acids and aristolactams present a C-2 aromatic proton (6 7.50-7.90) and C-3, C-4 hydroxy (6 lo), methoxy (6 3.90-4.10), or methylenedioxy (6 6.35-6.55) substitution on ring A. There is only one proton on ring B (H-9). It is also to be noted that the presence of a strongly deshielding nitro group results in a downfield shift about 0.9 ppm of the H-9 to form a chemical shift at 6 8.40-8.70 in aristolochic acids, but in aristolactams H-9 appears rather upfield at 6 7.05-7.40; these signals are very easy to assign. The analysis of proton signals on ring C is very useful in elucidating the structure of compounds in this series. The chemical shift of H-5, which can be recognized by its downfield position, is the same as in the phenanthrene nucleus. The most aristolochic acids and aristolactams have one or two substitutions in the form of hydroxy and/or methoxy groups on ring C; therefore, interpretation of coupling constants is useful to determine the ortho (J = 7-9) or meta (J = 1-3) H-H splitting and thus the position of substitutions. Aristoloside, an aristolochic acid derivative, was isolated from a stem of A .

TABLE I 'H-NMR Spectral Data of Aristolochia Alkaloids H- 1 Aristolochic acids Aristolochic acid U (2) Aristolochic acid la (50) Aristolochic acid UIa (4) Aristolochic acid I(1) Aristolochic acid UI (3)

P

0

7-Hydroxyaristolochic acid 1(7) Aristolochic acid IVa (6) 7-Methoxyaristolochic acid I (8) Aristolochic acid

-

H-2

H-3

7.76 s O-CH2--0

H-4

H-5

6.44 s 8.98m

H-6

H-7

H-8

H-9

H-10

Ref.

7.76m

7.16m

8.20m

8.50 s

7.66 dd (J = 8, 8) OH 10.55 s

7.20 d (J = 8) 8.06 d (J = 9) 7.30 dd (J = 9, 1.5) 7.42 dd (J = 8, 2)

OH

8.48 s

7.25 d (J = 9) OCH, 4.00 s (3H) 8.16 d (J = 8)

8.44 s

OH 10.33 s

OCH, 3.91 s (3H)

8.40 s

-

28

6.88 d (J = 2) OCH, 4.00 s (3H)

OCH, 4.06 s (3H) OCH, 4.00 s (3H)

8.55 s

-

37

8.43 s

-

28

6.92 d (J = 1.5) 7.32 d (J = 8) 6.70 d (J = 2.1) 7.13 d (J = 2) 7.75 m

OCH, 4.00 (3H) OCH, 4.06 (3H) OCH, 4.01 (3H) OCH, 4.07 (3H) 1.19 d (J = 7.5) 7.93 d (J = 7)

s

8.44 s

s

8.61 s

s

8.73 d (J = 0.7) 8.50 s

(w)

-

1.72 s O - C H 2 4

-

7.72 s M H 2 4

6.44 s 8.46d (w) (J = 8) 6.45 s 8.44 s

(w) _.

7.78 s M H 2 4

6.43 s 8.58 dd

(w) (J = 9, 1.5)

-

1.72 s M H z 4

6.44 s 8.48 d (w) (J = 2)

-

7.76 s M H 2 4

6.42 s 8.66 d (w) (J = 9)

-

7.85 s M H 2 4

6.55 s 8.11 d (J = 2) 6.41 s 8.66 d (w) (J = 9)

1.78 dd (J = 9, 9) ow 3 3.92 s (3H) 7.46 d (J = 9) OH 8.50 bn

(w)

-

7.70 s M H 2 4

-

7.72 s G-CH,--O

N (5) Aristolochic acid COOCH, 3.76 s I methyl ester Aristolochic acid COOCH, 3.68 s IV methyl ester Aristoloside (10) -

7.70 s M H 2 - - 0

Aristolochic acid COOCH, 3.88 s I1 methyl ester Compound 12 CORY

7.76 s M H 2 - - 0

6.44 s 8.06 d (w) (J = 1.5) 6.48 s 8.62 d

(w) 7.73 s O - € H 2 - 0

6.33 s

(w) 7.78 s M H 2 4

6.44 s 6.49 s 6.39 s

(w) 7.53 s M H Z - - O

6.35 s

(w)

7.72 d (J = 9)

OCH, 3.92 s (3~) 1.78 dd (J = 8) (J = 8, 8) 8.11 dd OCH, 3.98 s (J = 2.1, 0.7) (3H) 8.35 d (J = 2) 9.12 d 7.75 m (J = 7.5) 9.03 d 7.70 m (J = 7)

7.70 m

s

8.50 s 8.50 s

8.50 s 8.22 s

Aristolactams Aristolactam Il (14) (cepharanone A) Aristolactam (13)

2

-

7.64 s M H 2 4

-

7.53 s M H 2 4 7.52 s M H 2 4

7.60 s M H , + 7.62 s W H 2 4 7.89 s O-CH,--O

7.80 s M H 2 4

7.55 m

7.91 rn

7.11 s

NH 10.78 s

43

1.42 dd (J = 8, 8) OCH, 3.91 s (3H)

7.11 d (J = 8) 6.77 d (J = 2)

OCH, 4.00 s (3H) OCH, 3.98 s

7.27 s

NH 10.68 s

43

7.27 s

NH

43

7.96 d OH (J = 2.5) 7.38 dd 8.04 dd (J = 8.5, 2.5) (J = 8.5, 8.5) 7.23 d OH 9.80 sbr (w) (J = 2)

7.14 dd (J = 8.5, 2.5) 7.08 dd (J = 8.5, 2.5) 7.03 dd (J = 8, 2)

7.78 d (J = 8.5) OH 7.75 d (J = 8)

7.69 s

-

89

6.52 s 8.23 d (J = 8)

7.62 dd (J = 8, 8)

7.30 d (J = 8)

OCH, 4.07 s (3H)

7.80 s

-

37

OCH, 4.08 s (3H) OCH, 4.08 s (3H) OCH, 4.02 s (3H) OCH, 4.03 s (3H) OH -

7.54 m

7.54 m

7.93 m

7.08 s

6.43 s 7.99 d (w) (J = 8) 6.40s 7.60 d (w) (J = 2) 6.46 s (2H) 6.46 s (2H) 6.40 s

(w) 7.62 s OH 10.22 s

(2)

__

7.65 s OH 10.22 s

Aristolactam AIIIa (27)

-

7.63 s OH -

Aristolactam BU (22) (cepharanone B) Doryflavine

-

7.85 s OCH, 4.06 s (3H)

-

7.22 s OCH, 3.96 s

Aristolactam BIII

-

7.81 s OCH, 4.05 s

(25)

(23)

7.55 m

(w)

Aristolochic acid IVa lactam methyl ether Aristolactam UIa (18) Aristolactam Ia (17) Aristolactam IIIa N-p-Dglucoside (20) Aristolactam I N-@-Dglucoside (19) Aristolactam AII

Aristolactam A111

6.48 s 8.48 m

(3H)

9.13 m

10.68 s

(3H)

7.35 s

NH 10.68 s

43

7.38 s

NH

43

10.69 s

NH

43

10.77 s

__

8.67 d (J = 3.5)

OCH, 3.95 s (3H)

7.25 dd (J = 9, 3.5)

8.57 d (J = 2.5)

OH -

7.99 d 7.76 d (J = 8.5, 2.5)

7.03 s

NH 43 10.62 s

9.12 m

7.55 m

7.55 m

7.93 m

7.13 s

NH 10.78 s

OH

7.48 dd (J = 8, 2) 7.22 dd (J = 9, 2.5)

7.84 (J = 7.84 (J =

7.11 s

8.22 d (J = 2) OCH, 8.86 d 4.05 s (J = 2.5) (3H)

-

OCH, 3.92 s (3H)

7.89 d (J = 9)

d 8) d 9)

7.08 s

7.07 s

-

Nn 10.70 s

43

43

6 43

(continued)

TABLE I (Continued) H- 1 Aristolactam BI (21)

-

H-2

H-3

7.85 s OCH, 4.04 s (3H)

H-4

H-5

OCH, 8.72 dd 4.04 s

H-6 7.55 dd

H-7 7.18 dd

H-8 OCH, 4.04 s

H-9 7.43 s

H-10

Ref.

Nn 10.73 s

43

NH 12 s

46

(3H)

4,5-Dioxoaporphineand other alkaloids Tuberosinone 33

-

Tuberosinone-P-D -glucoside (34) ComDound 49

-

7.63

C+CH,-O

7.89 s M H 2 4 8.10 s OH -

6.50 s 8.12 d (w) (J = 2) 6.54 s 8.28 d (w) (J = 2) OCH, 9.46 dd

OH 10 s OH 10 s 7.66 dt

7.14 dd

7.74 d

(J = 8, 2)

(J = 8)

7.16 dd (J = 8, 2) 7.66 dt

7.78 d

8.05 s 8.27 s

- 46

7.50 s

- 64

(J = 8) 7 93 dd

4.06 s (3H)

6.47s

(-)-(R,R)-7’-O-Methylcuspidaline (35)

6.56s

J=8.2,

(J=8)

1.56 d CH3 ( J = 7 )

I

50


43

manshuriensis. Nakanishi et al. illustrated the structure as ~ - O - @- Dglucopyranoside of aristolochic acid D. They found that both H-5 (6 8.45) and H-7 (6 6.99) showed respective NOE enhancements of 20 and 9%) on irradiation of the anomeric proton (6 5.15), indicating the presence of a 6-O-glucoside linkage in aristoloside (30).

IV. Chemical Reactions and Structural Determination A. STRUCTURE OF ARISTOLOCHIC ACIDI The structural determination of aristolochic acid I (1) was first accomplished by Pailer et al. Aristolochic acid I(C,,H,,O,N) is easily soluble in alkali as well as sodium bicarbonate. It was esterified with diazomethane in dioxane to give a methyl ester (C,,H,,O,N), and the methyl ester was readily saponified to recover aristolochic acid I. Zinc distillation of 1gave a phenanthrene (Scheme 6). Aristolochic acid I was decarboxylated with copper powder in quinoline to yield a nitro phenanthrene derivative (O,,H, ,O,N,51). Aristolochic acid I showed only one methoxy group. Catalytic hydrogenation of 1or its methyl ester with PtO, or Pd-C in HOAc or reduction by zinc powder in acetic acid yielded a corresponding amino acid, which easily underwent ring closure to a lactam (C17H,,0,N,13). When distilled with 80% H,PO,, Aristolochic acid I underwent cleavage; formaldehyde was detected. The other functional group must be a methylenedioxy; therefore, the partial structure of aristolochic acid I is C,,H,(OCH,)(COOH)(NO,)(-O-CH,-O-)(72). The decarboxylated compound 51 was oxidized with H,O, to give a carboxylic acid (C,,H,,O,, 52). This nitrogen-free substance was treated with concentrated HC1 to form a lactone (CI3HSO4,53). It could be methylated to a dimethyl derivative and was further oxidized with KMnO, to a methoxy phthalic acid (54) (25). Pailer et al. synthesized the lactone 53 by the route of 1,5,6-trimethoxyphenanthrenequinone-(9,lO) (56):The 1,5,6-&imethoxyphenanthrenecarboxylic acid-(10) (55) was oxidized with Na,Cr,O, to 56 and then further oxidized with H,O, to give a dicarboxylic acid (57). Compound 57 was cleaved with HC1 and gave a lactone which was identical with the degradation product of natural aristolochic acid I. Therefore, Pailer and co-workers deduced the structure of aristolochic acid I as 1(25).Sasagawa reduced 51 with zinc powder and NH,OH to an amino compound (58) and then removed the amino group through the diazotization method to give a phenanthrene compound (60), which had previously been obtained from the Hofmann degradation of stephanine (41) ( 2 7 ) .

44


P

‘:

CH

13 59 R=Ac

c

41

61

SCHEME6

B . OTHERARISTOLOCHIC ACIDS The structure of aristolochic acid I1 (2) was determined by Pailer and Schleppnik in the same way as aristolochic acid I. Decarboxylation of aristolochic acid I1 gave a nitro compound (62). Oxidation of 62 and cleavage with HCl formed

45


Br

CH

v

COOH 65

66

67

68

64

62

SCHEME

L

7

3,4-benzo-8-hydroxycoumarin (63). Compound 62 was also reduced by catalytic (64) (Scheme 7) hydrogenation to 3,4-methylenedioxy-l0-aminophenanthrene (73). The Pailer-Schleppnik synthesis of 64 employed the condensation of 65 and o-nitrobenzaldehyde for the formation of the phenanthrene ring and then proceeded with Curtius rearrangement (74). After the elucidation of the structure of aristolochic acid I, several related compounds, such as aristolochic acids 111, IIIa, IV, and debilic acid, were determined in the same way by Pailer (26), Pailer and Bergthaller ( 7 3 , Tomita and Sasagawa (24), and Tseng and Ku (29,76,77).

C . MISCELLANEOUS REACTIONS Reduction of aristolochic acid I with NaBH, was investigated by It0 et al. They found that aristolochic acid I was reduced to 9,lO-dihydroaristolochicacid I (69) at room temperature (85% yield), and they also isolated a nitrogen-free product, aristolic acid (70)(Scheme 8) (5% yield). When this reaction takes place at 90-100°C for 3 hr, however, the main product obtained was aristolic acid. Decarboxylation of 9,lO-dihydroaristolochicacid I with copper powder in

46


Quinoline

69

(85%)

70

(75%)

1

12 hr

+@ *c

&

UOiHj

71

’

72

j.

0

W O W 73 (41%)

3 78

SCHEME 8

quinoline gave a mixture of 71 and 72, and 9,lO-dehydrogenation occurred simultaneously (78). In a program of search for the antifertility principle of aristolic acid, Mukhopadhyay et al. modified the NaBH, reduction procedure to get sufficient amounts for the purpose of biological testing. They reduced aristolochic acid I in 1% aq. NH,OH solution at 25°C for 4 hr and obtained a high yield of aristolic acid (90%) (79). Pakrashi et al. isolated 6-methoxyaristolic acid (78) from A . indica, and they prepared 78 by means of denitration of aristolochic acid IV (5) with NaBH, in the same manner (32). The structural determination of N-glycosides of Aristulochia alkaloids was also conducted. Some aristolactams and 4,5-dioxoaporphine alkaloids occur in nature as N-glycosides. For instance, aristolactam-P-D-glucoside (19) was exceedingly resistant to mineral acid hydrolysis, but reduction of 19 with LiAlH, in THF yielded 74, which was readily hydrolyzed to the aglycone 75 and glucose (Scheme 9). This property paralleled the behavior of an N-glycoside of a pyrimidine nucleoside. The aglycone 75 can be directly prepared by LiAlH, reduction of aristolactam (13) (37). The N-glucoside of 4,5-dioxoaporphine alkaloids can also be hydrolyzed by the same method (46).Achari et al. found that

47


SCHEME 9

such glycosides effected the hydrolysis in one step, by heating with 85% formic acid at 175°C for 2 hr, rather than by the two-stage process of LiAlH, reduction followed by mild acid treatment (80). Maldonado and co-workers isolated an aristolactam taliscanine (21) from A. tuliscunu. Methylation of taliscanine was carried out by treatment with dimethyl sulfate and K,CO, in acetone and yielded N-methyltaliscanine (76). Compound 76 was ozonized to give 77 and then further oxidized with CrO,-AcOH to give a carboxylic acid (79) (38).

CH ?O ' 3

:

:gi

c.Fi CH-0

R

\

iICH30 ' '

CHO

/

'

OCH3 21 R=H 76 R=CH

-.CH

OCH3

77

O

, '

F -CH

COOH OCH3

79

3

V. Chemical Synthesis A. SYNTHESIS OF ARISTOLOCHIC ACIDS AND ARISTOLOLACTAMS

1. Partial Synthesis 3,4,6,7-Tetramethoxy aristolochic acid (80) was obtained by nitration from the corresponding 3,4,6,7-tetramethoxy-phenanthrene-l-carbo~ylicacid (81), which was obtained from glaucine (82) via exhaustive Hofmann degradation (twice) followed by oxidation. Catalytic hydrogenation with Pd-C afforded the relevant aristolactam (83) (Scheme 10) (82). Kunitomo et al. reported that air oxidation of dehydroaporphines , including 2,lO-dimethoxydehydroaporphine(84a), dehydronuciferine (85a), and dehydronantenine (86a), with tert-BuOK in DMSO gave corresponding N-meth-

48


'

CH,N2

Nitratio: CH ?OJ

O2

I I

CH 3O

80

n

'2/

Pd

SCHEME 10

ylaristolactam-type substances. N-Methyl-3,4-methylenedioxy-7,8-dimethoxyaristolactam (87b) was also obtained by the same method from dehydrocrebanine (87a) (Scheme 11) (83,84). 3,4-Methylenedioxy-6-methoxyaristolactam(91) was prepared from the methyl ester of aristolochic acid IIIa (4) by Zn-AcOH reduction, and it was also obtained by treatment of the methyl ether of tuberosinone (33) with sodium hydroxide (46,85). Similarly, 3,4-methylenedioxy-6-methoxyaristolactam-N-~D-glucoside (92) can be obtained from tuberosinone-N-P-D-glucoside(86). 2. Total Synthesis Kupchan and Worrnser achieved the first total synthesis of aristolochic acid involving photocyclization of substituted 2-iodostilbenes. Piperonal (93) provided a suitable skeleton to build ling A of aristolochic acid (Scheme 12). Compound 93 was reduced to the piperonyl alcohol (94) with LiAlH,. Bromination of 94 afforded 6-bromopiperonyl bromide (95). The benzyl bromide 95 was then hydrogenated to the corresponding 2-bromo-4,5-methylenedioxytoluene (96), using the n-butyllithium carbonation method. The toluic acid 97 was prepared and converted to the acid chloride 98 by the action of oxalyl chloride, and bromination of 98 produced 99 by radiation with a 200-W tungsten lamp. Methanolysis of 99 afforded the crystalline ester 100. Treatment of 100 with silver nitrate produced methylester (101). Synthesis of ring C of aristolochic acid involved a sequence of 11 steps from 102 to 113 (Scheme 13). 2-Nitro-6-methoxytoluene (105) was oxidized to the nitroaldehyde 109 by the Kronhke reaction. Conversion of 109 to the oxime 110


49

SCHEME 11

and via Sandmeyer reaction to the iodaldehyde 112 was effected by the general method of Mayer. The condensation of 101 with the n-propylidene base 113 was effected in glacial acetic acid; 2-carbomethoxy-4,5-methylenedioxy-2'-iodomethoxy-a-nitro-cis-stilbene(114) was obtained. Photolysis of this stilbene afforded aristolochic acid I methyl ester (115) (86). Similarly, photolysis of 2-carbomethoxy-4,5-methylenedioxy-2'-iodo-a-nitro-cis-stilbene (117), which was prepared by condensationof 116 with 101, gave

50


CH2N02 I

J?

0I

CHrO

OocH3

101

SCHEME 12

aristolochic acid I1 methyl ester (118) (87,88). Aristolochic acids I and I1 were prepared by hydrolysis of their respective esters according to the method of Pailer and Schleppnik (73). Cohare and co-workers reported that aristolactam BII (22) was prepared, following Kupchen’s method, by Perkin condensation of 6-bromo-3,4-dimethoxy phenyl acetic acid (119) and o-nitrobenzaldehyde (120) (Scheme 14). The 2-bromo-4,5-dimethoxy-2’-nitro-cis-stilbene-ol-carboxylic acid (121) was obtained. The nitro group of 121 was reduced with ferrous sulfate and ammonium hydroxide, and the resulting 2-bromo-4,5-dimethoxy-2’-amino-cisstilbene-a-carboxylic acid (122) without purification was submitted to the Pschorr phenanthrene synthesis to yield 1-bromo-3,4-dimethoxyphenanthrene-10-carboxylic acid (123). The phenanthrylamine 124 was prepared from 123 via a Schmidt reaction, and, by treatment with n-butyllithium and CO,, 124, afforded 22 (42).

B.

SYNTHESIS OF

4,5-DIOXOAPORPHINES

1. Partial Synthesis The partial synthesis of 4,5-dioxoaporphine has been achieved. Preparation of (84d), 4 3 cepharadione B (43), 2,10-dimethoxy-4,5-dioxodehydroaporphine dioxodehydronantenine (86d), and 4,5-dioxodehydrocrebanine (87d) was achieved in DMSO by air oxidation of the corresponding dehydroaporphines with an alkali catalyst as described above (Section V,A,1). Oxidation of nan-

02 1

611

52


0

SCHEME15

tenine (125) or dehydronantenine (86a) with an excess of KMnO, in acetone afforded corydione (126) along with oxonantenine (127) and nandazurine (128) (Scheme 15) (21,92). Pontevedrine (46) and cepharadione B (43) were also obtained by photooxidation of corresponding dehydroaporphines (Scheme 16). Pontevedrine was obtained by irradiation of an ethanol solution of dehydropontevednne with a mercuCH 3O -CH3

CH 3O

R

hV

I

’*

V

130 131

O2

R1 =R 2=OCH3 R1=R2=H SCHEME16

53


0

-CH3

I;, o r

3

* DDQ

CH30

46

SCHEME 17

ry lamp under argon or nitrogen, while cepharadione B was prepared using a Hanovia 450-W lamp in a stream of oxygen (93,94).Castedo and co-workers reported that pontavedrine (46) was prepared from 4-hydroxyglaucine (catatine, 45) by oxidation with iodine or dichlorodicyanoquinone (DDQ) (Scheme 17)

(59).

2. Total Synthesis Castedo et al. reported the total synthesis of pontevedrine (46) (Scheme 18). The starting bromolactam 132, prepared by a known method ( 9 9 , was oxidized by oxygen in 0.1% methanolic sodium hydroxide to afford 1-(3’,4’-dimethoxy-6’-bromobenzyl)-1,6,7-trimethoxyisoquinoline-3 ,4-dione (133). Compound 133 was transformed to 1-(E,E)-3‘,4’-dimethoxy-6’-bromobenzylidene-6,7-dimethoxyisoquinoline-3,4-dione(134). Subsquently, UV irradiation of

1

-

CH 3O

CH 3O

0

c

OCH3

132

OCH3

Br 133

CH30

0

CH $

CHgO 46

135

SCHEME 18

134

54


134 in ethanolic alkali solution under an argon atmosphere afforded norpontevedrine (135) in 43% yield; thus, treatment of 135 with sodium hydride in dry DMF, to prevent the decarbonylation, followed by addition of methylfluosulfonate gave pontevedrine (46) in 76% yield. A “one-pot’’ conversion of 132 to norpontevedrine (135) was also carried out by irradiation of 132 in ethanolic alkali solution under an oxygen atmosphere in 33% yield. It may be stated that this method of synthesis of 4,5-dioxoaporphine seems to be of wide scope and therefore that different alkaloids of this type may be synthesized in a similar manner (96).

VI. Pharmacology and Clinical Use The genus Aristolochia comprises approximately 200 species, many of which have played important roles in folk medicine for treating sore throat, venomous snakebites, wounds, fevers, and tuberculosis. The chemistry and pharmacology of aristolochic acid, the main active principle, was researched by many scientists. Many worthy achievements in the pharmacology of aristolochic acid have been published. A. ANTITUMOR ACTIVITY Kupchan and Doskotsch (9) found that an alcoholic extract of A . indica possessed reproducible activity against the adenocarcinoma 755 test system. The active principle, aristolochic acid I, was isolated and characterized. Kamatsh and co-workers (97)reported that growth of mouse sarcoma-37 cells incubated with aristolochic acid at concentration of 100-200 pg/ml for 3 hr was completely inhibited. Treatment of mice with aristolochic acid (1.25-5 mg/kg ip per day) for 3 days after subcutaneous implantation of sarcoma-37 cells inhibited tumor growth in 40-50%. A dose of 2.5-5 mg/kg ip per day for 5 days remarkably prolonged survival. The cytotoxic effect on HeLa cells in culture was observed at a concentration of 25 pg/ml. Aristolochic acid I was used in clinical trials in cancer therapy; however, it was abandoned due to liver and kidney toxicity (98). It is interesting that the cytotoxicity of aristolochic acid, not only previously observed in animal cells, has also been confirmed for plant cells (99). Aristoloside (lo), isolated from A . manshuriensis, possessed antitumor activity (31). B . IMMUNOMODULATING ACTIVITY

Experiments performed in rabbits and guinea pigs showed marked stimulation of leukocyte phagocytosis following application of various dilutions of


55

Aristolochia extracts. Aristolochic acid I was characterized as the active principle. The acid was capable of offsetting chloramphenicol- and prednisone-impaired phagocytic activity. When phagocytosis was impaired by prednisone, the effect of the acid depended on the dose of prednisone: from 2.5 mglkg prednisone upwards its lesional activity could not be influenced, but for doses under 1 mg/kg values were clearly normalized by treatment with aristolochic acid I. Offsetting of damage by cyclophosphamide to phagocytosis was seen even after higher drug doses. As expected, the number of leukocytes was not influenced by aristolochic acid I. Further investigation of the effects of aristolochic acid I found that it has a protection activating effect on the phagocytosis of leukocytes. This effect was also noted in cold-blooded animals including carps, Aesculopius snake, and Elaphe Zongssima (100). Aristolochic acid I stimulated the reticuloendothelial system (REiS) and abolished the RES-depressing effect of chloramphenicol in mice and rats, using the carbon-clearance test. In mice infections with pneumococci were influenced very satisfactorily by aristolochic acid I. Rats with wounds infected with Staphylococcus aureus were treated intraperitoneally or orally with aristolochic acid I; compared to controls, the treated animals recovered much faster. Rabbits after intravenous application of aristolochic acid I showed an increased antibactericial action of serum (97). Mice infected with bacteria including Staphylococcus aureus, Diphococcus pneumoniae, and Streptococcus pyogenes could be protected by treatment with 50 Fg/kg ip of aristolochic acid I (97). Treatment with aristolochic acid I increased the oxygen consumption and thus the metabolic activity in mice liver cells and splenocytes (102). Aristolochic acid is not a new antibiotic. It acts not on the invading pathogens but on the naturally existing endogenous defense of the diseased organism, via vigorous stimulation of the phagocytic activity of host leukocytes (100).

C . ANTIFERTILITY ACTIVITY The roots of Aristolochia indica, commonly known as an “Indian birthwort,” are reputedly used in Indian folk medicine as an emmenagogue and as an abortifacient. Aristolochic acid and its methyl ester, sesquiterpene (12S)-7,12secoishwaran-12-01, isolated from this plant, possessed significant antifertility activity in mice (103-105). Recently, Wang and Zheng reported that aristolochic acid, isolated from A. mollissima, when given orally to mice at a dose of 3-4 mg/kg showed significant antiimplantation and early pregnancy-interruptingeffects; however, these effects were not observed in rats. This acid showed neither estrogenic nor antiestrogenic actions. Treatment with exogenous progesterone failed to prevent its pregnancyinterrupting action.

56


In addition, intraamniotic injection of aristolochic acid I in mid-term pregnant dogs and rats led to termination of pregnancy (106). Later, Che et al. reported that four Aristolochia alkaloids, aristolochic acid I and its methyl ester, aristolic acid, and (12S)-7,12-secoish-waran-12-01 were ineffective in antifertility tests, when administered to mice, hamsters, or rats (107). D. MISCELLANEOUS Aristolochic acid inactivated snake venoms including hose of Naja atra and Bungarus multicinctus but did not inactivate Trimeresurus muorosquamatus, Agkistroden acutus, or T . gramineus venoms (108). Moupinamide, a new alkaloid isolated from A. moupinensis, was found in vitro to inhibit rat platelet aggregation and MDA formation in platelets (109). Jaxena reported that aristolochic acid I was an insect chemosterilant (62).

E. CLINICALUSE Wu et al. reported the use of aristolochic acid I, containing a small amount of aristolochic acids I1 and IIIa, for treatment of 44 cases of tumors and 15 cases of leukemia. The cases received aristolochic acid at 0.9 mg per day PO for 4-6 months while maintaining routine chemotherapy and radiotherapy. The clinical results showed that the numbers of rosette-forming cells (RFC) of patients treated with aristolochic acid significantly increased compared with the control group (p < .01). WBC counts elevated significantly (p= .02).DNCB induced delayed hypersensitivity. Responses were positive in 78.6% of patients who were negative before aristolochic acid administration. It was concluded that aristolochic acid possessed stimulatory activity of both T lymphocytes and macrophages. Aristolochic acid produced regession of cancer in about 50% of cases (110). Wu and co-workers did not find any detectable renal toxicity during the period of treatment (110). Aristolochic acid was tested for therapy of tuberculosis, chronic bronchitis, bronchial asthma, pneumocardial diseases, etc. Clinical results showed curative effects, and the index of immune function of cases increased significantly compared to the control group (111).In Germany, an aristolochic acid preparation called Tardolyt that had been used as an antiinflammatorywas canceled due to its potential carcinogenicity (12).

F. TOXICITY Aristolochic acid has been tested in the clinical treatment of cancer; however, it was found to produce toxicity in kidney and liver (98). Peter reported that a single injection of aristolochic acid at 30 mg/kg in rats induced kidney failure

TABLE 11 Physical Data on Previously Reported Aristolochia Alkaloids Molecular formula

Molecular weight

Aristolochic acid I (1) (aristolochic acid A)

C17H1107N

Aristolochic acid Ia (50)

C16H907N

Compound

mp CC)

[alD (")

Plant source

341.053554

275-278 (DMFEtOH); 280 (EtOH) 283-285 (MeOHCHC13)

-

237.037904

278

-

A. acuminata (99),A. argentina (116,117), A. badamae (52),A. baetica (118), A. bumbusifolia (119), A. bracteata (29,47,76, 77,120), A. championii (113,115,121), A. chilensis (122),A. clematitis (26.28,52,61, 73,114,123-125,127,129), A. cucurbitoides (130),A. debilis (29,76,77,120), A. elegans (52,55),A. esperanzae (116), A. fangchi (22,24,131,139),A. jimbriata (52),A . grifithii (133),A. heterophylla (134,154), A. indica (9,32,34,37,44,135,136),A. kaempferi (120). A. kwangsiensis (81,128, 132,137,138), A. longa (33,44,67,124), longgangensis (140),A. manshuriensis (30), A. maurorum (100,141), A. muxima (124), A. mollissima (57,126,142,143),A . moupinensis (144),A. multiflora (115),A. ornithocephala (52),A. pallida ( I d ) , A. reticulata (44,133, A. rotunda (52,61,123), A. serpentaria (34,44,124), A. sipho (52,53,124,126),A. tagala (147),A. triangularis (148),A. tuberosa (85), A. westandii (149) A. argentina (65,122),A. chilensis (122)

(continued)

TABLE 11 (Continued)

Compound

ul 00

Molecular formula

Molecular weight

mp CC ')

Aristolochic acid II (2) (aristolochic acid B)

C16H906N

311.042987

267-271

Aristolochic acid I1 methyl ester Aristolochic acid IIIa (4) (aristolochic acid C)

C17H1106N

325.058639

277

C16H907N

327.037904

280

Aristolochic acid 111 (3) Aristolochic acid IVa (6) (aristolochic acid D)

C17H1107N

341.053554

C17HllOXN

357.048469

270-272 (methyl ester) 254-259

Aristolochic acid IV ( 5 )

IXH130XN

371.064119

328-340 (methyl ester)

C19H150xN

385.079770

240-241

CxXHl307N

355.069204

285-286

Aristolochic acid IV methyl ester Aristolochic acid I methyl ester

[WID

(")

Plant source

A. argentina (65,122),A. clematitis (73,125, 126,128), A. debilis (24,77,141), A. esperanzae (116),A. fangchi (24), A. longa (33,67),A. manshuriensis (70), A. moupinensis (144),A. rotunda (123),A. sipho (146) A. argentina (65),A. indica (32),A. pallida (16) A. bambusifolia (119),A. clematitis ( 7 9 , A. debilis (24,26-28,61), A. fangchi (24),A. longgangensis (140),A. rotunda (1231, A. tagala (147,151), A. tuberosa (M),A. watsonii (152) A. argenrina (116), A. clematitis (26), A. esperanzae (116), A. longa (33) A. acuminata (99),A. argentina (I16),A. clematitis (153), A. esperanzae (116),A. heterophylla (134),A. indica (32,37), A. manshuriensis (30),A. mollissimu (57,142), A. rnoupinensis (1441, A. multiflora (99) A. argentina (116), A. clematitis (26),A. esperanzae (116), A. longa (33),A. molIisima (57,126) A . kwangsiensis (81,139, A. moupinensis (144), A. championii (115) A. argentina (65),A. indica (127)

v,

a

7-Hydroxy-aristolochic acid I (7) 7-Methoxyaristolochic acid I (8) Debilic acid (9) 2-(Phenanthr0[3,4-d]- 1,3dioxole-6nitro-5-carboxamido)propionic acid methyl ester (12) Argentinine (32)

Aristoloside (10) Aristolamide (11) N-@-Hydroxyphenethy1)-pcuomaramide N-@-Hydroxyphenethy1)-ferulamide (moupinamide) Cepharanone A (aristolactam 11)

357.048469

282

-

A. debilis (28), tagala (147)

37 1.064119

284

-

A. debilis (28)

355.069204 396.095753

>300 -133 (CHC13)

-

A. debilis (76,155), A. manshuriensis (70) A. longa (33)

295.157229

-

A. argentina (44,116)

5 19.101294

176-177 (oxalate) 235-236 (picrate) 193- 196

-69.5 (MeOH)

A. manshuriensis (30)

271.084459 283.120844

293-294 235-239

-

-

A. indica (32) A. moupinensis (144)

313.131409

84-86

-

A. moupinensis (144)

263.058244

297-298

-

A. argentina (43)

279.053 159

>350

-

A. argentina (43)

(14)

Aristolactam Ia (17)

(continued)

TABLE I1 (Continued)

Compound

Molecular formula

Molecular weight

mp ("C)

Plant source

[alD (")

111

293.068809

297-304

-

A. argentina (43)

IIIa

279.053 159

>350

-

A. argentina (43)

AIIIa

281.068809

>350

-

A. argentina (43)

IV

323.079374

345

-

A. argentina (43), A. indica (37)

AIa

281.068809

>350

-

A. argentina (43)

Aristolactam A11 (24)

265.073894

27 1

-

A. argentina (43), A. indica (64), A. long-

Aristolactam BII (22) Aristolactam I (13)

279.089544

264-265

gangensis (140), A. mollissima ( 5 3 , A. tagala (151) A. argentina (42)

293.068809

315-3 17

A. argentina (43,116), A. debilis (24), A.

Aristolactam AIII (25) Aristolactam BIII (23) Aristolactam BI (taliscanine) (21) Aristored

295.084459

275

fangchi (24), A. indica (37), A. rotunda (123) A. argentina (42,43), A. mollissirnu (57)

309.100034

225

A. argentina (42.43)

309.100034

272-277

A. argentina (43),A. taliscana (38)

355.105589

286.5

A. bracteata (156), A. reticulata (44,135),A

Aristolactam (15) Aristolactam (18) Aristolactam (27) Aristolactam (16) Aristolactam (26)

C19H1 7°6N

serpentaria (44)

286 >320

-97.1

A. argentina (43), A. bambusifolia (119), A indica (80),A . tuberosa (89)

Aristolactam C N-p-D-glucoside (20)

441.105984

Aristolactam N - p D-glucoside (19) Tuberolactam (18) 4,5-Dioxodehydro-asimilobine (49) Tuberosinone (33)

455.121634

331-33

279.053159 293.068809

298-300 310-3 12

-

A. tuberosa (89)

-

A. indica (64)

307.048074

340

-

Tuberosinone N-P-D-glucoside (34) Magnoflorine (28)

469.100899

235-237

-

A. longgangensis (140), A. tagala (151), A tuberosa (85,89) A. tuberosa (85,89)

342.170534

248-249

(pentaacetate), (CHC13)

- 14 (NzO)

+200 (MeOH)

Asimilobine (29) Cyclanoline (30) Hydrastine (31)

(-)-(R,R)-7’-0Methylcuspidaline (35) 1-Curine

267.125927 341.162709 283.136889 624.319938

-

215-220 149 (picrate)

-

- 105

A. indica (32,37, 80),A. longgangensis (140)

A. argentina (42),A. baetica (118), A . bracteata (158), A. clematitis (159), A , debilis

(160,157), A. elegans (120), A . fangchi (24), A . heterophylla (134), A. indica (79), A. kaempferi (24,120),A. macedonica (145), A . moupinensis (144) A . kaempferi (150) A. debilis (157) A. serpentaria (44) A . elegans (50)

(CHC13)

594.257338

221

-337 (EtOH)

A . indica (48)

62


with a decrease in the glomerular filtration rate (GFR) and increased urea and creatinine concentrations in plasma; it caused impairment of urinary concentrating ability as well (112). It was also probable causative agent in Balkan endemic nephropathy (114).

VII. Summary of Physical Properties Table I1 summarizes physical data for Aristolochia alkaloids REFERENCES 1. Foon-Chew How, “A Dictionary of the Families and Genera of Chinese Seed Plants” 2nd ed. p. 43. Science Press, Beijing, China, 1985. 2. “Pharmacopeia of the Peoples Republic of China,” Vol 1, pp. 36, 38. Peoples Press, Beijing, China, 1985. 3. Shi-Zhen Li, “Ban Tso Gan Mo” (1595); 1977 ed., Peoples Health Press, Beijing, China, 1977. 4. K. Kimura and T. Kimura, “Medicinal Plants of Japan in Colour,” p. 63. Koikushe Publishing Co., 1981. 5. M. Pailer, Fortschr. Chern. Org. Naturst. 18, 66 (1960). 6. D. B. Mix, H. Guinaudeau, and M. Shamma, J . Nut. Prod. 45, 657 (1982). 7. L. S. Ding and F. C. Lou, Zhung Tsao Yuo 14, 40 (1983). 8. P. Homsberger, Schweiz. Apoth. Ztg. 109, 380 (1971). 9. S. M. Kupchan and R. W. Doskotsch, J . Med. Pharm. Chem. 5, 657 (1962). 10. Br. Pat. 895,037; CA 57, 2350f. 11. L. N. Filitis and P. S. Massagetov, Vopr. Onkof. 7, 97 (1961). 12. Anonymous, Pharm. Ztg. 126, 1373 (1981). 13. V. P. Arya, Drugs Future 4, 475 (1979). 14. Anonymous, Drugs Future 8, 640 (1983). 15. Z. L. Chen, B. S. Huang, D. Y. Zhu, M. L. Yin, Z. C. Chui, W. Z. Bao, C. Guei, and J. F. Zhou, Zhung Tsao Yao 9, 8 (1978). 16. B. Podolesov and Z. Zdrarkovski, Actu Pharm. Jugosl. 31, 249 (1981); CA 96, 82732j. 17. L. Gracza and P. Ruff, Dtsch. Apoth. Ztg. 121, 2817 (1981). 18. G. Kamphuis, P. Patt, and W. Winkler, Osterr. Apoth. Ztg. 24, 535 (1970); G. Kamphuis, P. Patt, and W. Winkler, Osterr. Apoth. Ztg. 24, (1970). 19. Ger. Pat. 1,768,090; CA 75, 80260~;Ger. Pat. 1,186,980; CA 63, 161388. 20. Ger. Pat. 2,646,545; CA 89, 117789t. 21. Rum. Pat. 55,389; CA 81, 111458~. 22. Jpn. Pat. 7,127,834; CA 75, 343989~. 23. H. Rosenmund and T. Reichstein, Pharm. Actu Helv. 28, 243 (1943). 24. M. Tomita and S. Sasagawa, J . Pharm. SOC.Jpn. 79,974 (1959);M. Tomita and S. Sasagawa, J . Pharm. SOC. Jpn. 79, 1470 (1959). 25. M. Pailer, L. Belohlav, and E. Simonitsch, Monatsch. Chem. 87, 249 (1956). 26. M. Pailer, P. Bergthaller, and G. Schaden, Monatsch. Chem. 96, 863 (1965). 27. S. Sasagawa, J . Pharm. SOC. Jpn. 82, 921 (1962). 28. Z. L. Chen, B. S. Huang, D. Y. Zhu, and M. L. Yin, Acta Chem. Sinica 39, 237 (1981). 29. Y. T. Ku and K. F. Tseng, Kexue Tongbao, 568 (1957); Y. T. Ku and K. F. Tseng, Kexue Tongbuo, 761 (1957). 30. T. Nakanishi, K. Iwasaki, M. Nasu, I. Miura, and K. Yoneda, Phytochemistry 21, 1759 (1982).


31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41.

63

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74. M. Pailer and A. Schleppnik, Monutsch. Chem. 89, 175 (1958). 75. M. Pailer and B. Bergthaller, Monutsch. Chem. 97, 484 (1966). 76. K. F. Tseng and Y. T. Ku, Actu Pharm. Sinicu 6,174 (1958); K. F. Tseng and Y.T. Ku, Actu Phurm. Sinica 6 , 316 (1958). 77. K. F. Tseng and Y. T. Ku, Acta Chem. Sinicu 23, 156 (1957). 78. K. Ito, H. Farukawa, and M. Haruna, J . Pharm. SOC. Jpn. 92, 92 (1972). 79. S. Mukhopadhyay, S. Funayama, G. A. Cordell, and H. S. H. Fong, J . Nut. Prod. 46, 507 (1983). 80. B. Achari, S. Chakrabarty, and S. C. Pakrashi, Phytochemistry 20, 1444 (1981). 81. F. X. Zhou, P. Y. Liang, S. C. Chu, and C . Wen, Chin. Pharm. Bull. 16, 56 (1981). 82. P. Gorecki and H. Otta, Phurmazie 30, 337 (1975). 83. J. Kunitomo, Y. Murakami, and M. Akasu, J . Phurm. SOC.Jpn. 100, 33 (1980). 84. J. Kunitomo, Y. Murakami, M. Oshikata, T. Shingu, M. Akasu, S. T. Lu, and I. S. Chen, Phytochemistry 19, 2735 (1980). 85. D. Y . Zhu, B. D. Wang, B. S. Huang, R. S. Xu, Y. P. Qiu, X. Z. Chen, and D. J. Quan, Actu Chem. Sinica 41, 74 (1983). 86. S. M. Kupchan and H. C. Wormser, J . Org. Chem. 30, 3792 (1965). 87. S. M. Kupchan and H. C. Wormser, J . Org. Chem. 30, 3933 (1965). 88. S. M. Kupchan and H.C. Wormser, J . Org. Chem. 30, 3935 (1965). 89. D. Y. Zhu, F. X. Jiang, R. S. Xu, Y . P. Qiu, and X. Z. Chen, Zhung Tsuo Yuo 12,529 (1981). 90. H. C. Wormser, Diss. Abttr. 26, 2640 (1966). 91. I. I. Kunitomo, Y. Murakami, and M. A. Akasu, J . Pharm. SOC. Jpn. 100, 337 (1980). 92. H. G. Kiryakov, E. Iskrenova, B. Kuzmanov, and L. Evstatieve, Pluntu Med. 43, 51 (1981). 93. V. B. Chervenkova, N. M. Mollov, and S. Paszye, Phytochemistry 20, 2285 (1981). 94. 3. M. Saa, M. J. Mitchell, and M. P. Cava, Tetrahedron Lett., 601 (1976). 95. T. Kametani, S. Shibuya, H. Sugi, 0. Kusama, and K. Fukumoto, J . Chem. SOC. (C), 2446 (1971). 96. L. Castedo, R. J. Estevez, J. M. Saa, and R. Suan, J . Heterocycl. Chem. 19, 1319 (1983). 97. N. Kamatsh, H. Nawata, K. Tadashi, J. Shoji, and A. Tada, Showu Igukkui Zusshi 33, 776 (1973); CA 82, 68199~. 98. L. Jackson, Cancer Chemother. Rep. 42, 35 (1964). 99. C. Moretti, M. Rideau, J. C. Chenieux, and C. Viel, Pluntu Med. 35, 360 (1979). 100. J. R. Mose, Arzneim. Forsch. 16, 118 (1966). 101. A. K e y , A. A. Askari, and K. A. Sharefi, Znt. J . Crude Drug Res. 21, 141 (1983). 102. J. R. Mose and J. Porta, Arzneim. Forsch. 24, 52 (1974). 103. A. Pakrashi and B. Chakrabarty, Experientia 34, 1377 (1978). 104. A. Pakrashi and C. Shaha, Experientiu 34, 1192 (1978). 105. A. Pakrashi and C. Shaha, Experientiu 33, 1498 (1977). 106. H. W. Wang and J. H. Zheng, Actu Phurm. Sinicu 19, 405 (1984). 107. C. T. Che, M. S. Ahmed, S. S. Kang, D. P. Waller, A. S. Bingel, A. Martin, P.

108. 109. 110. 111. 112. 113. 114. 115.

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-CHAPTER3 -

CHROMONE ALKALOIDS PETERJ. HOUGHTON Chelsea Department of Pharmacy Kings College London (KQC) London SW3 6LX, England I. Introduction 11. Botanical Distribution A. Flavonoid Alkaloids B. Noreugenin-Related Alkaloids 111. The Flavonoidal Alkaloids A. Isolation B . Structural Elucidation C. Spectral Characteristics D. Synthesis and Derivatives E. Pharmacology IV. Noreugenin-Related Alkaloids A. Isolation B. Structural Elucidation C. Spectral Characteristics D. Synthesis and Derivatives E. Pharmacology References

I. Introduction The term “chromone alkaloid” is used to describe a structure consisting of a pyridine, piperidine, or pyrrolidine ring linked to the A ring of chromone (1). In

1 Chromone nucleus

all the compounds so far isolated the chromone nucleus exists either as rings A and C of a flavonoid (2) or as noreugenin (3). It is reasonable to classify these 67

THE ALKALOIDS, VOL. 31 Copyright 0 1987 by Academic Press, Inc. All rights of reproduction in any fom reserved.

68

PETER J. HOUGHTON

3'

2 Flavonoid nucleus

3 Noreugenin

two types together since the ring A in both types is generally considered to have a common biogenetic origin, being formed from acetate units (I, 2 ) . The structures used for the alkaloids in this chapter are numbered conventionally for the flavonoid or noreugenin moiety. The carbon atoms of the nitrogen-containing ring are numbered separately l ' , 2', etc. These alkaloids are of interest due to their amphoteric nature, being both bases and phenols, and also because of the reputed biological activity of some of the plants which contain them.

11. Botanical Distribution A. FLAVONOID ALKALOIDS

The first flavonoidal alkaloids to be isolated were ficine (4) and isoficine ( 5 ) in 1965 from Ficus pantoniana King. (Moraceae) ( 3 ) . These alkaloids have not

4 Ficine

5 Isoficine

been reported from any other source, nor have any similar alkaloids been reported from the Moraceae. In 1980 phyllospadine (6), another pyrrolidine flavonoid, was isolated from the leaves of a monocotyledon, Phyllospadix iwatensis Makino (Zosteraceae) ( 4 ) , an aquatic species growing in waters off Japan. The next reported isolation of a flavonoidal alkaloid was that of vochysine (7)

69

3. CHROMONE ALKALOIDS

bH 6 Phyllospadine

7 Vochysine

from the fruits of Vochysiu guiunensis (Aubl.) Poir (Vochysiaceae) from French Guyane (5). Most recently a series of piperidinyl-flavonoid alkaloids have been isolated from two Buchenuviu spp. (Combretaceae) (6).The leaves of B . mucrophyllu Eichl. yielded buchenavianine (8) and N-demethylbuchenavianine (9). The fruits

8 (R = CH3) Buchenavianine 9 (R = H) N-Demethylbuchenavianine

of the same species were also found to contain 8 as well as four other alkaloids, namely 0-demethylbuchenavianine (lo), 0,N-bisdemethylbuchenavianine(ll),

10 (R = CH3) 0-Demethylbuchenavianine 11 (R = H) 0,N-Bisdemethylbuchenavianine

N-demethylcapitavine (12), and 5,7-dihydroxy-6-(N-methy1-2”-piperidinyl)flavanone (13). The seeds of B . cupitutu Eichl. were found to contain three other such alkaloids. These were named capitavine (14), 5,7,4’-trihydroxy-6-(N-meth-

70

PETER J. HOUGHTON

12 (R = H) N-Demethylcapitavine 14 (R = CH3) Capitavine

13 (R = H) 5,7-Dihydroxy-6-(N-methyl-2”-piperidinyl)flavanone 16 (R = OH) 5,7,4’-Trihydroxy-6-(N-methyl-2”-piperidinyl)flav~one

15 5,7,4’-Trihydroxy-6-(~-methyl-2”-piperidinyl)flavone

yl-2”-piperidinyl)flavone(15) and 5,7,4‘-trihydroxy-6-(N-methyl-2”-piperidiny1)flavanone (16). The flavonoidal alkaloids have thus been found widely scattered throughout the higher plants. In view of the ubiquitous occurrence of flavonoids and the simplicity of the nitrogenous component in the compounds so far isolated, it is quite possible that they may occur in more species. The occurrence of the flavonoid alkaloids in Buchenavia but not TerminaEia has been used to confirm the taxonomic distinction between these genera (6).

B . NOREUGENIN-RELATED ALKALOIDS To date the noreugenin-related alkaloids have been isolated from only two families, Meliaceae and Rubiaceae. Rohitukine (17) was the first of this type of


71

OH 0 17 Rohitukine

alkaloid to be isolated. It was extracted from the leaves and stem of Amoora rohituku (Meliaceae) Wight and Am. in 1979 (7). An alkaloid with identical characteristics has been found in another meliaceous species, Dysoxylum binectariferum Hook. (8).Two other alkaloids were isolated from A. rohituku (7), but the elucidation of their structures has not been reported. Rohitukine (17) has also been isolated from Schumunniophyzon mugnificum Harms. (Rubiaceae) (13).This genus occupies a section of the Rubiaceae which has been somewhat neglected phytochemically. Recent work on Schumanniophyton has resulted in the extraction of several noreugenin alkaloids. The first of these were reported in 1978 from the root bark of S. problematicum (A. Chev.) Aubrev. from the Ivory Coast (9). Schumanniophytine (M), a nicotinic

0

18 Schumanniophytine

acid-noreugenin congener, and two unnamed noreugenin-piperidine-2-one derivatives (19 and 20) were the compounds found.

19 (R = H), 20 (R = CH3) Unnamed compounds isolated by Schlittler and Spitaler

72

PETER J. HOUGHTON

Subsequent phytochemical interest has focussed on S. magnificum Harms. The stem juice of this species is used in Nigeria for the treatment of snakebite (11). However, most of the work performed has dealt with the rootbark since this contains the highest proportion of alkaloids. The noreugenin-piperidine compounds schumannificine and N-methylschumannificine, first isolated by Okogun et al. (10) and subsequently by Houghton and Yang ( ] I ) , were given structures 21 and 22, respectively. The latter workers also isolated four other alkaloids.

R’

22 (R

WCH

N

21 (R = H) Schurnannificine(original structure) = CH3) N-Methylschumannificine(original structure)

Two of these, anhydroschumannificine and N-methylanhydroschumannificine, were analogs of 21 and 22 and assigned structures 23 and 24. Recently the

0

OH

0

23 (R = H) Anhydroschumannificine(original structure) 24 (R = CH3) N-Methylanhydroschurnannificine (original structure)

structures of these four alkaloids have been revised to give schumannificine (25), N-methylschumannificine (26), anhydroschumannificine (27), and N-methylanhydroschumannificine (28) (12).

25 (R = H) Schumannificine (revised structure) 26 (R = CH3) N-Methylschurnannificine (revised structure)


13

27 (R = H) Anhydroschumannificine (revised structure) 28 (R = CH3) N-Methylanhydroschumannificine(revised structure)

The other two alkaloids isolated by Houghton and Yang were very similar to schumanniophytine (18). They were originally thought to be two new compounds and were assigned structures 29 and 30 (11). Recent work has shown that

29 Isoschumanniophytine

0

30 Schumanniophytine isomer

in fact one of them is identical to 18, and the other has the structure 29 and was named isoschumanniophytine (12). Later work by Houghton and Yang (13) on the water-soluble fraction of the root bark has resulted in the isolation of the Nmethyl derivatives of 18 and 29, the quaternary alkaloids 31 and 32. Two other alkaloids isolated were named schumaginine and N-methylschumagnine and given structures 33 and 34, respectively (13).The betaine, trigonelline (35), was also isolated from the aqueous portion of the root extract and found to occur in large amounts in the stem and leaves. Although not a chromone alkaloid it is not

14

PETER 3. HOUGHTON

31 N-Methylschumanniophytine

32 N-Methylisoschumanniophytine

R I

lN\

33 (R = H) Schumaginine 34 (R = CH3) N-Methylschumagnine

35 Trigonelline

difficult to envisage its relationship to 31 and 32. Another quaternary alkaloid, schumanniofoside (36), which is also a glycoside, has recently been isolated from S. magnificum (14). No data or chemical confirmation of the structure assigned have yet been published. Although Schumanniophyton is the only genus of the Rubiaceae in which this type of alkaloid has been found it should be noted that related genera have shown


75

HO

OH

HO 36 Schumanniofoside

the presence of alkaloids in screening procedures (Z5,Ze.All such genera await the isolation and structural elucidation of the alkaloids present, however, and it might well be that new compounds will be found. The same consideration applies to the Meliaceae.

111. The Flavonoidal Alkaloids A. ISOLATION Details of the extraction methods for ficine (4) and isoficine (5) were not given. Phyllospadine (6) was isolated from the flavonoid-containing n-butanolsoluble extract from dried plant material (4). The alkaloids from Vochysia and Buchenavia were isolated by conventional procedures, utilizing acid-base extraction and subsequent column or thin-layer chromatography using silica gel or alumina (5,6).

B . STRUCTURALELUCIDATION 1. Ficine (4) and Isoficine (5) (3)

The flavonoidal moiety of ficine was deduced from its UV spectrum, which was very similar to chrysin (37),and the bathochromic shift indicated a saturated alkyl substituent on ring A. Treatment with Gibb’s reagent to detect the presence of a proton para to a phenolic OH ( 1 7 ) gave a positive result for 5 but not 4. Although no molecular ion could be seen in the mass spectrum, the peaks obtained were equivalent to the sum of the individual spectra of chrysin (37)and

76

PETER J. HOUGHTON

37 Chrysin

N-methylpyrrole. It was assumed that pyrolysis occurred at the inlet temperature and that ficine and isoficine consisted of chrysin substituted with N-methylpyrrole at positions 8 and 6, respectively. The presence of chrysin as part of the molecule was confirmed by its formation from 4 by alkaline hydrolysis. The IH-NMR spectra confirmed these structures; they showed characteristic signals for the flavone part of the molecule such as an aromatic H singlet at 6 6.25 in 4 and 6 6.33 in 5. This indicated that the aromatic ring A was pentasubstituted. The more downfield shift of this signal in 5 is consistent with the structures assigned, as it is established that 5,7-dialkyloxyflavones give a signal for H-8 more downfield than that given by H-6. The 'H-NMR spectrum also showed that the N-methylpyrrole was linked to the flavonoid through C-2". The 2"-H gave a 1H triplet at 6 4.15 coupled with a 2H multiplet at 6 2.08 given by the 3"-CH,.

2. Phyllospadine (6) (4) Phyllospadine was characterized as its triacetate. Its alkaloidal nature was detected by a positive Dragendorff's reaction and its flavonoidal nature by its UV spectrum and the co-occurrence of the parent flavonoid hispidulin (38). The 'HNMR spectrum showed signals identical to those of 38 apart from the lack of the signal at 6 7.22 attributed to 8-H. The attachment of the nitrogenous ring was therefore reckoned to be at this position. The characterization of the ring as N-

38 Hispidulin

methylpyrrole was made from the mlz peak of 84 in the mass spectrum and the similarity of the signals for this ring to those given by ficine (4) and isoficine (5) (3).


77

3. Vochysine (7) (5) The phenolic nature of vochysine was deduced from the bathochromic shift in the presence of alkali observed in the UV spectrum. The UV spectrum showing peaks at 215 and 275 nm together with peaks at mlz 272, 153, and 120 in the mass spectrum indicated the presence of a 4’-OH flavan. The peak at mlz 69 was indicative of pyrrolidine substituent. The ‘H-NMR spectrum features confirmed the proposed C ring structure as it showed a 4H aromatic AB system. An isolated aromatic proton signal at S 5.93 indicated a pentasubstituted A ring. The 3H singlet at S 3.65 showed that one of these was a methoxy substituent. The other two were thought to consist of OH and the pyrrolidine ring. The actual positions of substitution were determined by comparison with various derivatives and analogs. Ethanolic degradation produced a compound whose lH-NMR spectrum showed no signals corresponding to the pyrrole ring but an extra aromatic H signal meta coupled to the existing aromatic H. Dimethyl sulfate methylation of this product resulted in the formation of a substance identical to 5,7,4’-trimethoxyflavan. Thus the substitution of the pyrrole ring at C-8 was confirmed. The question as to whether the methoxy group in the original compound was at C-5 or C-7 was resolved by the formation of 7,4’-dihydroxy-5-methoxyflavan and the 7-methoxy isomer from naringenin (39). The vochysine degradation product was identical to the 7-methoxy isomer.

39 Naringenin

The attachment of the pyrrole ring at C-8 was confirmed by noting that the shift of the aromatic H in the ‘H-NMR spectrum moved from 6 5.93 to 6.38 in the acetylated product. This showed that the free proton is ortho to the phenolic OH at C-5 and that the pyrrole must therefore be at C-8. Further proof of the structure of vochysine was obtained when it was synthesized from 5,4’-dihydroxy-7-methoxyflavan and an alcoholic solution of pyrroline. 4. Buchenuviu Alkaloids (6) The flavonoidal moiety in Buchenavia alkaloids was deduced from their UV spectra. The more detailed structure determination for individual alkaloids is outlined below.

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PETER J. HOUGHTON

a. Buchenavianine (8). The mass spectrum of 8 gave a molecular ion at mlz 365 and a large peak at mlz 98 corresponding to N-methylpiperidine. The

'H-NMR spectrum showed a 5H aromatic multiplet due to the unsubstituted B ring and two other isolated aromatic protons at 6 6.70 and 6.40. 3H singlets at 6 4.00 and 2.33 were assigned to aromatic OMe and NMe, respectively. Consideration of the 13C-NMR spectrum established that buchenavianine was either 5or 7-methoxychrysin substituted with N-methylpiperidine at either 6 or 8. A negative Gibb's test indicated that the piperidine ring was probably substituted at C-8. NOE difference spectra with irradiation at the aromatic methoxy frequency showed that the 6-H signal at 6 6.40 was enhanced, but no such event occurred in any of the signals of the piperidine moiety. THe OMe group was therefore deduced as being at C-5. The 13C-NMR spectrum showed that C-4 gave a signal at 178.3. If C-5 were OH substituted the C-4 signal would be seen at 184 due to the influence of hydrogen bonding. Thus the OH must be at C-7.

b. N-Demethylbuchenavianine (9). The spectra of N-demethylbuchenavianine (9) showed many features similar to those of 8. However, the molecular ion was less by 14, and there was an absence of the NMe peak from the 'H-NMR spectrum. c. O-Demethylbuchenavianine (10). The spectral data of O-demethylbuchenavianine (10) also agreed very closely with that given by 8. Differences were seen in that the molecular ion was less by 14 mass units and no OMe peak was observed in the 'H-NMR spectrum. d. Capitavine (14). Capitavine (14) gave the same molecular ion peak as 10 and was similar in many ways in the features observed in the various spectra. The flavonoidal carbon atoms gave 13C-NMR signals identical to those given by apigenin (40). In distinction to 8, 9, and 10, however, it gave a positive Gibb's reaction, indicating that the piperidine ring was attached at C-6 rather than C-8.

e. 0,N-Bisdemethylbuchenavianine (11). The UV spectrum of 11 indicated the presence of a flavone nucleus, and other spectral characteristics were similar to those of 10 and 14. However, the molecular ion was only mlz 337, 28 less than 8. The 'H-NMR spectrum showed no signals corresponding to Nmethyl or methoxy groups. Compound 11 gave a negative Gibb's reaction and so was reckoned to be substituted at C-8 with the N-methylpiperidine ring.

40 Apigenin


79

f. N-Demethylcapitavine (12). N-Demethylcapitavine (12)had the same molecular weight as 11 and gave spectra very similar in all respects. Since it gave a positive Gibb's test it was reckoned to be the C-6 substituted isomer of 11. g. 5,7-Dihydroxy-6-(N-methyl-2"-piperidinyl)flavanone (13). The molecular ion given by 13 was mlz 353, 2 more than given by buchenavianine (8). The mass spectrum showed the presence of N-methylpiperidine as a large peak at mlz 98. Some features of the 'H-NMR spectrum were similar but an important difference was the absence of the C-3 H signal at 6 6.70 seen for 8. However, the two coupled signals at 6 5.38 and 2.90 were typical of the 2-CH-3-CH2 system seen in flavanones. The 13C-NMR spectrum confirmed this assignment, showing signals for the two relevant C atoms at 6 79.5 and 43.0, respectively. Since the Gibb's reaction and other spectral features were very similar to capitavine, 13 was proposed as the structure.

h. 5,7,4'-Trihydroxy-6-(~-methyl-2"-piperidinyl)flavone (15). TLC behavior showed that compound 15 was more polar than most of the other Buchenavia alkaloids. The molecular ion was 16 greater than buchenavianine (8) and capitavine (14).The 'H-NMR spectrum showed many similarities to those of 8 and 14,but a major difference was the 4H AB aromatic system at 6 7.78 and 6.95 instead of a 5H multiplet. This was taken to indicate that ring B was substituted at 4'. The substituent was identified as OH by comparison of the 13CNMR spectrum of 15 with that of apigenin (40). A positive Gibb's reaction showed that 15 was the 4'-OH derivative of capitavine (14). i. 5,7,4'-Trihydroxy-6-(N-methyl-2''-piperidinyI)flavanone (16). The molecular ion for 16 of 369 was 2 mass units higher than that for 15. Both the 'H- and I3C-NMR spectra showed signals similar to those given by 13, indicating a flavanone nucleus. The 4'-OH substituent on the B ring was shown by a pair of doublets similar to those seen for 15.Compound 16 was therefore considered to be the 4'-OH derivative of 13.

C. SPECTRAL CHARACTERISTICS 1. Ultraviolet Spectra The UV spectra of all flavonoidal alkaloids is related entirely to the flavonoid part of the molecule. Table I lists the data reported for each alkaloid. Flavones exhibit maxima in the region of 270-325 nm whereas the flavanones show maxima at about 250-320 nm. The flavan vochysine shows an absorbtion only at 275 nm since there is no conjugation system in ring C.

80

PETER J . HOUGHTON TABLE I Ultraviolet Spectra of Flavonoid Alkaloids Compound

Ficine (4) Isoficine (5) Phyllospadine (6) (acetate) Vochysine (7) Buchenavianine (8)

N-Demethylbuchenavianine (9) 0-Demethylbuchenavianine (10) Capitavine (14)

0,N-Bisdemethylbuchenavianine (11) N-Demethylcapitavine (12)

5,7-Dihydroxy-6-(Nmethyl-2-"piperidiny1)flavanone (13) 5,7,4'-Trihydroxy6-(N-methyl-2"piperidiny1)flavone

Solvent

Maxima, nm (log E)

Ethanol NaOH aq. Ethanol NaOH aq. Methanol

275 (4.5), 329 (4.0) 282, 349 275 (4.5) 262, 280 264, 302

Ethanol Ethanol + NaOH Ethanol Ethanol + NaOH Ethanol + HCI Ethanol Ethanol + NaOH Ethanol + HC1 Ethanol Ethanol + NaOH Ethanol HCI Ethanol Ethanol NaOH Ethanol + HCl Ethanol Ethanol + NaOH Ethanol HC1 Ethanol Ethanol NaOH Ethanol + HCI Ethanol Ethanol + NaOH Ethanol + HCl Ethanol Ethanol NaOH Ethanol + HC1

215 (4.15), 275 (3.34) 228 (4.46), 245 (4.42), 288 (3.57) 216, 263, 326 217, 241, 250, 339 216, 263, 311 217, 240, 272, 344 220, 236sh, 280, 346 217, 263. 302 215, 275, 347 217, 265, 284, 347 215, 270, 338 218, 277, 341 218, 246, 275, 374 215, 269, 316 216, 242sh, 266sh, 279, 324 244sh, 267sh, 283, 390 216, 246sh, 270, 313 214, 241, 276, 352 216, 236sh, 264, 272sh, 240 212, 249, 267, 302 217, 251sh, 323 217, 296, 337 217, 227, 289, 330 220, 278, 311, 346 220, 279, 333, 400 216, 270, 345

Ethanol Ethanol + NaOH Ethanol + HC1

220, 326 220, 249, 332 225, 228, 326

+ +

+ +

+

Ref.

3 17 17 17 4

5

6

6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6

(15)

5,7,4'-Trihydroxy6-(N-methyl-2"piperi-diny I) flavanone (16)

6 6 6

2. Infrared Spectra Table I1 lists the IR characteristics of the alkaloids. The IR spectra are of little use in structural identification apart from noting the absence of a carbonyl peak in the flavans and the bands for phenolic and aromatic bonds in the 3200 and 1590 cm- regions, respectively.

81


TABLE I1 Infrared Spectra of Flavonoid Alkaloids Important peaks (cm-1)

Ref.

Compound

Medium

Vochysine (7) Buchenavianine (8) N-Demethylbuchenavianine (9) 0-Demethylbuchenavianine (10) Capitavine (14) 0,N-Bisdemethylbuchenavianine (11) N-Demethylcapitvaine (12)

KBr Chloroform KBr KBr

3300, 3440, 3400, 3440,

1595, 755 1700, 1600 1655, 1595 1660, 1612, 1595

5

Chloroform KBr

1630, 1600, 1590 3420, 1675, 1620, 1605, 1590

6

Chloroform

3400, 1650, 1630, 1590 1700, 1640

6 6

3400, 1635, 1570

6

1630

6

5,7-Dihydroxy-6-(N-methyl-2”- Chloroform piperidiny1)flavanone (13) 5,7,4’-Trihydroxy-6-(N-methKBr yl-2”-piperidinyl)flavone(15) 5,7,4‘-Trihydroxy-6-(N-methyl-T’-piperidiny1) flavanone

KBr

6 6 6

6

(16)

3. Mass Spectra In the mass spectra of some of the first compounds to be isolated, i.e., ficine (4), isoficine (3,and vochysine (7), the molecular ion peak was not seen, but significant peaks corresponding to the flavonoid and nitrogenous ring parts of the molecule were seen, The mlz value for these enabled both the substitution on the flavonoid and the size of the N-containing ring to be deduced. Thus a pyrrolidine ring gives an ion mlz 69, e.g., vochysine (7),an N-methylpyrrolidine mlz 84, e.g., fincine (4), and an N-methylpiperidine mlz 98, e.g., buchenavianine (8). Later work on ficine by Leete (17), however, showed that it was possible to obtain a molecular ion if the inlet temperature was reduced to 200°C from the 290°C initially used. The molecular ions of some of the alkaloids isolated more recently have been obtained and have been useful indicators of the substituents present on a common nucleus, particularly for the Buchenuviu alkaloids (6). All spectra so far reported have been obtained using electron impact fragmentation. Table I11 lists the fragmentation patterns reported. Thus far no studies have been made on the breakdown mechanisms, but the cleavage of the flavonoid and nitrogenous rings is obviously an important process. 4. ‘H-NMR Spectra As is the case with many natural products isolated in the last 25 years, ‘HNMR spectroscopy has played a major role in the structural elucidation of the

82

PETER J . HOUGHTON

TAELE 111 Mass Spectra of Flavonoidal Alkaloids Compound Ficine (4) Isoficine (5) Phyllospadine (6), triacetate Vochysine (7) Buchenavianine (8) N-Demethylbuchenavianine (9) 0-Demethylbuchenavianine (10)

Capitavine (14) 0,N-Bisdemethylcapitavine (11) N-Demethylcapitavine (12)

5,7-Dihydroxy-6-(N-methyl-2"-

Major peaks m/z (relative intensity) 338 (29), 337 (100, M + ) , 336 (29), 322 (lo), 294 (48), 280 (39), 84 (92) 337 (51, M + ) , 322 (loo), 280 (31), 294 (12), 254 (17), 84 (11) 509.1695 (M') 272 (91), 153 (loo), 120 (46), 69 (42) 365 (loo), 350 (14), 281 (27), 267 (35), 98 (68) 351 (86), 322 (loo), 294 (21), 91 (36), 83 (50), 57 (93) 351 (loo), 336 ( l l ) , 322 (ll), 308 (24), 294 (29), 280 (45), 98 (84) 351 (46), 336 (loo), 268 (27), 98 (20), 91 (100) 337 (87), 308 (loo), 295 (28), 281 (48), 267 (22), 98 (19) 337 (90), 320 (35), 309 (48), 308 (loo), 281 (58), 254 (97), 98 (20) 353 (loo), 311 (18), 296 (19), 98 (82)

piperidiny1)flavanone (13) 5,7,4'-Trihydroxy-6-(N-methyl-2"- 367 (48), 352 (loo), 283 (30), 98 (16) piperidiny1)flavone (15) 369 (loo), 354 (78), 234 (36), 98 (78) 5,7,4'-Trihydroxy-6-(N-methyl-2"piperidiny1)flavanone (16)

Ref. 17 17 4 5

6 6

6

6 6 6 6 6 6

flavonoid alkaloids. The presence or absence of signals and couplings for the aromatic protons yield information on the substitution pattern of the aromatic parts of the molecules. The characteristic peaks for 0- and N-methylation are also important. Table IV records the 'H-NMR data reported for the alkaloids, and significant features are described above (Section IILB).

5. 13C-NMR Spectra

13C-NMR spectral data have been recorded for vochysine (7) (5) and the Buchenavia alkaloids (8-16) (6) (Table V). In both cases comparison of the spectra with those of the parent flavonoid enabled the identity of this part of the molecule to be established. The chemical shifts of the A ring carbon atoms in some of the Buchenavia alkaloids have also been used to determine the point of substitution of the piperidine ring as described above, e.g., for buchenavianine

(8).

83


TABLE IV 1H-NMR Spectra of Flavonoidal Alkaloids Compound Ficine (4) (CDCL,)

Isoficine (5) (CDC13)

Phyllospadine (6), triacetate (CDCL3)

Vochysine (7) (CDC13)

Buchenavianine (8) (CDCI,)

N-Demethylbuchenavianine (9)

O-Demethylbuchenaviaine (10) Capitavine (14)

0,N-Bisdemethylbuchenavianine (11) (CF3COOD) N-Demethylcapitavine (12)

5,7-Dihydroxy-6-(N-methyl-2"piperidiny1)flavanone (13) 5,7,4'-Trihydroxy-6-(N-methyl-2"piperidinyl)flavone(15) 5,7,4'-Trihydroxy-6-(N-methyl-2"piperidiny1)flavanone (16)

Signals observed (6, ppm, from TMS) in CDC13

Ref.

12.6 1H bs (5-OH), 12.0 1H bs (7-OH), 8.07.3 5H m (ring B Hs), 6.60 1H s (3-H), 6.25 1H s (6-H), 4.15-1.99 6H m (N-ring Hs), 2.43 3H s (N-CH3) 13.0 1H bs (5-OH), 11.0 1H bs (7-OH), 8.07.3 5H m (ring B Hs), 6.55 1H s (3-H), 6.33 1H s (8-H), 4.06-1.80 6H m (N-ring Hs), 2.38 3H s (N-CH3) 7.78 2H d (2',6'-H), 7.19 W d (3',5'-H), 6.53 1H s (3-H), 6.08 1H t (2'-H), 3.82 3H s (6OCH3), 2.45 3H s (5-OAc), 2.33 3H s (7OAC), 2.30 3H s (4'-OAc), 2.42 3H s (NCH3), 2.74-2.17 6H m (N-ring CH2) 7.24 2H d (2',6'-H), 6.76 2H d (3',5'-H), 5.93 1H s (6-H), 4.82 1H dd (2-H), 4.58 1H dd (2"-H), 3.65 3H s (OCH,), 3.20-1.75 1OH m 8.0-7.4 5H m (ring B Hs), 6.7 1Hs (3-H), 6.4 1H s (6-H), 4.0 3H s (OCH,), 2.33 3H s (N'33) 7.24 5H m (ring B Hs), 6.12 1H s (3-H), 5.93 1H s (6-H), 3.76 3H s (OCH3) 7.65 5H m (ring B Hs), 6.56 1H s (3-H), 6.23 1H s (6-H), 2.28 3H s (N-CH3) 8.0-7.3 5H m (ring B Hs), 6.47 1H s (3-H), 6.24 1H s (8-H), 2.26 3H s (N-CH3) 8.2-7.5 5H m (ring B Hs), 7.38 1H s, 7.06 1H s 7.8-7.3 5H m (ring B Hs), 6.33 1H s (3-H), 6.1 1H s (8-H) 7.33 5H m (ring b Hs), 5.95 1H s (8-H), 5.38 1H dd (2-H), 2.90 2H m (2-H), 2.21 3H s (N-CH3) 7.78 2H d (2',6'-H), 6.5 1H s (3-H), 6.42 1H s (8-H), 2.32 3H s (N-CH3) 7.30 2H d (2',6'-H), 6.95 2H d (3',5'-H), 6.00 1H s (8-H), 5.32 1H dd (2-H), 3.0-2.75 2H m (3-CH2), 2.50 3H s (N-CH,)

3

3

4

5

6

6 6 6 6 6 6

6 6

D. SYNTHESIS AND DERIVATIVES 1. Biosynthesis No- studies have been carried out on the biosynthesis of the flavonoidal alkaloids. It is assumed, however, that the flavonoid moiety is formed by the usual

84

PETER J . HOUGHTON TABLE V '3C-NMR Spectra of Flavonoidal Alkaloids" Compound

Carbon No. 2 3 4 4a 5 6 7 8 8a 1' 2' 3' 4' 5' 6' 2" 3" 4" 5" 6" O-CH3 N-CH3

8

9

10

14

12

13

15

16

76.8 29.2 19.3 105.4 154.7 89.6 156.9 102.5 155.6 132.2 127.5 115.1 157.7 115.1 127.5 55.9 33.1 25.1 44.7 55.3

160.1 108.5 178.3 106.4 156.0 97.2 163.2 107.5 160.0 131.8 125.8 129.1 131.3 129.1 125.8 62.4 31.5 24.0 25.4 56.1 56.0 43.9

160.6 107.5 178.9 104.1 156.4 100.9 171.4 103.6 160.6 131.4 125.7 129.4 131.8 129.4 125.7 54.8 28.1 22.9 23.7 45.4 56.1

164.9 105.8 182.6 104.6 154.1 100.5 163.4 105.4 161.1 31.7 126.1 129.3 131.9 129.3 126.1 62.1 31.7 24.0 25.5 56.0 -

166.2 105.4 182.5 103.9 158.0 110.0 163.8 95.1 157.4 131.6 126.3 129.1 131.7 129.1 126.3 61.2 30.8 23.7 25.4 55.7

44.0

45.6

165.4 105.8 183.2 104.7 158.3 106.7 162.4 94.9 159.7 129.8 126.8 129.6 132.7 129.6 126.8 53.2 27.9 22.6 23.5 46.5 43.6

79.5 43.0 194.7 101.0 159.3 105.2 164.0 98.8 172.3 139.5 129.0 129.2 126.2 129.2 129.0 62.7 31.1 23.6 25.1 55.6 43.0

169.9 103.2 182.8 103.0 158.6 109.0 165.0 96.9 161.6 123.0 128.7 116.5 161.6 116.5 128.7 62.6 30.6 23.7 25.3 56.0 43.3

79.4 42.4 195.9 101.2 158.1 103.4 163.7 97.4 163.7 130.0 128.2 116.0 161.3 116.0 128.2 62.6 30.0 23.4 24.7 56.6 -

~

a

7

~

-

-

~

Spectra were run in CDC13, except for that of 7 which was run in DMSO.

pathways. The N-containing ring may be formed from ornithine or lysine for 5and 6-membered rings, respectively, in a way similar to other alkaloids. It is proposed that the A ring of the flavonoid undergoes electrophilic substitution by the N-containing ring (5,6,19).

2. Synthesis

a. Ficine (4) and Isoficine (5). The first synthesis of (+)-fiche was reported as a nine-step process by Anjaneyulu and Govindachari (19). The details are shown in Scheme 1. The pyrrolidine-ring A part of the molecule was formed by conjunction and subsequent cyclization of GABA and trimethylbenzene. The introduction of the C ring carbonyl bridge by the Friedel-Crafts reaction was followed by condensation with benzaldehyde to yield ring B. A later one-step synthesis was designed as a biomimetic process (18). The N methyl pyrrolidine ring in alkaloids such as nicotine is derived from ornithine via

85


n

SCHEME1 . Synthesis of ficine (4) (18).

86

PETER J. HOUGHTON

a N-methyl-2'-pyrrolinium salt, and the biomimetic synthesis of several such alkaloids has been accomplished using such a compound. The same approach was used whereby the pyrrolinium salt 41 was reacted with chrysin (37) (the flavonoid part of ficine) to give a mixture of ficine and isoficine (3.6 and 4.3%, respectiueiy). The 5- and 1 -OH groups acfhate the 6 and 8 pskions 101ekctrophilic attack by the pyrrolinium salt. CN+-CH,

x41 Pyrrolinium salt used in synthesis of ficine

b. Vochysine (7). Vochysine has been synthesized by a process similar to that used for the biomimetic synthesis of ficine referred to above. The parent flavonoid, 7-methoxy-5,4'-dihydroxyflavan,was reacted with an ethanolic solution of 1-pyrroline to give a 34% yield of vochysine (5).

3. Derivatives The triacetates of phyllospadine (6) and vochysine (7) have been prepared by conventional procedures ( 4 3 . Although not reported, there seems no reason why the other alkaloids should not form similar derivatives. Cleavage of ficine (4) to yield the parent flavonoid has been achieved, using pyrolysis or mild alkali in methanol (3). Vochysine (7) has been cleaved in the presence of alcohol to give the parent flavan (7). The nitrogenous part of the molecule cannot be detected after cleavage as it breaks down under alkaline conditions. Interconversion of ficine (4) and isoficine (5) has been carried out by refluxing in 70% HC1 ( 3 ) .The mechanism involved was thought to be due to a WesselyMoser rearrangement. N-Methylation of vochysine (7) took place when it was treated with sodium cyanoborohydride in 30% HCHO and acetic acid (5). Additional methylation of OH groups was accomplished by refluxing with methyl iodide in acetone containing potassium carbonate (5).

E. PHARMACOLOGY No work has been reported on the pharmacology of any of the alkaloids isolated. There is also very little known about the traditional medicinal uses of the plants from which they have been obtained.


8.1

IV. Noreugenin-Related Alkaloids A. ISOLATION All reports of isolation of the less polar alkaloids show that a similar pattern has been followed. It consists of an initial alcoholic extraction followed by fractionation on a silica gel column. The alkaloids first isolated from Schumanniophyton problematicum were extracted from the root bark with methanol containing 2% acetic acid (9). Rohitukine (17) was obtained from the leaves and stem of Amoora rohituku following conventional acid-base workup for alkaloids (7). The same technique was used for its isolation from Dysoxylum hinectariferum (8).The first alkaloids reported from S. magnifcum were isolated from fractions following column separation of an ethanolic extract (ZO,IZ). The more polar alkaloids rohitukine (17) and the N-methyl derivatives of schumanniophytine (31) and isoschumanniophytine (32) have been separated from the water-soluble fraction of the crude ethanolic extract using droplet counter-current chromatography (13). The fact that these alkaloids have both phenolic and alkaloidal properties causes some problems in extraction from aqueous media by conventional means, particularly for the secondary amines. Thus schumagnine (33) and N-methylschumagnine (34)were present in the aqueous fraction of the alcoholic extract of S. magnificum but on acidification were taken into chloroform (13).

B . STRUCTURAL ELUCIDATION 1. Introduction

The co-occurrence of the chromone noreugenin (3) with all the alkaloids so far isolated enabled the recognition of this structure as part of the alkaloid molecule (9). Degradations, interconversions, and spectral studies have been used to determine the structure of the alkaloids. 2. Schumanniophytine (18) Schumanniophytine was characterized by Schlittler and Spitaler (9). Mass spectral studies gave a molecular ion of 295 which by accurate mass measurement gave the formula C,,H,NO,. The formation of a monoacetate indicated that at least one OH was present. The noreugenin part of the molecule gave characteristic features in the UV, IR, and 'H-NMR spectra. Signals at S 8.48, 8.97, and 9.58 in the 'H-NMR spectrum indicated a 3,4-disubstituted pyridine portion. Degradation of 18 with concentrated nitric acid yielded cinchomeric

88

PETER J. HOUGHTON

acid and with strong alkali yielded 4,6-dihydroxybenzopyrano-5,4-pyridine-9one (42). These products showed that the pyridine ring was attached to the noreugenin via a lactone bridge to the 7 position and directly to the 8 position of noreugenin. The signal at 6 13.47 in the ‘H-NMR spectrum confirmed that the 5OH was free.

OH 42 Schumanniophytine hydrolysis product

3. Isoschumanniophytine (29) Isoschumanniophytine was isolated from Schumanniophyton magnificum and originally given structure 30 (11). Another isomeric alkaloid isolated at the same time was first given structure 29 but was subsequently shown to be schumanniophytine (18) (12). Isoschumanniophytinehad the same molecular weight as 18 and showed many of the same spectral characteristics. Differences included a golden-yellow rather than a lemon-yellow fluorescence wherrviewed on silica gel under UV light and different values for the pyridine ring protons in the ‘H-NMR spectrum. Instead of three separate signals, two obviously from ortho coupled protons, 29 showed a 2H broad singlet at 6 8.93. When the diacetate was prepared this resolved into two doublets easily assignable to ortho protons. It was assumed that in 29 the 5’ and 6’ protons had the same chemical shift. The 5’-H would normally be more upfield but is presumably deshielded by the presence nearby of an acetylable OH group. In both structures 29 and 30 this could be the case. Structure 30 was originally chosen for isoschumanniophytine(ZI), but further work has showed that 29 is more likely to be correct (12). Compound 29 gives a positive Gibb’s test, indicating that the 8-H is free. NOE experiments showed that there was no enhancement of the aromatic H signal at 6 6.94 when irradiated at the frequency of the 5-OH seen at 6 15.6. Therefore it is unlikely that the aromatic H is ortho to this phenolic group and so must be at C-8. The very low shift of the 5-OH signal in 29 was explained by the proximity of the pyridine ring. If 30 were the structure it is unlikely that the 7-OH would have such a lowfield signal since it is not hydrogen bonded to the 3a carbonyl as is the 5-OH.


89

4. N-Methylschumanniophytine (31)

A very polar compound with a yellow color was isolated from the aqueous fraction of the root bark extract of Schumanniophyton magnificum (13). Its spectral features were very similar to those of schumanniophytine (18). The UV spectrum showed a peak at 355 nm, and the 'H-NMR spectrum was almost identical apart from a 3H singlet at 6 4.3. This signal is the same as seen for the quaternary methyl in trigonelline (35). Since the molecular ion at mlz 310 was 15 higher than that given for 18, it was decided that the compound in question was the N-methyl derivative. This view was confirmed by the formation of 31 from 18 by methyl iodide methylation. 5. N-Methylisoschumanniophytine(32) Small amounts of another yellow compound co-occurring with 31 were isolated. By comparing spectra with 29 and by methyl iodide methylation of 29, this compound, N-methylisoschumanniophytine,was given structure 32.

6. Piperidine-2-one-Noreugenin Compounds (19 and 20) Schilttler and Spitaller isolated two alkaloids from Schumanniophyton problematicum which they did not name (9). These compounds were very similar to one another, having a molecular weight difference of mlz 14. Spectral data showed that noreugenin was present having two free OH groups. The major difference between the two compounds as far as the 'H-NMR spectrum was concerned was that the higher molecular weight compound showed a 3H singlet at 6 2.84 attributable to an N-methyl whereas the other compound showed a N-H signal at 6 7.53. The two compounds were thus reckoned to be N-CH, and N-H homologs. IR and double resonance NMR evidence was used to show the presence of the piperidine-2-one ring attached at C-6. More recent work on related compounds, however, has raised the question as to whether the point of attachment is actually at C-8 (12). 7. Rohitukine (17) Rohitukine was the first noreugenin alkaloid to be isolated (7). The molecular formula was established as C,,H,, NO, by high-resolution mass spectroscopic measurement and elemental analysis. The IR spectrum showed that a ketone and an OH were present and also showed a pyrone structure. No N-H bands were seen so the nitrogen was presumed to be tertiary. 'H- and 13C-NMR studies confirmed the presence of the N-methyl group and also suggested a resorcinol or

90

PETER J. HOUGHTON

phlorglucinol portion in the molecule. The spectra also showed that a carbinol proton was present at 6 4.44 and also some methylene groups. The final structure was determined by X-ray crystallography. 8. Schumannificine (25)

Schumannificine was first isolated by Okogun et al. from Schumanniophyton magnificum (10). They assigned it structure 21. The molecular ion at mlz 317 gave a formula C,,H,,NO,. Alkaline hydrolysis yielded noreugenin, showing it to be part of the molecule. The other hydrolysis product could not be isolated. When the 'H-NMR spectra of schumannificine and noreugenin (3) were compared, it was seen that schumannificine exhibited only one aromatic proton signal, indicating that substitution occurred at either C-6 or C-8. Okogun et al. proposed C-6 as the point of attachment because no alkylation took place when schumannificine was refluxed with methyl iodide and siver iodide in chloroform. They reasoned that C-alkylation should have taken place if C-6 was free. They also considered that C-8 was free because of the shift of the aromatic proton at 6 6.67 was very similar to that given for the 8-H in noreugenin (10). Acetylation and methylation reactions showed that two OH groups were present, only one of them being aromatic. It was thought that there must be another linkage through the 7-OH of noreugenin since the signal for this was missing in the lH-NMR spectrum of schumannificine. A 1H doublet at 6 5.70 suffered a downfield shift on acetylation and was therefore reckoned to be a carbinol proton flanked by a tertiary carbon on one side and a nitrogen atom on the other. Taking these factors into consideration 21 was proposed as the most likely structure. Recent NOE studies on the N-methyl analog of schumannificine (26) have proposed that schumannificine should in fact have structure 25 (12) although this was rejected by the original authors. When Houghton and Yang isolated Schumannificine they showed that it consisted of a 5 : 1 mixture of the 8OH a and 8-OH p isomers by consideration of the duplicate peaks in the 'HNMR spectrum (11). The diacetates of the two isomers could be separated. 9. N-Methylschumannificine (26)

The spectral features and chemical derivatives of N-methylschumannificine, first isolated by Okogun et al. ( l o ) , were very similar to those of schumannificine (25). The molecular weight was 14 mass units greater, and a 3H singlet seen at 6 2.95 in the 'H-NMR spectrum was reckoned to be due to an N-methyl group. Structure 22 was assigned on the same basis as 21 was given for schumannificine. More recently, however, it has been shown that N-methylschumannificine does not give a positive Gibb's test as would be expected from the free H-8 in 22 (12).In addition NOE experiments showed an enhancement in the 'H-


Y1

NMR signal for the aromatic proton at 6 6.35 when irradiated at 6 12.6, the frequency of the 5-OH. Such enhancement could only occur if the proton were ortho to 5-OH. This evidence was considered proof that 26 is the right structure. When N-methylschumannificine was isolated by Houghton and Yang (11) they found NMR evidence for a mixture of two compounds which were presumed to be isomers about C2’. When acetylation was performed two compounds were obtained and separated from each other. The configuration at C-2’ was established for each by consideration of their ‘H-NMR spectra, particularly the shifts of the N-CH3 signals. The major isomer present was shown to have the 2’-H p configuration (11). 10. Anhydroschumannificine (27) Houghton and Yang isolated an alkaloid from Schumanniophyton magnificum root bark with a molecular weight of 229 (11). The mass and ‘H-NMR spectra showed the presence of the noreugenin moiety. The molecular weight was 18 mass units less than schumannificine (25), and since it formed only an aromatic monoacetate it seemed that the OH group had been lost. A 1H doublet at 6 7.78 in the ‘H-NMR spectrum coupled with the N-H signal was assigned to 2’-H where C-2’ 2

78 R = COCH, 81 R = CHO 82 R = CH,CH3 83 R = CH,CH2COCH3

Nukui (124-126). UV and IR spectra of 78 and 81-83 are characteristic of lupinine alkaloids of the cytisine series containing an a-pyridine ring. MS fragmentation patterns are similar to those of cytisine alkaloids. The structures of these alkaloids were confirmed by synthesis from cytisine by reaction with HCOOH (81), (CH,CO),O (78), C,H,Br (82), or CH,=CH--COCH, (83).

149

5. LUPINE ALKALOIDS

C. VIRGIDIVARINE AND VIRGIBOIDINE Virgidivarine (C,,H,,N,O,) and virgiboidine (C,,H,,N,O) were isolated from Virgilia divaricata and V. oroboides (67,127,128). Virgidivarine easily splits off a water molecule in methanol solution at room temperature to afford virgiboidine. Virgidivarine's mass spectrum showed a molecular ion M + (266) and an ion at mlz 248 obtained by loss of water. Further fragmentation was similar to that of virgiboidine. There are absorption bands of a transquinolizidine system (2750-2930 cm-'), a lactam group 1635 cm-'), and an ally1 group (3070, 910 cm- l) in the IR spectrum of virgiboidine. On the basis of the above data, combined with results of 'H- and 13C-NMR spectroscopy, virgiboidine (84) is considered to be tricyclic with a butenyl group attached to N-16, while virgidivarine (22)is a ring B-open analog.

84

22

D. ALKALOID LC-2

The new alkaloid LC-2 was isolated from Lupinus cosentinii (87). It is considered to be a multiflorine derivative, probably an intermediate product in the biosynthesis of the latter alkaloid and occurring in plants together. There are absorption bands at 1580-1625 (-N-CH=CH-€O-), 920, and 990 cm(-CH=CH,) in the IR spectrum of this alkaloid. In the 'H-NMR spectrum there are proton signals presented as doublets at 6 4.92 and 6.86, as in multiflorine (85). Alkaloid LC-2 is converted to desoxyhexahydrorhombifoline (86) by reduction with zinc in 2 1V HC1 (Scheme 4). Alkaloid LC-2 appears to be a tricyclic quinolizidine alkaloid, and its structure is given by formula 87.

E. (-)-1 ~-ALLYLCYTISINE AND ( -)-TINCTORINE 1l-Allylcytisine (89) was isolated from the seeds of Sophoru secundiflora (129). There are characteristic IR bands at 2800-2700 (trans-quinolizidine), 1645 (a-pyridone), and 914cm-' (--CH=CH,). The 'H-NMR spectrum is analogous to that of cytisine but a signal at 6 5.75 (m, 1H) suggests the presence of vinylic protons. MS shows the presence of M + at 230. Further MS fragmentation is similar to that of cytisine. Catalytic hydrogenation of 89 over PtO,

afforded hexahydrodeoxoangustofoline(90), a reduction product obtained from angustofoline (91) (Scheme 5).

150

KH. A. ASLANOV, YU. K. KUSHMURADOV, AND A. S. SADYKOV

t

87 /LC-2/

86

4

85 SCHEME4

'

88

n

89

90

91

SCHEME5

(-)-Tinctorhe is considered to be an N-methyl derivative of allylcytisine but with a different configuration at C-1 1. (-)-Tinctorhe was isolated from Genistu tinctoria (130,131). There are absorption bands in its IR spectrum at 1660, 1580, and 1550 cm- characteristic for a-pyridone ring. The absorption bands at 915, 985, and 3085 cm- bespeak the presence of vinyl group in the alkaloid molecule. There are two characteristic absorption maxima at 235 and 311 nm in the UV spectrum of tinctorine (92). The presence of the a-pyridone ring is supported by a positive reaction with ferrous chloride. Reduction with LAH gave hexahydrodesoxytinctorine (93) with bands at 2800-2700 cm-I in its IR spectrum. There are signals of three olefinic protons in the 'H-NMR spectrum of tinctorine, suggesting the presence of a vinyl group (6 5.5,5.0) as well as aN-methyl group (6 2.16). The signals at 6 6.3, 7.16, and 5.85 correspond to a,p, and y protons of the a-pyridone ring. Catalytic reduction of tinctorine (92) over PtO, in acetic acid afforded the hexahydro derivative (94) and gave hexahydrodesoxytinctorine (95) in 2 N HCl (Scheme 6). The main fragments in the mass spectrum of tinctorine (92) were M + and ions at m/z 203, 160, 146, 108, 98, and 58. The fragment mlz 203 originates by splitting of an ally1 radical. The structure proposed for tinctorine (92) is confirmed by the fact that the fragment miz 58 observed was also seen in the fragmentation of N-methylcytisine (77). The configuration of tinctorine was established (131) on the following basis

5 . LUPINE ALKALOIDS

151

0 92 SCHEME 6

(Scheme 7): (-)-Hexahydrotinctorine (94) obtained by hydrogenation over PtO, in acetic acid was identical with N-methyldihydroangustifoline (98) obtained from angustifoline (91) by methylation and hydrogenation (except that it has opposite optical rotation). The reduction product (+)-hexahydrodesoxytinctorine

\

0

91 SCHEME7

152


(95) is the antipode of ( -)-N-methyldihydrodesoxyangustifoline (97). The absolute configuration suggested for 95 is (6S,7R,9R,11R). The alkaloid isolated from Thermopsis alterniflora Bge. described as “alteramine” (132,133),is, in our opinion, identical with tinctorine. F. (-)-ARGENTINE Argentine was first isolated from Ammodendron argenteum 0.Ktze. (134). It has also been obtained from Sophora griffithi Stocks (133, Thermopsis lanceolata R. Br. (136), and Thermopsis alpina Ldb. (137).There are two bands in = 232 and 308 nm, log E = 4.19 and 4.16) that are its UV spectrum (A,,, typical for an a-pyridone ring. IR spectral data showed the presence of a lactam group by bands at 1645 and 1665 cm- l . Four moles of hydrogen were absorbed by catalytic hydrogenation of argentine (99), and octahydroargentine (100) was formed (Scheme 8). There were no bands at 1500-1600 cm-’ in the IR spectrum corresponding to conjugated double bonds. The lactam absorption was shifted to 1615-1645 cm-l.

0

0

SCHEME 8

Mass spectral investigation of argentine showed a mass spectrum which looked like that of cytisine up to rnlz 190 (138). In addition, there was a molecular ion M + at 406 and peaks at mlz 217 (M+ - 189) and 189 (M+ 217). Octadehydroargentine showed an M + (414) and the ions at mlz 221 (M+ - 193) and 193 (M+ - 221), respectively. The fact that ion peaks appear at mlz 406, 217, and 189 is evidence of the presence of two a-pyridone nuclei in the argentine molecule, and since argentine contains two a-pyridone rings and since its ‘H-NMR spectrum is similar to that of cytisine the presence of two cytisine moieties in argentine was suggested. The low basicity of argentine and the possibility that a change of proton signals in its spectrum could be due to the presence of a group connecting two cytisine fragments by nondivided electron nitrogen pairs suggested structure 99 for argentine. This was confirmed by the following reaction: Hydrolysis with 30% NaOH at 140- 150°C afforded cytisine (3)quantitatively. Argentine (99) was synthesized according to Scheme 9 (139).

153

5. LUPINE ALKALOIDS

G. ( +)-DIMETHAMINE

Dimethamine was isolated from Therrnopsis alternijloru (140). There are two ion peaks at m / z 146 and 160 in the mass spectrum of dimethamine suggesting the presence of a 1,3-disubstitutedtetrahydroquinolizonesystem. This fragementation is similar to that observed with N-methylcytisine (77). Hydrogenation of dimethamine (101) in acetic acid over PtO, (Scheme 10) led to tetrahydrodimethamine (102) with a UV absorption maximum at 270 nm, IR absorption bands at 1630 and 1680 cm-l. (amide carbonyl and double bond, respectively), and ‘H-NMR signals of two N-methyl groups present as singlets at 6 1.97 and 2.13. Catalytic hydrogenation of 101 in alcoholic 2 N HC1 afforded hexahydrodimethamine (103), and the absorption band typical for the double bond had disappeared from the IR spectrum. Pyrolysis of 101 under reduced pressure resulted in the formation of (-)-N-methylcytisine (77). On the basis of these data it was assumed that dimethamine is a bimolecular alkaloid consisting

.CH3

SCHEME 10

154


of N-methylcytisine and dihydro-N-methylcytisine residues, connecting the pyridone rings. The presence of two olefinic protons in dimethamine at 6 5.77 and 6.18 as doublets with J , = J2 = 10 Hz, a splitting of the y-proton signal at J = 3 Hz, and the absence of olefinic protons in 102 suggested 33’-(3’,5‘dihydro)-di-N-methylcystisine(101) as structure of dimethamine.

H. TSUKUSHINAMINES A, B,

AND

C

Tsukushinamines A, B, and C, isolated from Sophora franchetiana (66,118,119), are considered to be isomeric compounds. Tsukushinamines A (21) and B (104) are epimers at C-14, and tsukushinamine C (105) differs from them in the position of the double bond and affords 21 on heating to 200°C in a 15

i6

17

0

0

0 21

CH,-CH=CH

CH,-CH=CH,

CH,-CH=CH,

104

105

sealed tube in a nitrogen atmosphere. The structure and absolute configuration of these alkaloids were established on the basis of their spectral data and confirmed by X-ray analysis (66,119).The configuration of the tsukushinamine alkaloids at C-7 and C-9 is the same as that of cytisine (3) and rhombifoline (88) (7R,9S). This is supported by the formation of a mixture of 21 and 104 by intramolecular photocyclization of rhombifoline (88) (Scheme 11) (141).

SCHEMEI 1

155

5. LUPINE ALKALOIDS

VI. Tetracyclic Quinolizidine Alkaloids of the Sparteine Group A. (-)-y-HYDROXY-

P-ISOSPARTEINE

7-Hydroxy-P-isosparteine (106) was isolated from Lupinus sericeus (142). The reduction of the iodo derivative of the alkaloid with LAH resulted in the formation of P-isosparteine (14) (Scheme 12). The hydroxyl groups were supposed to be at C-7 because of their low reactivity. This was confirmed by the (107) via oxidaformation of the monolactam 7-hydroxy-10-0x0-P-isosparteine tion of 106 with potassium ferricyanide.

OH

OH

0

106

14

107

SCHEME12

B . ~0,~7-DIOXO-~-ISOSPARTEINE

10,17-Dioxo-P-isoparteinewas isolated from Lupinus sericeus (143). The mass spectrum, with M at m/z 262 and signals at m/z 234 (M - 28) and 206 (M+ - 56), is characteristic for 10- and 17-oxosparteines and successive splitting of two carbonyl groups. Oxidation of p-isosparteine (14) by potassium fenicyanide resulted in 10-oxosparteine (108) as well as 10,17-dioxo-~-isosparteine (109) (Scheme 13). This confirmed the alkaloid structure. Although 109 was found as a natural compound it had already been synthesized by Bohlmann et al. (144). The problems of configuration and conformation of sparteine (6),aisosparteine (7), and P-isosparteine (14) were discussed (145). +

+

0

0 109

14 SCHEME13

156


C. EPIAPHYLLINE Epiaphylline was isolated from Lupinus hurmegii (146-147). The mass spectrum of this alkaloid is characterized by peaks at miz 248 (70), 247 (46), 220 (45), 137 (47), 136 (loo), 97 (53), and 96 (45%) that are tyical for sparteine alkaloids. The peak at miz 220 originates from the splitting of a carbonyl group. Epiaphylline (IlO), in contrast to aphylline (108), did not react under mild catalytic hydrogenation conditions, but under harsher conditions epiaphylline (110) converted to P-isosparteine (14) (Scheme 14). This established the presence of a carbonyl group at C-10.

0 14

110

0 108 SCHEME14

D.

(-)-4ol-HYDROXYSPARTEINE

4a-Hydroxysparteine was obtained from Acasmium punumense (148). The mass spectrum of this alkaloid, with M + at m / z 250 and signals at m/z 233,221, 209, 153, 136, 122, 114, 110,98,97, 96, 84,54, and41, is typical forhydroxy derivatives of sparteine alkaloids with a hydroxyl group in ring A. The reduction product of the known alkaloid multiflorine (85) obtained with sodium borohydride in methanol was identical with 4-hydroxysparteine (111) (Scheme 15). On the other hand, 4-hydroxysparteine (112) obtained from nuttalline (113) by reduction with sodium borohydride in methanol was not identical with 111, suggesting that 111 and 112 are epimers with the hydroxyl group in 111 in equatorial and in an axial position in 112. E. ( +)-THERMOPSAMINE

Thermopsamine was isolated from Thermopsis lunceolutu R. Br. (137). There are two absorption bands of an axial hydroxyl group at 3370 and 1023 cm- and bands representative of truns-quinolizidine at 2680-2800 cm- in the IR spectrum. Heating of thermopsamine with hydrogen iodide over red phosphorus

157

5. LUPINE ALKALOIDS

111

85

112 SCHEME 15

resulted in formation of a desoxy base identical with the alkaloid pachycarpine (6) (Scheme 16). Thermopsamine is thus hydroxypachycarpine. Ketone 14 was obtained from thermopsamine by Oppenauer oxidation, confirming the presence of a secondary hydroxyl group. Formation of thermopsamine from 13-hydroxylupanine (116) by reduction with LAH positioned the hydroxyl group to (2-13. On this basis the formula of 13a-oxypachycarpine (115) was proposed for thermopsamine.

115

114 SCHEME 16

F. (-)-LINDENIANINE Lindenianine was isolated from Lupinus lindenianus and L. verbasciformis (149,150). There are two IR absorption bands at 3330 (hydroxyl) and 1620

158


6

Il5

\

0 119 SCHEME17

cm-l (lactam carbonyl) in the IR spectrum. Lindenianine’s mass spectrum showed peaks for M + at mlz 264 and peaks at mlz 247 (M+ - 171), 236 (M+ - 28), 207 (M+ - 57), 152, 138, 137, 136, 134,97,96, and 84, suggesting the alkaloid to be a member of the sparteine series. Lindenianine (117) absorbed 2 mol of hydrogen over PtO, in 2 N HC1 and afforded 13P-hydroxysparteine(115) (Scheme 17). The latter gave sparteine (6) after dehydration with P,O, and hydrogenation. Lindenianine (117) and virgiline (119) were easily oxidized to ketolactam 118 by Oppenauer oxidation. Virgiline (119) was characterized by absorption bands at 1715 (six-membered ring carbonyl) and 1624 cm- (>N-CO-) in the IR spectrum. Treatment of 118 with NaBH, in methanol gave 117, establishing the hydroxyl group in lindenianine to be in the thermodynamically stable equatorial orientation, further evidenced by a wide multiplet (-40 Hz) at 6 3.70. Wolff-Kischner reduction of 118 gave aphylline (108). This established the lactam carbonyl at C-10, and lindeniane (117) and virgiline (118) appeared to be epimers at C-13. Conversion of virgiline (118) to lindeniane (117) was reported (150).

159


G. 5,6-DEHYDROLUPANINE AND 5,6-DEHYDRO-a-ISOLLJPANINE

The bases 5,6-dehydrolupanine and 5,6-dehydro-a-isolupaninewere isolated from species of Lupinus and Thermopsis, Echinosophoru koreensis, and Clathrotropis brachypetala (126,151-154). Their mass spectra are identical and show the presence of a double bond at C-5=C-6. Catalytic hydrogenation of 5,6-dehydrolupanine gave lupanine. 5,6-Dehydrolupanine (120) is supposed (152) to be an intermediate product in the biosynthesis of anagyrine (121) from lupanine (15) (Scheme IS), while 5,6-dehydro-c~-isolupanine (122) is an intermediate product in the biosynthesis of thermopsine (124) from a-isolupanine (123) (Scheme 19).

0

0 15

0 120

121

SCHEME 18

0

0

0 123

122

124

SCHEME 19

H. ( +)-NUTTALLINE Nuttalline was isolated from Lupinus nuttallii L. (155).The tetracyclic structure of nuttalline was established by dehydration of deoxonuttalline (112), obtained from nuttalline (113) by reduction with sodium borohydride, and by catalytic reduction to sparteine (6) (Scheme 20). Oppenauer oxidation of nuttalline gives 2,4-dioxosparteine (125). The UV spectrum of this 1,3-diketone was pH dependent. Thus, deoxonuttalline and 4a-hydroxysparteinc appear to

he

epimers, and nuttalline has the structure of 4P-hydroxy-2-oxosparteine (113).

I. (+)-CHAMAETINE Chamaetine was isolated from a species of Chamuecytisus (156,157). Chamaetine (127) was reduced by LAH to hydroxysparteine (lll),and further reduction with red phosphorus in the presence of iodine gave sparteine (6) (Scheme

160

KH. A. ASLANOV, YU. K. KUSHMURADOV, Ah'DA. S . SADYKOV

0 113

126 SCHEME 20

21). Heating chamaetine in the presence of P,O, gave anhydrochamaetine (126), which afforded lupanine (15) on hydrogenation over 5% PdIC. The 'H-NMR spectrum of chamaetine showed a secondary hydroxyl group between two CH, groups. The mass spectrum had the ion peak M + at mlz 264 and peaks at mlz 235 and 165. The fragment rnlz 235 is the result of C,H, (M+ - 29) splitting, showing that ring D was not substituted. The fragment at miz 165 contains two oxygen atoms and points to the presence of a hydroxyl and carbonyl group in ring A. That position C-4 bears the hydroxyl group is shown by the three CH, multiplets observed. On the basis of the NMR analysis, the hydroxyl group in chamaetine (127) is equatorial and axial in nuttallin (113).

J. 10,13-DIOXYLUPANINE 10,13-Dioxylupanine was isolated from Cadia purpurea (109). Its structure (128) was proved by IR and mass spectroscopy.

161

5. LUPINE ALKALOIDS

111

\

126

/

15

6 SCHEME 21

K. CALPURMENINE Calpurmenine was isolated from Culpurniu uureu (158). The mass spectrum showed peaks typical for a lupanine skeleton, containing two hydroxyl groups, but the alkaloid differed from 10,13-dioxylupanine (128). The peaks at miz 168, 150, 132, and 112 showed the second hydroxyl group to be in ring C or D. XRay analysis established the position and configuration of the two hydroxyl groups in calpurmerine, having the structure of a 12p,13a-dihydroxylupine (129).

0

OH 128

Q

129

L. ESTERSOF HYDROXYLUPANINES Several alkaloids (130-142) were isolated from plants of the genera Cudiu, Culpurniu, Surothumnus, and Genistu. They are believed to be ethers and esters of hydroxylupanine derivatives (159-1 78). Alkaloid esters on hydrolysis gave the respective organic acids and hydroxylupanines. The structures of these alkaloids have been established mainly by spectral methods.

162

KH. A. ASLANOV, YU. K. KUSHMURADOV, AND A. S . SADYKOV

130 1 3 - E t h o ~ y b p a n i n e : 131

Cadiaine:

132 10-oxy-13-0-

R'=H; R'=H;

R3=H; R'=-OC,H,

R' =H; R1 =H; R' =H; R4 =-OCOCH,-

h -pyrr olylcarb onyl/-lupan i n e : R'=H; R*=OH; R3=H; R ' = - O C O/ G\

133 13-0-/2-pyrrolylcarbonyL/

calpurmenine:

R'=H; R'=H;

R'=OH;

XN;

R~=OCO

H

OCH~

134

Cinevanine:

R' =H; R2=H; R3=H; R4=OC0=(-&OH

135

Isocinevanine:

R'=H; Rz=H; R3=H; R'=OCO+,

136

Cineverine:

OCH3 R'=Hi RL=H; RJ=H; X 4 = O C O G 4 C H ,

137

Cinegallme:

138

Cinegal'leine:

141

Cafalauverine:

OH

-

on

R3=Hi R 4 = O C O - @ X H , OH R'=H; R2=H; R'=H; R 4 = O C O e F C HOCH, ,

R ~ = H , R'=H;

OH

OCHB

R' =OH; R L = H R3=H; R4=OCO+OCH

M. ( +)-ARGENTAMINE Argentamine was isolated from Ammodendron argenteum 0.Ktze. (134). Its UV spectrum has two maxima at 232 and 308 nm (log E = 4.31 and 4.41), typical for an a-pyridone chromophore. There were bands in the IR spectrum at 3260 (wide) and 1045 cm- l , belonging to the hydroxyl and carbonyl group, respectively. The argentamine mass spectrum (mlz 260 M + , 243, 215, 160, 152, 146, 114, 96, and 88) is typical of quinolizidine alkaloids. On catalytic


145

163

7 SCHEME 22

hydrogenation over nickel, argentamine (143) absorbed 2 mol of hydrogen and was converted to tetrahydroargentamine (144) (Scheme 22) (179). Reduction of 143 in 2 N HCl over PtO, gave desoxohexahydroargentamine (145). Hydration of the latter followed by hydrogenation gave a-isosparteine (7). The 1R spectrum of 143 differed from that of baptifoline (146) and showed trans-quinolizidine bands. On the other hand, 144 appeared to be identical to 13-hydroxy-a-isosparteine, suggesting a trans-coupling of rings C/D in argentamine and the position of the hydroxyl group at C-13. Argentamine and baptifoline are epimers at C- 13.

N . (+ )-DITERMAMINE Ditermamine was isolated from the aboveground portions of Thermopsis lunceoluta R. Br. (180). The IR spectrum showed two absorption bands in the region 2600-2800 cm- l , suggesting the presence of a trans-quinolizidine system. Bands at 1670, 1645, and 1610 cm-’ originate from lactam carboxyls and conjugated double bonds. The “fingerprint” region is similar to that seen in thermopsine. The UV spectrum showed an absorption maximum at 280 nm (log E = 3.6). There were ion peaks at m / z 146 and 160 in the mass spectrum of ditermamine, suggesting the presence of a 1,3-substituted tetrahydroquinolizinone. Ozonization of ditermamine and thermopsine (124) gave the identical product (148) (Scheme 23). Thus, ditermamine has the thermopsine structure 124 with a substitpent at ring A. Hydrogenation of ditermamine in acetic acid over Pt gave tetrahydroditermamine (149). There were absorption bands in the IR spectrum of 149 at 1630 cm- (>N-CO-) and at 1680 cm-l (double bond). There were no signals for olefinic protons in the ‘H-NMR spectrum. Catalytic hydrogenation of diter-

’

164

KH. A. ASLANOV, YU. K . KUSHMURADOV, AND A. S. SADYKOV

149

t

f

/

/

150

1

0

147

\

151

148

124 SCHEME23

mamine over PtO, in alcoholic HC1 led to 150, showing no double bond absorption in the IR spectra. Reduction of 150 with LAH gave 151, lacking amide carbonyl bands in the IR spectrum. There are signals of two olefinic protons in the 'H-NMR spectrum of ditermamine present as doublets at 6 5.75 and 6.12 with J = 10 Hz. This points to f3 and y position of the olefinic protons in the pyridone ring and structure 147 for ditermamine.

VII. Tetracyclic Alkaloids of the Leontidine Group (Quinolizidine-Indolizidine Alkaloids) A. (-)-LEONTIDINE Leontidine was obtained from Leontice and Camoensia (181-183). The prescence of a-pyridine ring was evidenced by UV and 'H-NMR spectroscopy. The IR spectrum showed a transquinolizidine system (2800-2700 cm- '). The mass spectrum of leontidine is characterized by intensive ion peaks at mlz 160 and 146 typical €or quinolizidine alkaloids. Ion peaks at mlz 96 and 84 speak

for the pesence of a five-membered heterocyclic ring. Leontidine (152) when hydrogenated over PtO, in acetic acid gave tetrahydroleontidine (153), which formed leontidane (154) on reduction with LAH (Scheme 24). Oxidation of leontidine with potassium permanganate gave

165


oxoleontidine (155), lacking trans-quinolizidine bands in the IR spectrum, and dehydrogenation over palladized asbestos gave tetradehydroleontidine (156). The proposed structure for leontidine (152) was confirmed by partial synthesis from 11-allylcytisine(89) by treatment with hydrogen iodide (Scheme 25) (181). The absolute configuration of leontidine (7R,9R,1IS) was established by comparing CD spectra of different optically active alkaloids containing an a-pyridine ring (184).

0

0 153

/

\

\

0 152

0

\ I

154

.

156 SCHEME 24

SCHEME 25

B. CAMOENSINE, CAMOENSIDINE, AND HYDROXY DERIVATIVES Camoensine and camoensidine were isolated from Camoensia maxima Welw . ex Benth. (183). Camoenzine is considered to be an isomer of leontidine. The mass spectra of these alkaloids were identical. Dehydrogenation of carnoensine (157) with mercury acetate formed the immonium base (158), which was converted to leontidine (152) by sodium borohydride (Scheme 26). Camoensine

166


/fN

*

*

157

158

152

SCHEME26

159

160 27

153

SCHEME

(157) has the absolute configuration (7R,9R, 11R). Camoensidine (159) proved identical with tetrahydrocarnoensine obtained from the immonium base (160) by reduction with sodium borohydride (Scheme 27). The results of photochemical oxidation of camoensidine (159) and tetrahydroleontidine (152) were described (185). 12-Hydroxy derivatives of camoensine and camoensidine (161 and 162) as well as 12-hydroxy-16-methoxy-11,12,13,14-tetrahydrocamoensine (163) were isolated from Camoensia brevicalyx Benth. (186).The structures and position of hydroxyl and methoxyl groups in these alkaloids were determined on the basis of IR, NMR, and mass spectra.

OCH,

T N , pyz7+Fd2H P

N

"OH

0

0

161

A N '-,

OH

N\/

0

162

163

C . DESOXOCAMOENSIDINE ( 11-EPILEONTIDINE) Desoxocamoensidine was isolated from Maackia arnurensis Rupr. and Maxim. (187).The structure of the alkaloid (164) was established by its identity with the product obtained from camoensidine (159) with LAH (Scheme 28).

159

164 SCHEME 28

167

5. LUPINE ALKALOIDS

VIII. Tetracyclic Alkaloids of Aloperine Group A. ( -)-ALOPERINE,(+)-N-METHYLALOPERINE, AND N-ALLYLALOPERINE

Aloperine, N-methylaloperine, and N-allylaloperine were isolated from Sophora alopecuroides L. (188-191). Later aloperine was also isolated from Leptorhabdos pawzjlora Benth. (192). On reductive methylation, aloperine gave N-methylaloperine (167) (190-Z93), and interaction with ally1 bromide gave Nallylaloperine (170) (Scheme 29) (189). Hence, one of the two nitrogen atoms in aloperine was considered to be secondary. High-resolution MS showed aloperine to be different from all known types of quinolizidine alkaloids by fragmentation. It was demonstrated that cleavage of one heterocycle takes place first, accompanied by elimination of nitrogen fragments CH,N, C,H,N, and C3H,N. The splitting of a CH3N fragment confirmed the presence of a secondary nitrogen atom. Mass spectra of N-methyl- and Nallylaloperine revealed a different fragmentation pattern to that observed for aloperine. Aloperine (165) contains one double bond, which is hydrogenated in the presence of PtO, with the formation of dihydroaloperine (166).

OH

\

167

/

168

169 R = CH, 170 R = CHZCH =CH, SCHEME29

168


The nature of the double bond was deduced by NMR spectra of 165 (6 5.27, J = 6.5 Hz). Mild dehydrogenation with sulfur gave the tetradehydro derivative

167, while oxidation with potassium permanganate gave dioxylactam 168. Three signals of a, p, and y protons of a pyridine ring were observed in the NMR spectrum of 167. Thus, aromatiziation was accompanied by migration of the double bond. The presence of a quinolizidine nucleus and support for,the extra double bond were confirmed by the mass spectrum of 168. The spectrum showed fragments (m/z 136, 137, and 150) typical for a quinolizidine nucleus and the hydroxyl-containing fragments (mlz 134, 148, and 195), explaining the oxygenated part. The presence of weak Bohlmann absorption bands in the IR spectrum of aloperine and their absence in N-methyl, N-acetyl, and N-benzyl derivatives proved rings AIB to be cis-fused. B . NITRARAMINE AND N-HYDROXYNITRARAMINE

Nitraramine and N-hydroxynitraramine were isolated from Nitruria schoberi (194,195).There are active hydrogen absorption bands in the IR spectrum of nitraramine at 3280 and 3530 cm-l and a low intensity band at 1660 cm-I (double bond). Acetylation of nitraramine (171) gave N-acetyl and N , 0-diacetyl derivatives. Hydrogenation over Adams’ catalyst in acetic acid gave dihydronitraramine (172) and dihydrodesoxynitraramine (173) (Scheme 30). The presence of peaks typical for quinolizidine alkaloids in the mass spectra of 171-

OH

172

OH

171

0

174

CH, 173

175 SCHEME 30

176

5. LUPINE ALKALOIDS

169

173 and the presence of >NH groups in their IR spectra as free bases allowed classification of nitraramine into the aloperine group of alkaloids. Formation of 173 from 171 on hydrogenation pointed to the presence of an allylic alcohol group in 171. This was confirmed by oxidation of 171 to ketone 174. There were strong bands at 1650 and 1580 cm-' in the IR spectrum of 174 typical for a -CO-C=C-Nsystem. The absence of olefinic protons in the NMR spectrum of 171 suggested the double bond to be at C - 1 1 4 - 1 6 , while a hydroxyl group is positioned at C-15 or C-17. Dehydrogenation of 171 by Pd/C resulted in dehydro base 175. The 'H-NMR spectrum of 175 showed the a-proton signals of the pyridine rings as two multiplets at 6 8.49 and a muitiplet centered at 6 7.04 (5H, Ar-H). The methylene group showed two one-proton triplets at 6 4.48 and 4.13 (J = 4 Hz) arising from interaction with the axial proton at C-8. The quartet (2H) at 6 2.98 was attributed to the protons at C-8, while the multiplet at 6 2.13 is supposed to belong to the proton at C-7. On the basis of structure 175 the hydroxyl group at nitraramine was placed at C-17. Oxidation of 171 with 5% hydrogen peroxide gave Nhydroxynitraramine (176), identical to that isolated from natural sources. Compound 176 was reduced by sodium borohydride in methanol and with LAH in ether to 171. IX. Tetracyclic Alkaloids of the Matrine Group A. ( -)-SOPHORIDINE AND ( +)-SOPHORIDINE (-)-Sophoridine was isolated from Sophora alopecuroides L. (190,191), Leptorhabdos parvgora Benth. (192), S . jlavenscens Ait. (22), and Euchresta japonica Benth. (40).(+)-Sophoridine was also isolated from Leontice albertii Rgl. (196,197). The structure of the carbon-nitrogen skeleton was established with the formation of octodehydromatrine (177) on dehydrogenation over palladized

177

asbestos (198). Bohlmann bands in the region 2800-2700 cm- and the relative dehydrogenation rates of matrine (4), allomatrine (5), and sophoridine allowed

170


4

25

5

178

determination of the rings in sophoridine as A/B-, A/C-, B/C-trans, and C/D-cis (199,200). Sophoridine was shown to isomerize by hydrogenation over PtO,/H, (196,201,203) to isosophoridine (25) with rings A/B- and A/C-cis, B/C- and C/D-trans. Reduction of sophoridine iodomethylate gave sophoridane iodomethylate (178), characterized by the absence of an absorption at 28002700 cm-l (199, 202, 203). The spatial structure of 179 was suggested for sophoridine (204). 7

0 179

181

8

N

6 180

8 10

5. LUPINE ALKALOIDS

171

Sophoridine (8) was converted by oxidation with mercury acetate to 5-hydroxy-6,7-dehydromatrine (180) with C/D-trans-fused rings as in matrine and allomatrine. Therefore spatial structure 181 for sophoridine was proposed (196,203,205). The controversial views regarding the configurations of sophoridine may be explained by different conformations of the molecule in solution (different from 179 or 181). The structure of sophoridine is conformationally labile since the nitrogen atoms are capable of inversion. To establish the conformation of sophoridine in solution it was necessary to use methods that did not affect conformational equilibria. 'H-NMR and INDOR methods led to proposed structure 8 for sophoridine, with rings A/B-, A/C-, C/D-trans, and B/C-cis. Rings A and D have chair, and rings B and C, boat conformations (206).This is supported by spectral analysis, including 13C-NMR analysis (11,12,36,37),and has been confirmed by X-ray analysis (71,72). Conformation 8 agrees with the chemical transformations of sophoridine obtained earlier (203). Matrine isomers are known to react faster by dehydrogenation over palladized asbestos or with mercuric acetate if they contain cis hydrogens. Sophoridine has been shown to dehydrogenate faster than allomatrine (9, but slower than matrine (4) (196).Since there are three cis hydrogens (H-5, H-6, H-7) in matrine and none in allomatrine, the sophoridine molecule is supposed to contain two cis hydrogens; a cis orientation of H-6 and H-7 in 8 meets this requirement. On dehydrogenation with mercuric acetate, matrine, allomatrine, and sophoridine afforded the same dehydro product, 5-hydroxy-6,7-dehydromatrine(180) (196,203).The attachment of a hydroxyl group to C-5 and the double bond in the 6,7 position eliminate differences in the molecular conformations of 4, 5, and 8. The absence of trans bands in the spectrum of 178 may be explained by isomerization taking place during reduction. Examination of Sophoru ulopecuroides L. sprouts led to the isolation of sophoridine N-oxide as the main alkaloid (191,207). Later the N-oxide also was isolated from Euchrestu juponicu Benth. (40). Oxidation of sophoridine by mchloroperbenzoic acid resulted in two N-oxides in a ratio of 1 : 5. The minor Noxide was identical to the natural one, and its conformation corresponds to that of sophoridine (8). The other N-oxide (10) as suggested by IH- and I3C-NMR spectra, appears to be the N-oxide of one of the labile conformations (38,39). B. ( +)-ISOMATRINE Isomatrine was isolated from Sophoru fluvescens Ait. (79,208). There are absorption bands of a lactam group at 1620 cm- and a truns-quinolizidine at 2740, 2760, and 2780 cm-l in the IR spectrum. Heating of isomatrine (29) in aqueous solution with PtO,/H, results in epimerization, and a mixture of matrine

172

2-2 +g KH. A. ASLANOV, YU. K. KUSHMURADOV, AND A. S. SADYKOV

NH

29

4 SCHEME31

5

(4) and allomatrine (5) is formed (Scheme 31). The configuration of 29 was determined by NMR and X-ray analysis (79). Rings A, B, C, and D in isomatrine have, respectively, chair, boat, boat, and chair conformations, and its absolute configuration is (5R,6R,7S,11R).

C. (+)-ALBERTIDINE Albertidine, isolated from Leontice Albertii Rgl. (Z96,197), is a crystalline, optically active tribase. There are IR absorption bands for a trans-quinolizidine system at 2750 and 2793 cm-’ and a six-membered lactam carbonyl at 1640 cm- The absorption in the “fingerprint” region is similar to that of matrine. The mass spectrum of albertidine is characterized by ion peaks at mlz 247 (M l), 219, 205, 192, 177, 150, 137, 98, and 96 which are typical for matrine alkaloids (209). On the basis of spectroscopic data and taking into account the trans-quinolizidine band in the IR spectrum, the probable structure 182, with rings AIB-trans, was proposed.

182

D. (-)-DARVASINEAND ( +)-DARVASAMINE Darvasine, isolated from Leontice darvasica Rgl. (2Z0,21l ) ,is a monoacidic tribase. There are absorption bands in its IR spectrum that are typical for a double bond (1670 cm-l) and a lactam (1645 cm-*). There is one UV maximum at 244

I

group. The mass specnm (log E = 4.3), typical for a --C=CH-N--C=O trum differs from that of leontalbine in the intensity of some peaks. This suggests that darvasine and leontalbine might be diastereomers. Dehydrogenation of dar-

173


4 -

I_t

N

N

184

183

177

SCHEME 32

vasine over palladized asbestos gave octadehydromatrine (177) (Scheme 32). The 'H-NMR spectrum of this alkaloid showed a single olefinic proton in the a position to nitrogen at 6 6.81, which corresponds to the proton of the double bond at C-5-C-17. There were no Bohlmann bands in the IR spectrum of darvasine. The alkaloid appears, therefore, to be a representative of the matrine group of alkaloids and most probably has the structure of 5,17-dehydroisomatrine (183). (+j-Darvasamine (184), isolated from Leontice Albertii Rgl. (211,212), turned out to be dihydrodarvasine.

E. ( -)-LEONTALBINE Leontalbine, isolated from Leontice Albertii Rgl. (213), is considered to be monoacidic unsaturated tribase (214). The IR spectrum is characterized by absorption bands typical for a trans-quinolizidine system (2800-2700 cm- l ) , a double bond (1670 cm- l ) , and a lactam (1640 cm- l ) . Reduction of leontalbine (185) with LAH gave deoxoleontalbine (186) with the double bond preserved (Scheme 33). Hydrogenation of deoxoleontalbine gave a diacidic tribase that appeared to be the antipode of (+)-deoxomatrine (187). Leontalbine perchlorate could not be reduced with sodium borohydride, while deoxoleontalbine perchlorate afforded deoxodihydroleontalbine.The double bond in leontalbine is, therefore, situated in ring C between the a and @ carbons of the nitrogen atoms, as shown in 185. The olefinic proton is shown as a singlet at 6 6.9 in the 'H-NMR spectrum of the base and is a-positioned with respect to the amide nitrogen. This alkaloid is known to have a (-) rotation and appears to be the antipode of (+j-5,17-dehydromatrine (215).

185

186 SCHEME33

187

174


F. ( -)-LEONTALBININE Leontalbinine was isolated from Leontice Albertii Rgl. (216). It is considered to be monoacidic tribase. It shows IR absorption bands typical for a trans-quinolizidine (2800-2700 cm- l ) , a double bond (1670 cm- l ) , and a lactam carbonyl at (1645 cm- '). Reduction with LAH gave deoxoleontalbinine, which absorbed 1 mol of hydrogen on catalytic hydrogenation to give deoxodihydroleontalbinine. Hydrogenation of leontalbinine in acetic acid in the presence of platinum catalyst led to dihydroleontalbinine, identical by IR with allomatrine but different from allomatridine. Structure 187 was proposed for deoxodihydroleontalbinine. Leontalbinine perchlorate could not be reduced, while deoxoleontalbinine perchlorate was reduced by sodium borohydride. This suggested an a,P position of the double bond with respect to the amine nitrogen, which was confirmed by oxidation to glutaric acid, probably via the intermediate product 189 (Scheme 34). Since structure 188 proposed for leontalbinine is correct, structure 187 given to deoxodihydroleontalbinine is incorrect and has to be changed to 190.

gJ -a-3 HOOC/j

H

N

___c

-.-

H

COOH

COOH

2 $8 188

189

HNH

N

N

187

190

191

SCHEME 34

There are typical Bohlmann bands at 2800-2700 cm- in the IR spectrum, suggesting trans-fused AIB rings. This is confirmed with the formation of allomatrine by the catalytic hydrogenation of leontalbinine. Deoxodihydroleontalbinine (190) differs from allomatridine, suggesting a matrine-allomatrine type isomerization of leontalbinine during hydrogenation in the presence of platinum catalyst. Deoxodihydroleontalbinine (190) was obtained from 191 by catalytic hydrogenation, and 191 was prepared from leontalbinine (188) by reduction with

5. LUPINE ALKALOIDS

175

LAH. In the hydrogenation of 191, hydrogen approaches from the most favorable site giving the cis product 190. G . (+)-LEMANNINE

Lemannine was isolated from Ammothamnus Lehmanni Bgl. (217).The IR spectrum shows bands at 2680, 2750, 2770, and 2810 cm-' typical for a transquinolizidine and a band at 1650 cm- corresponding to a six-membered lactam. The mass spectrum shows ion peaks at rnlz 245 (M+- l), 232,217,203, 190, 188, 177, 159, 136, 122, 110, 98,97,96, 83, and 55, typical for the matrine series of alkaloids with a double bond in ring D. The double bond in ring D is not coupled with a lactam carbonyl since there was no chromophore --C=CH-C=O absorption in the UV spectrum of lemannine. The 'H-NMR spectrum shows signals of two olefinic protons at 6 5.6-5.9.Double resonance experiments showed the olefinic protons to be connected with H-1 1 spin-spin interaction. The double bond in lemannine (192) is therefore situated at C-124-13in ring D. Hydrogenation over Raney nickel gave matrine.

'

192

H. 13,14-DEHYDROSOPHORIDINE (+)-13,14-Dehydrosophoridinewas isolated from Sophora alopecuroides L. (218), and (-)-13,14,-dehydrosophoridinewas obtained from S. flavescens Ait. (80).There is an absorption maximum at 253 nm in the UV spectrum which is typical for an a,@-unsaturatedketone. The IR spectrum showed absorption bands at 2700-2800 cm-' of a trons-quinolizidine, at 1650 cm-' of an amide carbonyl, and at 1597 cm- of an a,@-unsaturatedlactam. There are several signals in the 'H-NMR spectrum of the free base: Two signals of olefinic protons present as a doublet of triplets at 6 5.73-6.25 and 3.74-3.26 (H-17e and H-11). The signals for H-2e, H-lOe, and H-17a occur at 6 2.86-2.30.Nonoverlapping multiplet signals occur at 6 2.24-0.82.The mass spectrum is characterized by the molecular ion peak at mlz 246 (83%) and by ion peaks at mlz 245 (loo), 231

'

(8.1),217 (9.1),203 (13.4),192 (3), 188 (4.3,177 (82),160 (12), 150 (91), 138 (53),122 (20),98 (18),and 96 (78%). This MS decay pattern is typical for quinolizidine alkaloids of the matrine group. The ions with mlz 217 and 203

176

2-g-2 KH. A. ASLANOV, YU. K. KUSHMURADOV, AND A. S. SADYKOV

N

N

3

N

0 193

30

8

SCHEME35

speak for the presence of a double bond in ring D. (219,220). 13,14-Dehydrosophoridine (30) is converted to sophoridine (8) on catalytic hydrogenation in the presence of Raney nickel or PtO, in acetic acid (Scheme 35). The N-oxide of 13,14-dehydrosophoridine(193) was obtained from Sophoru alopecuroides L. (221). I. (-)-NEOSOPHORAMINE Neosophoramine was isolated from Sophoru alopecuroides L. (191,207,222,223). There are no trans-quinolizidine bands in the IR spectrum, but there is a lactam carbonyl absorption band at 1650 cm- l . The MS spectrum is characterized by peaks of the molecular ions M (244) and M - 1 (243) and by ion peaks at m / z 215, 149, 136, and others, typical for matrine alkaloids containing an a-pyridine ring. A comparative study of UV, IR, 'H-NMR, and mass spectroscopic data of neosophoramine (194), sophoramine (199, and isosophoramine (196) showed that these alkaloids differ mainly in the configuration +

+

$gg N

N

194

195

196

of the A/B part of the molecule. The configurations of the three steroisomeric alkaloids was confirmed by an analysis of mass spectra of daughter ions (DADJ) (224).

J.

(-)-7,8-DEHYDROSOPHORAMINE

7,8-Dehydrosophoramine was isolated from Sophora flavescens Ait. (225). The IR spectrum of the base is characterized by the presence of an a-pyridone

177


197

195 SCHEME 36

ring (1650, 1570, 1535 cm- I ) . 7,8-Dehydrosophoramine (197), on catalytic hydrogenation over Pd/C benzene, gave sophoramine (195) (Scheme 36). The NMR spectrum of 197 showed signals of four olefinic protons (6 6.0,6.07,6.57, 6.85). The signal at 6 6.0 (multiplet) overlapped with the multiplet of H-12 and was attributed to the proton of the double bond conjugated with a-pyridone ring.

K. ( -)-ALBERTINE Albertine, isolated from Leontice Albertii Rgl. (216,226,227),is an optically active monoacidic tribase. There are the absorption bands at 1655 (lactam carbonyl), 1675 (double bond), 2795-2760 (truns-quinolizidine), and 3300 cm- ] (hydroxyl group) in the IR spectrum. The UV spectrum shows an absorption maximum at 224 nm (log E = 4.2) for a -C=C-N-C=O group. Albertine (198), on catalytic hydrogenation over PtO, in acetic acid, gave dihydroalbertine (199) (Scheme 37). Reduction of 199 with LAH gave deoxo base 200. The spectrum of this last compound lacked the double bond protons, while the band of the hydroxyl group was shifted to 3150 cm-'. Dihydroalbertine (199), on heating with P,O,, gave an anhydro base found to be identical to sophocarpine (201) by UV and MS analysis (227). Desoxohydroalbertine(200) on dehydration afforded 202, which gave matridine (157) on catalytic hydrogenation with PtO,. The position of the hydroxyl group in albertine was proved by dehydration with phosphorus anhydride, giving 195. L. ( +)-ALBERTAMINE, ( -)-LEONTALBAMINE, AND (+ )-LEONTISMIDINE (+)-Albertamine, (-)-leontalbamine, and (+)-leontismidine were isolated from Leontice ulbertii and L. Smirnovii (228,229).They have the same composition, CI5H,,N,O,. The IR spectra of these alkaloids are characterized by the absorption bands giving evidence for the presence of hydroxyl and amide carbonyl groups. There is also absorption (except in the albertamine spectrum) in the region of 2700-2800 cm- attributed to trans-quinolizidine systems. The UV spectra show absorption maxima at 220 nm. Reduction of albertamine (203), leontalbamine (204), and leontismidine (205)

178


200

202

187

\goH N

/

$OH N

199

J

198

195 SCHEME 37

20 1

with LAH gave the deoxo bases 206, 207, and 208, respectively (Scheme 38). Their mass spectra resembled those of saturated matridines. The ion peaks in the spectra of these deoxo bases coming from the lactam portion were shifted by 16 mass units. Heating deoxobases 206, 207, and 208 with P,O, gave anhydro bases 209, 210, and 211, which afford desoxodarvasamine (212), allomatridine (213), and sophoridane (214), respectively, on catalytic hydrogenation. Dehydration of 203,204, and 205 gave anhydro products 215,216, and 30 with UV spectra typical for ol,P-unsaturated lactams. On the basis of a comparative study of IR and MS spectra of these bases and 5-hydroxymatrine, it was suggested that the hydroxyl groups be located at C-13.

M.

(+)-9Ci-HYDROXYMATRINE

9a-Hydroxymatrine was isolated from Sophora macrocarpa (24). It shows IR absorption bands typical for a hydroxyl group, lactam carbonyl, and

179

5. LUPINE ALKALOIDS

6 N

215

8 H

N

216

30

(g OfiOH

N

203

tno" N

& 204

205

207

&OH 208 N

206

1

P l

I

1

&$ 8 N

209

210

I

I

p" &$ 1

21 1

1n

N

N . 3

212

213 SCHEME 38

M

214

180


217

trans-quinolizidine. MS fragments were typical for a matridine skeleton: M + (100%) with a peak at (M - 1) , average intensity signals at m/z 96, and a weak signal at mlz 98. Comparison of the I3C-NMR spectrum of matrine with that of the new alkaloid showed close similarity; the slight difference observed might best be explained by the presence of an equatorial hydroxyl group at C-9. NOE experiments also supported the structure of 9a-hydroxymatrine (217). +

N.

(-)-3a-HYDROXYSOPHORIDINE

3a-Hydroxysophoridine was isolated from Sophora alopecuroides L. (230). The mass spectrum is characterized by the peaks at m/z 264 M + (78%), 263 (M - 1) (loo%), 205, 193, 166, M - 17, etc. The type of fragmentation allows classification of the base into the alkaloids of the matrine series with sophoridine configuration (231,232). 3a-Hydroxysophoridine (218) differs in molecular weight from that of sophoridine (8) by 16 mass units. This also speaks for the

218

8

presence of hydroxyl group. The IR spectrum (3620 cm-l- hydroxyl, 2810 cm- trans-quinolizidine, 1620 cm- lactam carbonyl) is very similar to that of sophoridine and differs from the latter only by the additional absorption band at 3620 cm-'. The fact that 3a-hydroxysophoridine belongs to the sophoridine series is also suggested by the similar optical rotation dispersion curves of the two alkaloids, characterized by a smooth negative shape in the region of 600-300 nm. The position of the hydroxyl group and its configuration were determined by IHNMR analysis of 3a-acetoxysophoridine. The signal of the proton at the carbon with the acetoxy group showed as a multiplet centered at 6 4.82. The value of J

181


= 25 Hz gave evidence that the proton was axial with two methylene groups in the a positions. Double resonance spectroscopy and chemical shifts proved the methylene group to be adjacent to the nitrogen atom and together with the MS spectra allowed assignment of the hydroxyl group in 3a-hydroxysphoridine to c-3.

0. ( +)-DARVASOLINE AND ( +)-LEONTISMINE Darvasoline was isolated from Leontice Albertii Rgl. (233) and leontismine was obtained from L . Smirnovii Traut. (234). Both alkaloids have the same elemental composition (C,,H,,N,O,), and their spectral characteristics are very similar. The IR spectra showed bands of a hydroxyl group, lactam carbonyl, and trans-quinolizidine. Mass spectra also were identical, and were typical for matrine alkaloids with a hydroxyl group. Reduction of darvasoline (219) and leontismine (220) by LAH gave bases without any oxygen and apparently identical to matridine (187) to leontane (221), respectively (Scheme 39). Heating of darvasoline and leontismine with P,O, resulted in dehydration with simultaneous dehydrogenation and formation of sophoramine (195) and isosophoramine (196), respectively. This points to the presence of hydroxyl groups in both alkaloids considered to be steroisomers at C-11.

& n

N H

187

219

c -

195

8NH

221

220 SCHEME 39

196

182

KH. A . ASLANOV, YU. K. KUSHMURADOV, AND A. S. SADYKOV

P.

(+)-5a,!h-DIHYDROXYMATRINE

5a,9a-Dihydroxymatrine was isolated from Euchresta horsfeldii (235). There are absorption bands of two hydroxyl groups (3400 and 3250 cm-I), a lactam carbonyl (1602 cm- I ) , and a trans-quinolizidine (2700-2800 cm- l ) in IR spectrum of the base. The 'H-NMR spectrum is identical to that of sophoranole (5a-hydroxymatrine) and is characterized by the presence of one additional hydroxyl group at C-9. Structure 222 of this alkaloid is in agreement with these data.

222

Q. ( +)-SOPHORBENZAMINE

Sophorbenzamine, found in Goebelia pachycarpa C . A. Mey. (23),has a UV spectrum with maxima at 238 and 310 nm (log E = 4.10 and 4.16). The base is very similar to quinolizidine alkaloids with a a-pyridone ring in their structure. The IR spectrum of the base has typical absorption bands of carbon-carbon double bonds (1550, 1660 cm-'), an >N--CO group (1645 cm-l), a transquinolizidine system (2580, 2630, 2700 cm-l), and an a-pyridone ring (810 cm- l ) . Oxidation with chromic acid gave succinic and benzoic acids. Glycine, p-alanine, and a-aminobutyric acid also were obtained and identified by chromatography. This result is characteristic of quinolizidine alkaloids, and the appearance of benzoic acid speaks for the presence of an aromatic ring in the molecule. The mass spectrum of sophorbenzamineis characterized by the presence of the most intensive molecular ion peak at mlz 334. It should be noted that the (M 1)+ peak was much smaller than that of the M + ion. The ion peak at m / z 91 is a benzyl radical. The emergence of ion peaks at rnlz 305 (214 + 91) and 291 (200 91) and the bias of an m / z 149 peak suggested the benzyl group to be in ring D. The general pattern of the mass spectrum was similar to that of quinolizidine alkaloids of the matrine group. There were 18 signals in the 13C-NMR spectrum of sophorbenzamine which were assigned by analogy with spectra of other matrine alkaloids (11). Of particular interest were 8 signals between 162 and 102 ppm suggesting the presence of an a-pyridone ring and a benzyl group. Comparison of the 13C-NMR spectrum of sophorbenzamine with those of other

+

183

5. LUPINE ALKALOIDS

n

quinolizidine alkaloids containing an a-pyridone ring showed that the benzyl group is attached to C-14 as shown in 223.

R. (-)-GOEBELINE Goebeline, isolated from Goebelia pachycurpa C. A. Mey. (236),contains one double bond. On catalytic hydrogenation goebeline converts to dihydrogoebeline. There are absorption bands of a trans-quinolizidine and lactam group in the IR spectra of both goebeline and dehydrogebeline. Reduction with LAH or electrolytic reduction gave deoxotetrahydrogoebeline. Comparison of the IR spectrum of deoxotetrahydrogoebeline with that of matridine showed close similarity. Dehydrogenation of goebeline with palladized asbestos gave octadehydromatrine (177). Oxidation of dihydrogoebeline with chromic acid gave glutaric acid, while oxidation of goebeline gave succinic acid. The double bond in goebeline was therefore positioned in ring D between C-11 and C-12, as shown in 224. The fact that dihydrogoebeline was easily hydrolyzed with sulfuric acid to give goebelinic acid whereas goebeline was not supports this assignment. Another team of investigators, however, suggested the double bond in goebeline to be between C-13 and C-14, as shown in 225, and they supported their assignment by the UV

177

20 1

224

225

spectrum and the results of reduction with LAH, affording a saturated deoxo base (216). To establish the position of the double bond in goebelin an 'H-NMR comparison of sophocarpine (201) and goebeline was carried out (237). The molecular weight of goebeline of 492, corresponding to the molecular composition C30H,,N,0, (238), however, suggested goebeline might be a di-

184


226

227

mer. Since in matrine alkaloids hydrogen atoms a to lactam carbonyls are easily exchanged by deuterium and goebeline did not show any shift in its M-+ peak when heated in D,O in the presence of potassium carbonate, the authors suggested the dimeric structure 226 to represent goebeline, linking a matridine molecule with a sophocarpine molecule at carbon atoms C-14. The analysis of other dimeric alkaloidal structures was also derived by deuterium exchange, and one linking C-13 of matrine with C-14 of sophocarpine is shown in 227 (238). Synthesis of goebeline from sophocarpine (201)by thermolysis (239) does not answer the location of the interconnection of the two molecules. A Fourier spectral analysis of goebeline, matridine, matrine, and sophocarpine in the presence of europium shift-reagents proved structure 227 of a 13,14-13r,14r-didehydrodimatrine to be the correct structure of goebeline (20).

Acknowledgments Our appreciation is expressed to F. Kamayev for assistance in writing Section 11, ‘‘I3C-NMR Spectroscopy of Quinolizidine Alkaloids,” and to B. Ibragimov for assistance in writing Section 111, “X-Ray Structural Investigation of Quinolizidine Alkaloids. ”

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126. Murakoshi, I., Kidoguchi, E., Kubota, M., Haginiwa, I., Ohmija, S., and Otomasu, H. (1982). Phyrochemistry 21, 2385-2388. 127. Van Eijk, I. L., and Radema, M. H. (1982). Planta Med. 44, 224-226. 128. Van Eijk, I. L., De Kok, A. I., Romers, C., and Seykens, D. (1982). Planta Med. 44,221223. 129. Keller, W. I., and Hatfield, M. (1979). Phytochemistry 18, 2068-2069. 130. Knofel, D. (1971). “Abhandlungen der Deutschen Akademie der Wissenschaften zu Berlin, 4 Intemationales Symposium, Biochemie und Physiologie der Alkaloide, Halle (Saale),” Vol. B, S. 477. Akademie Verlag, Berlin. 131. Knofel, D., and Schiitte, H. R. (1971). J . Prakt. Chem. 312, 887-895. 132. Shaimardanov, R. A., Iskandarov, S . , andYunusov, S. Yu. (1970). Khim. Prir. Soedin., 276277. 133. Shaimardanov, R. A., Yunusov, S. Y., and Iskandarov, S. (1971). Khim. Prir. Soedin., 169174. 134. Kusshmuradov, Yu. K., Pham Hoang Ngok, Sadykov, A. S . , and Aslanov, Kh. A. (1968). Nauk. Tr. Tashk. Gos. Univ. 341, 95-98. 135. Primukhamedov, I., Gupta, P. C., Aslanov., Kh. A,, and Sadykov, A. S. (1968). Nauk. Tr. Tashk. Gos. Univ. 341, 102-108. 136. Orazgel’diev, K., Aslanov, Kh. A,, Sadykov, A. S . , and Abdullaeva, D. A. (1969). Nauk. Tr. Samark. Univ. 167, 154-158. 137. Vinogradova, V. I., Iskandarov, S., and Yunusov, S. Yu. (1971). Khim. Prir. Soedin., 463466. 138. Neuner-Iehle, N., Nesvadba, W., and Spiteller, G. (1964). Monatsh. Chem. 95, 687-709. 139. Pham Hoang Ngok, Kuschmuradov, Yu. K., Aslanov, Kh. A., and Sadykov, A. S. (1968). Nauk. Tr. Tashk. Gos. Univ. 341, 99-101. 140. Iskandarov, S . , Vinogradova, V. I., Shaimardanov, R. A,, and Yunusov, S . Yu. (1972). Khim. Prir. Soedin., 218-222. 141. Ohmija, S . , Otomasu, H., and Murakoshi, I. (1984). Chem. Pharm. Bull. 32, 815-817. 142. Carmack, M., Goldberg, S. I., and Martin, E. M. (1967). J . Org. Chem. 32, 3045-3049. 143. Chulle Kim, I., Balandrin, M. F., and Kinghorn, A. D. (1982). J . Agric. Food. Chern. 30, 796-798. 144. Bohlmann, F., Weiser, W., Sander, H., Hanke, H. G., and Winterfeldt, E. (1957). Chem. Ber. 90, 653-661. 145. Skolik, I., Wiewiorowski, M., and Jedrzeiczak, K. (1969). Bull. Acad. Pol. Sci. Ser. Sci. Chim. 17, 201-207. 146. Anderson, J. N., and Martin, R. 0. (1976). J . Org. Chem. 41, 3441-3444. 147. Wink, M., and Hartmann, Th. (1982). Z . Naturjorsch., C. Biosci. 37, 369-375. 148. Balandrin, M. F., and Kinghorn, A. D. (1982). Heterocycles 19, 1931-1934. 149. Nakano, T., Spinelli, A. C., and Mendez, A. M. (1974). J . Org. Chem. 39, 3584-3587. 150. Nakano, T., Azcunes, B. C., and Spinelli, A. C. (1976). Planta Med. 29, 241-246. 151. Kinghorn, A. D., and Smolenski, S. I. (1980). Planta Med. 38, 280-282. 152. Cho, Y. D., andMartin, R. 0. (1971). Can. J . Chem. 49, 265-270. 153. Hatfield, G. M., Keller, W. I., and Rankin, I. M. (1980). J . Nat. Prod. 43, 164-167. 154. Wink, M., Witte, L., Schiebel, H. M., and Hartmann, T. (1980). Planta Med. 38,238-245. 155. Goldberg, S. I., and Balthrs, V. M. (1969). Chem. Commun., 660-661. 156. Daily, A , , Dutschewska, H., Mollov, N., Spassov, S . , and Schumann, D. (1978). Tetrahedron Lett., 1453-1454. 157. Daily, A., Dutschewska, H., and Mollov, N. (1977). Planta Med. 32, 380-383. 158. Radema, M. H., van Eijk, I. L., Vermin, W., De Kok, A. I., and Romers, C. (1979). Phytochemisrry 18, 2063-2064. 159. Van Eijk, I. L., and Radema, M. H. (1972). Pharm. Weekbl. 107, 13-20.

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197. Kamalitdinov, D., Iskandarov, S., and Yunusov, S. Yu. (1967). Khim. Prir. Soedin., 352. 198. Rulko, F . , and Proskurnina, N. F. (1961). Zh. Obshch. Khim. 31, 308-313. 199. Sadykov, A. S., Aslanov, Kh. A,, and Begischeva, A. I. (1967). Dokl. Akad. Nauk Uzb. S.S.R., 25-27. 200. Begischeva, A. I., Petrochenko, 2. U., Aslanov, Kh. A , , and Sadykov, A. S. (1969). Khim. Pri. Soedin., 455. 201. Aslanov, Kh. A., Sadykov, A. S . , Leont’ev, V. B., and Begischeva, A. I. (1969). Khim.Prir. Soedin., 93-96. 202. Begischeva, A. I., Petrochenko, Z. U., Aslanov, Kh. A,, and Sadykov, A. S. (1971). Khim. Prir. Soedin., 452-455. 203. Begischeva, A. I., Aslanov, Kh. A,, Petrochenko, 2. U., and Sadykov, A. S . (1971). Khim. Prir. Soedin., 55-59. 204. Begischeva, A. I., Aslanov, Kh. A , , and Sadykov, A. S. (1968). Khim. Prir. Soedin., 371373. 205. Iskandarov, S., Kamalitdinov, D., Iagudaev, M. R., andYunusov, S. Yu. (1971). Khim. Prir. Soedin., 174-179. 206. Kamaev, F. G., Leont’ev, V. B., Aslanov, Kh. A,, Ustynjuk, Yu. A., and Sadykov, A. S . (1974). Khim. Prir. Soedin., 744-751. 207. Kuchkarov, S., Kuschmuradov, Yu. K . , and Aslanov, Kh. A. (1977). Khim. Prir. Soedin., 288. 208. Kojima, R., Fukushima, S., Ueno, A,, and Saiki, Y. (1970). Chem. Pharm. Bull. 18, 25552563. 209. Iskandarov, S . , and Yunusov, S. Yu. (1968). Khim. Prir. Soedin., 106-109. 210. Iskandarov, S., and Yunusov, S. Yu. (1969). Khim. Prir. Soedin., 132-133. 211. Zunnunzhanov, A., Iskandarov, S . , and Yunusov, S. Yu. (1974). Khim. Prir. Soedin., 373377. 212. Zunnunzhanov, A , , Iskandarov, S . , and Yunusov, S. Yu. (1971). Khim. Prir. Soedin., 851852. 213. Iskandarov, S., Nuritdinov, R. N., and Yunusov, S. Yu. (1964). Dokl. Akad. Nauk. Uzb. S.S.R., 32-33. 214. Iskandarov, S., Nuritdinov, R. N., and Yunusov, S. Yu. (1966). Khim. Prir. Soedin., 66-67. 215. Bohlmann, F., Rahtz, D., and Amdt, Ch. (1958). Chem. Ber. 91, 2189-2193. 216. Iskandarov, S., Nuritdinov, R. N., and Yunusov, S. Yu. (1967). Khim. Prir. Soedin., 26-31. 217. Kuschmuradov, Yu. K., Aslanov, Kh. A., and Kuchkarov, S. (1975). Khim. Prir. Soedin., 377-380. 218. Kuschmuradov, Yu. K., Kuchkarov, S.,and Aslanov, Kh. A. (1978). Khim. Prir. Soedin., 231-233. 219. Timbekov, E. Ch., and Aslanov, Kh. A. (1972). Khim.Rastitelnych Veschestv., Tashk. 4, 5465. 220. Vul’fson, N. S., and Zaikin, V. G. (1976). Uspekhy Khim. 45, 187#-It;94. 221. Kuchkarov, S., Kuschmuradov, Yu. K . , Aslanov, Kh. A,, and Sadykov, A.S. (1977). Khim. Prir. Soedin., 541-544. 222. Monakhova, T. E., Tolkachev, 0. N . , Kabanov, V. S., Perel’son, M. E., and Proskurnina, N. F. (1974). Khim. Prir. Soedin., 472-476. 223. Monakhova, T. E., Tolkachev, 0. N., Kabanov, V. S . , and Proskurnina, N. F. (1974). Khim. Prir. Soedin., 259-260. 224. Kuschmuradov, Yu. K., Eschbayev, Ph. Sch., Kasymov, A. K . , and Kuchkarov, S. (1979). Khim. Prir. Soedin., 353-355. 225. Ueno, A., Morinaga, K., Fukushima, S . , and Okuda, S. (1978). Chem. Pharm. Bull. 26, 1832- 1836.

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226. Iskandarov, S . , and Yunusov, S. Yu. (1968). Khim. Prir. Soedin., 137-138. 227. Iskandarov, S . , Kamalitdinov, D., and Yunusov, S . Yu. (1972). Khim. Prir. Soedin., 628631. 228. Sadykov, B., Iskandarov, S . , and Yunusov, S . Yu. (1974). Khim. Prir. Soedin., 377-381. 229. Yunusov, S. Yu. (1981). Alkaloids (Uzb. S.S.R., Tashk. 146. 230. Monakhova, T. E., Proskurnina, N. F., Tolkachev, 0. N., Kabanov, V. S., and Perel’son, M. E. (1973). Khim. Prir. Soedin., 59-64. 231. Vul’fson, N. S . , Ziyavidinova, Z. S . , and Zaikin, V. G. (1974). Khim. Heterosikl. Soedin., 25 1-260. 232. Iskandarov, S . , Raschkes, Ya. V., Karnalitdinov, D., and Yunusov, S . Yu. (1969). Khim. Prir. Soedin., 331-332. 233. Zunnunzhanov, A,, Iskandarov, S.,and Yunusov, S . Yu. (1974). Khim. Prir. Soedin., 115116. 234. Tkeshelashvili, E. C . , Iskandarov, S . , Mudzhiri, K. S . , and Yunusov, S. Yu. (1973). Soobshch. Akad. Nauk. Gruz. S.S.R. 69, 357-359. 235. Ohmija, S . , Higashijama, K., Otomasu, H., Murakoshi, S . , and Haginiwa, I. (1979). Phytochemistry 18, 645-657. 236. Pakanaev, Y. I., and Sadykov, A. S. (1961). Zh. Obsch. Khim. 31, 2428-2432. 237. Aslanov, Kh. A,, Kuschmuradov, Yu. K., Zainutdinov, U. N., and Sadykov, A. S. (1969). Dokl. Akad. Nauk. Uzb. S.S.R., 24-25. 238. Iskandarov, S . , Sadykov, B . , Rashkes, Ya. V., and Yunusov, S . Yu. (1972). Khim. Prir. Soedin., 347-350. 239. Sadykov, B., Iskandarov, S . , and Yunusov, S . Yu. (1975). Khim. Prir. Soedin., 606-610. 240. Wink, M., Hartmann, Th., Witte, L., and Rheinheimer, I. (1982). Z . Naturforsch. C: Biosci. 37, 1081-1086. 241. Rastogi, R., and Rajagopalan, T. R. (1984). J . Indian Chem. Soc. 61, 918-919. 242. Fitch, L., Dolinger, P. M., and Djerassi, C. (1974). J . Org. Chem. 39, 2947-2979. 243. McLean, S. Lau, P. K., Cheng, S. K., and Murray, D. G. (1971). Can. J . Chem. 49, 19761978. 244. Balandrin, M. F., Robbins, E. F., and Kinghom, A. D. (1982). Biochem. Sysr. Ecol. 10,307311. 245. Solatino, A,, and Gottlieb, 0. R. (1980). Biochem. Syst. Ecol. 8, 133-147. 246. Wink, M., Hartmann, T., Witte, L., and Schiebel, H. M. (1981). J . Nat. Prod. 44, 14-20. 247. Batra, V., and Rajogopalan, T.R. (1976). Indian J . Chem. 14B, 636-637. 248. Rodriquez, F., Gonzalez, A., and Mendez, A. (1966). An. Real. Soc. Espan. Fis. Quim. B 62, 853-856. 249. Mendez, A., Gonzalez, A,, and Rodriquez, F. (1971). Rev. Fac. Farm. Univ. Los Andes 8, 77-87. 250. Kuschmuradov, Yu. K.,GTOSS,D., and Schutte, H. R. (1972). Phyfochemistry 11, 34413445. 251. Ohmija, S., Otomasu, H., Haginiwa, I., and Murakoshi, I. (1978). Phytochemistry 17,20212022. 252. Zainutdinov, U. N . , Aslanov, Kh. A,, Kuschmuradov, Yu. K., and Sadykov, A. S . (1968). Nauk. Tr. Taschk. Gos. Univ., 341, 117-121.

-CHAPTER6 -

ALKALOIDS FROM ANTS AND OTHER INSECTS ATSUSHINUMATA Osaka University of Pharmaceutical Sciences Osaka 580, Japan AND

TOSHIRO IBUKA Faculty of Pharmaceutical Sciences Kyoto University Kyoto 606, Japan

I . Introduction 11. Occurrence and Function

A. Hymenoptera B . Lepidoptera C. Coleoptera (Beetles) D. Diptera (Flies and Mosquitoes) E. Orthoptera F. Hemiptera G. Blattariae (Cockroaches) H. Neuroptera I. Trichoptera (Caddisflies) J. Phasmida (Walking Sticks) K. Isoptera (Termites) and Other Insects L. Arthropods Excluding Insects M. Tabulation of Alkaloid Occurrences 111. Structure and Synthesis A. Piperidines B . Pyrrolidines C. Pyrrolizidines D. Indolizidines E. Quinolines F. Xanthommatin G . Papiliochromes H. Coccinellines I. Adalines J. Pyrazines K. Acyclic Amines L. Pederin M. Isoxazoles N. Quinazolinones 193

THE ALKALOIDS, VOL. 31 Copynght 0 1987 by Academ~cPress, Inc. All rights of reproduction in any form resewed.

194

ATSUSHI NUMATA AND TOSHIRO IBUKA

0. Pteridines and Purines P. Aristolochic Acid References

I. Introduction Quite a number of messages between members of the same or different species in animals are exchanged through the chemicals they produce. These molecules acting as chemical messengers are called ecomones ( I ) or semiochemicals (2) and are divided on a functional basis into pheromones, allomones, and kairomones. Insects deliver many kinds of ecomones, of which a greater part is volatile terpenes. However, quite a number of alkaloids have been found as chemical messengers in insects, and the study of alkaloids acting as attractants, defensive substances, trail pheromones, alarm pheromones, and aggregation pheromones has advanced particulariy in ants. This chapter surveys these alkaloids in insects including ants and arthropods such as millipedes, spiders, scorpions, and centipedes. Reviews on arthropod alkaloids by Tursch, Braekman, and Daloze (3) and by Jones and Blum ( 4 ) are useful sources on earlier work. The term alkaloid is used here in a very broad sense. The present review will cover biogenic amines, pigments, purines, tryptophan metabolites, and acyclic amines, some representatives of which are used for defenses and communications in arthropods.

11. Occurrence and Function

A. HYMENOFTERA

1 . Ants (Formicidae)

a. Myrmicinae. Unlike most insects, Hymenoptera (ants and wasps) can be sources of monocyclic and bicyclic alkaloids. The poison glands of myrimicine ants belonging to the subfamily Myrmicinae include many kinds of alkaloids such as piperidines, pyrrolidines, indolizidines, pyrrolizidines, indoles , pyridines, pyrazines, and histamine. The venoms of fire ants, Solenopsis (Solenopsis) species, are characterized by a predominance of 2-alkyl-6-methylpiperidines (1 and 2 ) , although some Solenopsis species belonging to the subgenus Diplorhoptrum also contain the alkaloid (Table I). The fire ant causes damage to a variety of crops and attacks livestock and human beings. The fire ant venom, secreted at the sting to human beings, is a potent necrotoxin, producing edema, pustule, and necrosis (3,and in addition possesses pronounced hemolytic (6), phytotoxic (3,insecticidal (8), antibac-

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terial (8), and antifungal (9) activities. It has been demonstrated that the predominant piperidine alkaloids of the fire ant venom are responsible for most of the activity. Thus, localized skin lesions are shown to be produced by four piperidines , cis-6-methyl-2-n-undecylpiperidine(lc), transd-methyl-2n-tridecylpiperidine (lf), cis-6-methyl-2-n-pentadecylpiperidine (lg), and cis-6-methyl-2-n-pentadecenylpiperidine(2c) (10). truns-6-Methyl-2-n-undecylpiperidine (Id), trans-6-methyl-2-n-tridecylpiperidine (If), and trans-6methyl-2-n-pentadecylpiperidine (lh), named solenopsin A, B , and C, respectively, inhibit a number of the gram-positive bacteria to some degree, and solenopsin A (Id) and B (If) slightly inhibit some species of gram-negative bacteria (11). Five of the 2-alkyl-6-methylpiperidines produce an inhibition of growth of 13 fungi (9). In addition to the above-mentioned properties, the piperidine alkaloids exhibit a wide range of physiological activities. Thus, neuromuscular transmission is shown to be blocked by l c and Id (12). Mitochondria1 respiration is decreased and oxidative phosphorylation uncoupled at low concentrations of l g (13), which, in addition to cis-6-methyl-2-(cis-6'-n-pentadecenyl)piperidine (2c), inhibits the reactions of the Na ,K -ATPase (14). Venoms from the fire ants Solenopsis invicta and S. geminata are free of detectable histamine but possess histamine-release activity. This activity can account for the edema, itch, redness, warmth, and possibly the pain and burning sensations resulting from fire ant stings. And it can be attributed to the piperidines which constitute the major component of the venom. It has actually been proved that 6-methyl-2-n-undecylpiperidines (lc and Id), components of S. geminata, possess the histamine-release activity (15). Due to some of the abovementioned various activities the piperidine alkaloids play roles as defensive compounds. In addition to 2-alkyl-6-methylpiperidines, their N-methyl derivatives (3) are found in S. pergandei, S. carolinensis, and S. conjurata, and 1piperideine derivatives (6 and 7) in S . sp. A (Puerto Rico) and S. xyloni (Table I). Thief ants, many species of Solenopsis (Diplorhoptrurn), steal brood from the nests of other species of ants (16,17). While invading the brood chambers and preying on the brood, the thief ants secrete a highly effective and long-lasting repellent secretion from the poison glands (18,19). The principal components of the poison gland secretion are 2,5-dialkylpyrrolidines (lo), which S. punctaticeps, a species more closely related to thief ants than fire ants, also include along with 2,5-dialkyl-l-pyrrolines(12) in the poison gland (Table 11). Thus, S. (Diplorhoptrurn)fugax secretes trans-5-butyl-2-heptylpyrrolidine (1Oc) in order to effectively repel several species of host ants, and hence it is the key element in the raiding strategy of this thief ant (16,18,19). Workers of pharaoh's ant, Monomorium pharaonis, utilize their poison gland secretion as an effective repellent in the same way as that of thief ants, Solenopsis (Diplorhoptrum) species, in order to steal brood from the nests of other +

+

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species of ants. In addition to this repellent or defense function, the venom plays a role as trail pheromone for the workers and queens of M . phuruonis (16). The poison gland secretion contains four 2,5-dialkylpyrrolidines (10a, 10f, log, and 10h, named monomorine 11, 111, IV, and V, respectively) as well as two indolizidines (16a and 18, named monomorine I and VI) (Table 11). The major components, (52,9E)-3-butyl-5-methylindolizidine(16a) and trans-2-(5-hexenyl)-5-pentylpyrrolidine(100 (monomorine I and III), have both attractant and trail-following activities. A mixture containing monomorine I (10 pg) and 111 (100 ng) is significantly more attractive than either of the single compounds. The mixture also acts as a repellent toward other insects and elicits alarm behavior. Monomorine 111, which is much more abundant in queens than workers, acts as an aggregation pheromone (16,19-23a, b ) . A terpene, faranal, from Dufour’s gland of the pharaoh’s ant, produces a much greater trail-following activity than that of monomorine (24). The venom of other Monomorium species appears to be utilized as repellents for other ant species and has been shown to contain 2,5dialkylpyrrolidines (lo), their N-methyl derivatives (ll),and 2J-diakyl- 1-pyrrolines (12) (Table 11) (16,25). Solenopsis (Diplorhoptrum)conjurutu and some other thief ants contain indolizidines and/or piperidines (Tables I and 11). (52,8E)-3-Heptyl-5-methylpyrrolizidine (48) has also been shown to be contained in the thief ant Solenopsis xenovenenum (Table IV). The poison glands of Aphaenogaster fulva and A . tennesseensis contain the tobacco alkaloid anabaseine (S), which functions as an attractant in A. fulvu (Table I) (26). Leaf-cutting ants of the genera Attu and Acromyrmex use trail-marking pheromone while foraging. The pheromone of the Texas leaf-cutting ant, Attu texunu (Buckly), which is produced in the true poison gland (27,28), has been identified as methyl 4-methylpyrrole-2-carboxylate (14) (Table 11). This compound shows trail-following activity to most other attine species (29), and it has also been isolated from the worker abdomens of Attu cephalotes, A. sexdens rubropilosu, and Acromyrmex octospinosus (Table 11). The bioassay of a number of synthetic analogs of 14 suggests that greatest activity is obtained with compounds having a free NH, an adjacent ester function, and a substituent at ring position 4 (30,31). In addition to the pyrrole (14), A . sexdens rubropilosu contains 3-ethyl-2,5dimethylpyrazine (20b) (Table 111) as the major component of the trail pheromone. Attu sexdens sexdens also responds strongly to the pyrazine (20b) (32). Although Acromyrmex octospinosus also contains the pyrazine (20b) and its isomer, 3-ethyl-2,6-dimethylpyrazine (21b) (Table 111), these compounds do not produce trail-following responses. 3-Ethyl-2,5-dimethylpyrazine(20b) has been identified as a single component of the trail pheromone of eight species of Myrmicu (Table 111). The same compound (20b) as well as 2,5-dimethylpyrazine (20a) have also been identified as the trail pheromone of Tetrumorium cuespitum


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(Table 111). A 70 : 30 mixture of 20a and 20b provides the highest activity in artificial trail-following tests (33). The plant growth regulator, P-indolylacetic acid (IAA) (139), has been isolated and identified together with phenylacetic acid (PAA) from the metathoracic glands of myrmicine ants such as Atta sexdens, Myrmica laevinodis, and Acromyrmex sp. (Table VIII). Analysis of the fungal garden cultivated by the leafcutting ants, A . sexdens, shows that these acids contribute to the ant-fungus symbiosis by promoting growth of the fungus (34).

b. Ponerinae, Formicinae, Dolichoderinae, and Myrmeciinae. A number of alkylpyrazines are isolated from the mandibular glands of the ponerine, formicine, dolichoderine and myrmeciine ants belonging to the subfamilies Ponerinae, Formicinae, Dolichoderinae, and Myrmeciinae, in addition to the myrmicine ant (Table 111). Pyrazines such as 3-isopentyl-2,5-dimethylpyrazine (20h) and 2,5-dimethyl-3-(2-methylbutyl)pyrazine(209, which are contained in the mandibular glands of the ponerine ants Odontomachus species, Hypoponera opacior, and Ponera pennsylvanica, the formicine ant Calomyrmex sp., and the myrmicine ant Wasmannia auropunctata (Table III), have been shown to act as alarm pheromones and/or defensive substances for the respective species (3540). In 0 . troglodytes there is a caste-specific difference in the behavioral response to the pyrazines of the mandibular glands. The males retreat from the pyrazines whereas the workers are not only attracted to but attack the pheromone source (36). The presence of a series of alkylamines and amides (114-120, 125-129) in the gasterothorax characterizes the two ponerine ants, Mesoponera species (Table VIII), which contain 3-isopentyl-2,5-dimethylpyrazine(20h) as the major exocrine compound in their heads (Table 111). The major amine is N-isoamyl-Nnonylamine (114). These compounds are perhaps utilized as defensive compounds against selected predators (41). Actinidine (9a) has been identified as an anal gland product of three species of dolichoderine ants in the genera Conomyrma and Iridomyrmex (Table I). The venoms of ants of the Myrmecia species are rich in histamine (136) (Table VIII), which can act as a defensive substance, together with hemolytic, smooth-muscle-stimulating, and histamine-releasing components. Pteridines are widespread in the animal kingdom, and particularly among insects (Table VI) (42). The red ants in the genera Formica, Lasius, and Raptiformica contain pteridines such as isoxanthopterin (67) and biopterin (70) (Table VI). One of the catecholamines, noradrenaline (133), is also detected from Formica rufa (Table VIII).

c. Dorylinae. Skatole (140) has been extracted from the heads of workers of army ants, Neivamyrmex nigrescens (Dorylinae) (Table VIII). This compound, probably produced by the mandibular glands, repels several insectivorous

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snakes and inhibits the growth of the bacterium Escherickia coli and the fungus Aspergillus parasiticus; it therefore may contribute to the survival of this ant (43). Agitated soldiers of the myrmicine ant Pkeidole fallax also produce skatole (140). In addition, males of the formicine ants Lasius neoniger, L . aliensus, and Acanthomyops claviger produce mixtures of skatole (140) and terpenes which originated in the heads (Table VIII). These mixtures are discharged during mating flights and probably are used as mating pheromones (44).

2. Wasps and Bees Many wasps belonging to the families Eumenidae, Sphecidae, Nyssonidae, Tiphiidae, and Larridae contain various alkylpyrazines (Table 111). The alkylpyrazines of the cephalic secretion of four species of eumenid wasps in the genera Ancistrocerus, Stenodynerus, Pseudodynerus, and Eumenes may have a role in the wasp’s presocial behavior, e.g., aggregating at nocturnal roosting sites (45). The venoms of many kinds of bees, wasps, and hornets (the genera Vespa, Polistes, Vespula, Ropalidia, etc.) contain biogenic amines such as histamine (136), serotonin (141), and catecholamines in addition to polyamines such as putrescine (lll),spermidine (110), and spermine (112) (Table VIII). The biogenic amines in the venoms act as the main pain-producing principles (46). The contents of these amines in the venom may affect the severity of pain production, edematous reaction of the skin, or increase in skin permeability by stings of these insects. Consequently these amines act as toxins for their defense, together with acetylcholine, enzymes, and peptides (47). Purines such as xanthine (91), hypoxanthine (92), guanine (93), and uric acid (95) are found in excreta of many insects (Table VI) (48). Uric acid (95) is known to be the main end product of nitrogen metabolism in almost all insects. Various purines are found in the wasp (Vespa) and the sawfly (Gilpinia) in common with other insects (Table VI). In addition, various pteridines occur in Vespa and in the honeybee (Table VI). The latter also contains xanthurenic acid (52) or kynurenic acid (53), xanthurenic acid 4,8-diglucoside (56), and a yellow pigment, xanthommatin (58), as tryptophan metabolites (Table V). B . LEPIDOPTERA

1. Butterflies

a. Pieridae. It was during initial studies on the naturally occurring pteridines that xanthopterin (65) and leucopterin (68) were isolated as wing pigments from the English brimstone butterfly (Gonepteryx rkamni) and the European cabbage butterfly (Pieris brassicae), respectively (49).Thereafter many kinds of


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pteridines have been isolated from many species of butterflies, moths, and other insects, along with purines (Table VI). The accumulation of pteridines in butterflies as wing pigments is, however, seen only in the Pieridae. Originally, pteridines must have been either synthesized as wing pigments or deposited in the cuticular scales as a form of excretion. In the Pieridae as represented by P . brassicae, the “extra” pteridines are stored as excretory products of the general nitrogen metabolism, with a secondary function of pigmentation (50).The marvelous coloration of some pierids may be a warning signal to would-be transgressors (51). The cabbage worm butterfly Pieris rapae crucivoru and the sulfur-colored Catopsilia crocale are both found to afford the anticancer component isoxanthopterin (67) (51). In addition, isoxanthopterin (67) from the skin of the European minnow, Phoxinus phoxinus, elicits the fright reaction and hence acts as the alarm substance (52). Butterflies and moths, in common with other insects, contain purines as an end product of nitrogen metabolism (Table VI). In Pieris rapae crucivoru, uric acid (95) is present in the male wings at three times the level in the female wings, and it occurs chiefly in the white parts. It is therefore believed to contribute partly to the sex differences of the wings under UV light, which are related to sexual behavior of this species. The male begins its mating behavior after recognizing the UV reflection of female wings (53). Isoguanine (94), which is found in Prioneris wings along with hypoxanthine (92), xanthine (91), and uric acid (95), shows antineoplastic activities (Table VI) (51). Isolation of urocanic acid (137) from this wing material represents the first detection of this histidine derivative in an arthropod (Table VIII). A nonpteridine pigment, xanthommatin (58) (cf. Section II,B,l ,b), is found in the larval body of Pieris brassicae (Table V) .

b. Nymphalidae. Males of the danaid butterflies belonging to the subfamily Danainae possess a pair of abdominal brushlike scent organs called “hairpencils.” During courtship flight, males protrude and expand their hairpencils which are brushed against the head and antennae of the female to subdue and seduce her (54-56). Therefore, hairpencils secrete aphrodisiac pheromones which stimulate females for mating ( 5 7 3 ) . Four dihydropyrrolizines (25-28) and one pyrrolizidine ester (29) have been found in hairpencils of many danaid butterflies (Table IV). Danaidone (25), which was first isolated from Lycorea ceres ceres (55) and Danuus gilippus berenice (59)by J. Meinwald et a l . , has been shown to act as an aphrodisiac pheromone necessary for successful courtship in D . gilippus berenice (57) and in D . chrysippus (56), since danaidone-lacking males have reduced courtship success (57,60). It seems likely that a similar role will be found for the closely related aldehydes, hydroxydanaidal(26) and danaidal(27). In addition to the hairpencils, male Danaus butterflies possess pockets on the

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hind wings which house a glandular organ. Independent of courtship behavior, a hairpencil is sometimes inserted into the wing pocket which itself contains danaidone (25). This contact behavior is shown by experiments on Danaus chrysippus to be prerequisite for the synthesis of danaidone (25) (56). Male danaid butterflies are strongly attracted to, and sometimes feed on, dead and withering plants, e.g., the genera Tournefortia, Heliotropium, and Cyanoglossum (family Boraginaceae), Senecio and Eupatorium (family Compositae), and Crotalaria (family Leguminosae) (61,62). These plants are not normally larval food plants, and all contain pyrrolizidine alkaloids (PAS) (61). Many danaid butterflies are shown to store ingested plant PASin their bodies (Table IV) (63-65). Danaidone (25) is not found in wing pockets and hairpencils unless male butterflies such as Danaus chrysippus are allowed to suck on a withered Heliotropium plant or feed on a mixture of PAS or the Heliotropium alkaloid, lycopsamine (29), found in hairpencils (66,67). Also, danaidone (25) does not appear on the hairpencil unless contacts between hairpencils and wing pockets are established or unless 25 is present in the wing pocket (56,67). Therefore, danaidone (25) occurs on the hairpencils only after the males have ingested plant PAS as precursors and then dipped the hairpencils into the wing pockets (56).In addition to the use as precursors for male pheromones, the toxic PASstored in the bodies act as defensive substances against predators (65,68). Three 3-alkyl-2-methoxypyrazines(24b, 24c, and 24d) are detected as odor components in the monarch butterfly, Danaus plexippus (Table 111). The wide variability in pyrazine content observed with this insect is correlated with similar variability in the larval food plants, Asclepias sp. It seems possible that the pyrazines may be one of the factors implicated in the food choice mechanism (69). Pigment groups other than pteridines including ommochromes and papiliochromes occur as wing pigments in butterflies. Ommochromes are divided into three subgroups, ommatin, ommidin, and ommin. Rhodommatin and ommatin D are present in the Nymphalidae, especially in the red and orange scales of the genera Vanessa, Aglais, Znachus, and Arginnis, and xanthommatin (58) occurs in wings of the genus Heliconius (Heliconidae) (Table V) (70). Vanessa urticae contain xanthommatin (58) in adult secretions and two biogenic amines, noradrenaline (133) and dopamine (134), in the larvae (Tables V and VIII).

c. Papilionidae. Papiliochromes including papiliochrome I1 (142), papiliochrome M, and papiliochrome R are found as wing pigments in Papilio butterflies. Papiliochrome TI (142; see Section III,G) is a major pigment of the pale yellow scales in the species Papilio demoleus, P. protenor, P. helenus, P. castor, P. polytes, P. xuthus, and P. dardanus (71). 3-Ribosyluric acid (98) is widely distributed in wings of lepidopterous insects such as Papilio xuthus (Table VI), suggesting a physiological role in wing formation (72). The swallowtail butterfly Pachlioptera aristolochiae, feeding on the leaves of


20 1

Aristolochia species (Aristolochiaceae), stores the constituents of the host plant (Aristolochia clematis), aristolochic acid I (143; see Section IILP), in body tissues as do the danaid butterflies (73). The aposematic butterfly Zerynthia polyxena, feeding on the same plant, stores aristolochic acid Ia (144) and aristolochic acid C (145; see Section 111,P); the former is found in A . debilis and A. watsonii, while the latter has not yet been detected in the host plant. These alkaloids play roles as the defensive substances (74).

2 . Moths Males of the arctiid moths (family Arctiidae) also have a pair of brushlike glandular structures, the coremata, which they evert from the abdomen during close-range precopulatory interaction with the female. The coremata of male arctiid moths of the genera Creatonotos and Utetheisa produce mainly hydroxydanaidal (26) (Table IV), which is shown to have a pheromonal role (75). This pheromone is derived from defensive PAS that the moths sequester from their larval food plants (Crotalaria sp.) (75,76). The PAS control the morphogenesis of the coremata (76).The cinnabar moths of the genus Callimorpha store plant PAS in their body tissues (Table IV) as do the danaid butterflies. Males of the chrysomelid beetle, Gabonia gabriela (Coleoptera: Alticinae), and adults of both sexes of the elegant grasshopper, Zonocerus elegans (Orthoptera: Pyrgomorphidae), are known to be attracted to and feed on withered plants of the genus Heliotropium containing PAS. It is assumed that these insects parallel the utilization of PAS by Lepidoptera (77.78). 3-Alkyl-2-methoxypyrazinesare found in moths of the genera Zygaena (Zygaenidae) and Amata (Amatidae) as odor components (Table 111). It seems that the striking pyrazine odors in these moths are a defense mechanism, alerting predators which hunt by smell to the dangerous qualities of the potential prey, in much the same way as the color red or black and yellow stripes alert predators which hunt by sight (69). Larvae of the brown-tail moth Euproctis chrysorrhoea (Lymantriidae) contain histamine (136) along with a protein and enzyme. These constituents are presumably responsible for the toxic reaction in skin penetrated by the hairs (79).The presence of histamine (136) has been demonstrated in venomous hairs or spines of other caterpillars (Table VIII). The silkworm, Bombyx mori (Bombycidae), contains in various body parts simple alkylamines, tryptophan metabolites, and pteridines (Tables V, VI, and VIII). One of the pteridines, violapterin (78), is synthesized from isoxanthopterin (67) by isoxanthopterin deaminase, occurring in the larvae and adults, and is stored in situ in the larval and adult integument (80). In addition, sepiapterin deaminase in the integument of the lemon mutant silkworm cqtalyzes the deamination of sepiapterin (81) to 7,8-dihydro-6-lactyllumazine(79) (81). Xanthommatin (58) and dihydroxanthommatin (59) are found as yellow and

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red pigments in the larval integument of the Mediterranean flour moth, Ephestza kiihniella, and pteridines such as xanthopterin (65), ekapterin (74), and pterorhodin (86) occur in their heads (Tables V and VI). Various purines, especially uric acid (95), are found in many kinds of moths in common with other insects (Table VI). In the larvae of the rice stem borer, Chilo suppressalis, 3-ribosyluric acid (98) is detected in the fat body and integument but not in the blood, suggesting that it may play a role in the transfer of uric acid from fat bodies to Malpighian tubes and hindgut (82).

C. COLEOPTERA (BEETLES)

1. Coccinellidae Ladybugs, in common with other insects, have the peculiar habit of emitting small droplets of blood from one or more points on their body surface when they are molested. This autohemorrhage, called “reflex bleeding,” constitutes an efficient protection against predators (83,84). The chemical deterrent present in the hemolymph droplets of the common European ladybug, Coccinella septempunctatu, was shown initially to be the novel alkaloids, precoccinelline (100) and its N-oxide, coccinelline (99) (85). From a variety of Coccinellidae and one species of Cantharidae have been found thereafter these and six other related alkaloids, convergine (101), hippodamine (102), myrrhine (103), propyleine (104), hippocasine (105), and hippocasine oxide (106) (Table VII). These ladybug alkaloids constitute an effective defense against ants, Myrmica rubra, and quails, Coturnix coturnix, but all the beetles containing alkaloids do not possess the same degree of protection (86). The bicyclic homotropane adaline (107) has been isolated from the defensive secretion of European ladybugs belonging to the genus Adalia (Table VII). It has been demonstrated to have repellent properties to various insects (87). A lower homolog (108) of adaline (107), previously isolated from the Australian plant Euphorbia atoto (88) and lately named euphococcinine (89), is found in the defensive secretion of the Australian mealbug ladybird, Cryptolaemus montrouzieri, along with 1-(6-methyl-2-piperidyl)propan-2-one(4) (Tables I and VII) (87). Euphococcinine (108) is also present in the blood of the Mexican bean beetle, Epiluchna varivestis (Table VII) . When attacked by predators, these beetles ‘‘reflex bleed,” emmiting droplets of blood from the tibiofemoral joints of the legs. The alkaloid in the released blood has been proven deterrent to spiders and ants (89). The ladybug, Hippodamia convergens, contains a novel aliphatic diamine, harmonine (121), identified as lt17-diaminooctadec-9-ene, beside hippodamine (102), convergine (101), and n-octylamine (113). Harmonine (121) is also present in Hurmonia leis conformis and other ladybugs (Table VIII).

(a-


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2. Staphylinidae It has been known for long that a component in the hemolymph of many species of staphylinid beetles (the genus Paederus) acts on the skin and eyes of human beings and other warm-blooded animals to cause dermotoxic symptoms-blister dermatitis, erythematic-vesicular dermatitis, and endemic ophthalmitis, etc.-called ‘‘pederosis” (90).The vesicant component has been isolated by M. Pavan and co-workers in a pure crystalline state from Paederus fuscipes and named pederin (147; see Section II1,L) (91).This compound is also found in P . melanurus, P . litoralis, P . rubrothoracicus, P . rufocyaneus, and P . columbinus (92). Furthermore, two other related components, pseudopederin (148) and pederone (149) have been isolated from P . fuscipes (91a,93).The latter is also found in P . columbinus (92). It is doubtful whether the insect uses pederin for defensive purposes, because it acts on the skin of animals only when it is crushed and not through mere contact with the insect, even if prolonged. It also has neither insecticidal nor repellent properties (92). However, it causes epidermic necrotization as acute pederosis and desquamation as chronic pederosis on human skin. On the other hand, it stimulates bedsore cicatrization in lower doses and leads to complete healing. Application to mouse skin produces dermatitis with necrosis or huge edema, and the damaged tissue is reconstituted with a permanent loss of hair. Beside this dermatoxic activity pederin (147) has various biological activities (92). When administered in appropriate doses to partially hepatectomized rats, this compound stimulates development of hepatic tissues. The inhibitory effect at the cellular level has been found in chicken heart fibroblast cultures, and mice embryo, dog kidney, HeLa, and KB cell lines. In plants, root growth of Lupinus albus is inhibited and mitosis in Allium cepa blocked at the metaphasic stage. Also, pederin (147) inhibits protein synthesis and growth of yeast cells. In addition, the treatment of rat ascites sarcoma with purified extracts of P . fuscipes produces almost complete regression. Pseudopederin (148) and pederone (149) display the phytoinhibition, the dermotoxic, and toxic endoperitoneal action in mice, as well as the inhibitory activities on various animal and human cell strains. However, their effects are much less than those of pederin (147). Pederone (149) causes less endoperitoneal toxicity in viva than the other two substances. Stenusin (5) is emitted from pygidial defense glands of an aquatic staphylinid, Stenus comma (Table I). When the beetle sometimes falls into the river during hunting for springtail or other actions, the alkaloid (5) can propel it toward the river bank owing to its extremely high spreading ability, in the same way ad a toy boat is propelled by camphor, and save it from drowning (94-96). This alkaloid may also have a protective function for this beetle, because it is weakly toxic to mice. Acridine (9a) is found in the defensive secretions of the rove beetles in the genera Cafius, Gabrius, Hesperus, and Philonthus (Table I).

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3. Lycidae The aposematic beetle, Metriorrhynchus rhipidius, contains three pyrazines as warning odor components and two amides as bitter principles (Tables 111, V, and VIII) (97). Of the three components with the beetlelike odor, the most characteristic is 2-methoxy-3-isopropylpyrazine (24b). The other two components are 2-methoxy-3-methylpyrazine (24a) and 2-methoxy-3-sec-butylpyrazine (24d). It would seem likely that these compounds will occur in the defensive systems of the aposematic beetles. The two amide components, detectable in the hemolymph exuded by adult beetles, are 3-phenylpropanamide(130) and 1-methyl-2quinolone (57), the latter being the major component. It seems likely that these bitter principles contribute to distastefulness to potential predators.

4. Chrysomelidae The defensive secretion of adult chrysomelid beetles (leaf beetles) belonging to the subfamily Chrysomelinae is characterized by the presence of two isoxazolin-5-one glycosides (150 and 151; vid. 1II.M) (98).These compounds, first found in Crysomela tremulae (tribe Phaedonini), have been detected in the Phaedonini, C . populi, Gastrophysa viridula, Prasocuris phelladrii, Hydrotassa marginella, and Phaedon brassicae, and the Phratorini, Phratora laticollis, P . tibialis, and P . vitellinae. 5. Dytiscidae and Noteridae

The pygidial glands of many species of water beetles (Dytiscidae and Noteridae) contain the plant growth regulator, 3-indoleacetic acid (139), along with benzoic acid, phenylacetic acid, and methyl p-hydroxybenzoate (Table VIII). The water beetles use these chemicals mainly for preventing attachment of microorganisms on their chitin surfaces. From time to time the beetles therefore leave the water and engage in a characteristic cleaning behavior, using their legs as brushes for coating their surfaces with pygidial gland secretions (99). The prothoracic defensive secretion in one of water beetles, Ilybius fernestratus, contains as a main component methyl 8-hydroxyquinoline-2-carboxylate (51) (Table V), which is not toxic to amphibians and fishes but produces clonic spasms in small mammals like mice (96,100,101). 6. Other Beetles

Some pteridines are found in mealworm beetles, Tenebrio moritor (Tenebrionidae), and some beetles in the family Catopidae; some purines, especially uric acid ( 9 9 , occur in several beetles (Table VI). In addition, T . moritor


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contains three catecholamines, adrenaline (132), noradrenaline (133), and dopamine (134). Putrescine (111) is detected in the May beetle, Melolonthu vulgris (Table VIII).

D. DIFTERA(FLIESAND MOSQUITOES)

1. Trypetidae A'-Pyrroline (12i) is emitted by sexually mature male Mediterranean fruit flies (Cerutitis cupitutu), together with 2-ethyl-3,5-dimethylpyrazine(21b) (Tables I1 and 111). This cyclic imine (12i) is the key component in the sexual attraction of virgin female flies to males (102). Xanthommatin (58) and two pteridines (81 and 84) are also found in this fruit fly (Tables V and VI). The rectal gland secretions of the male melon fly, Ducus cucurbitue, contain three pyrazines and three amides. The major pyrazine component is tetramethylpyrazine (22a); methylpyrazine (23a) and 2,3,6-trimethylpyrazine (21a) are present as minor components (Table 111). The amide components are Nisoamylacetamide (122), N-2-methylbutylacetamide(123), and 2-methoxy-Nisoamylacetamide (124) (103). The former two amides are also present in the rectal gland secretion of the males of Ducus tryoni and D . neohumerulis (Table VIII) (104). N-Isoamylacetamide (122) has been shown to elicit a zigzag flight response of virgin female D . cucurbitue toward the odor source (103). In D . oleue are found xanthommatin (58) and two pteridines (81 and 85) (Tables V and VI) . 2. Drosophilidae The eyes of the fruit fly Drosophilu melunoguster contain tryptophan metabolites such as xanthurenic acid (52), kynurenic acid (53), xanthommatin (58), and dihydroxanthommatin (59) (Table V) in addition to some purines and serotonin (141) (Tables VI and VIII). Although various pteridines are found in dipterous insects, the genus Drosophilu is characterized by the occurrence of drosopterin (87a), isodrosopterin (87b), neodrosopterin (88), aurodrosopterin (89), and fraction e (90) (Table VI). Pteridines including isoxanthopterin (67) in the ejaculatory bulb of D . melunoguster are suggested to be involved in the reproductive physiology of this species, probably playing a role in sperm transfer (105). 3. Cailiphoridae Xanthommatin (58) is detected in blowflies of the genera Culliphoru and Protophormiu beside xanthurenic acid (52) and kynurenic acid (53) in the latter

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(Table V). Some pteridines are found in species of Calliphora, Chrysomya, and Lucilia in addition to uric acid (95) in the last species (Table VI).

4. Culicidae, Muscidae, and Others Histamine (136) is detected in mosquitoes of the genera Aedes and Culex (Culicidae) beside uric acid (95) in the former (Tables VI and VIII). Catecholamines such as adrenaline (132), noradrenaline (133), and dopamine (134) are found in the larvae of the housefly, Musca domestica (Muscidae) (Table VIII). Some pteridines are found in species of the genera Cnephia (Simuliidae) and Piophila (Piophilidae) and in other Diptera. Species of the genus Glossina (Glossinidae) contain uric acid (95) (Table VI).

E. ORTHOPTERA 1. Acrididae (Locusts) Three acyclic amines, dimethylamine (109), putrescine (lll),and spermidine (110), have been isolated from the accessary sexual glands of the mature male desert locust, Schistocerca gregaria (Table VIII). In addition, A'-pyrroline (12i) has been identified as a volatile emanating from the mature male locust colony (Table 11). It is an oxidation product of putrescine and probably could be responsible for the maturation-accelerating effect observed to be specific to the mature male insect ( I 06). Some pteridines and uric acid (95) are detected in locusts of the genera Locust and Schistocerca (Table VI). Kynurine (54) is found in the genus Dociostaurus and xanthommatin (58) in the genus Locust, as tryptophan metabolites (Table V).

2. GryUidae (Crickets) A yellow pigment, xanthommatin (58), is found in crickets of the genus Gryllus, and uric acid (95) occurs in the genus Acheta (Tables V and VI). F. HEMIFTERA Pteridines and purines are found in many species of Hemiptera, as shown in Table VI. A red pigment, erythropterin (73), detected in almost all species of Heteroptera, is very often considered to be responsible for the sometimes bright red color of these species, together with carotenoids (107).Histamine (136) is detected in bedbugs of the genus Cimex (Heteroptera, Cimicidae) (Table VIII).

6 . ALKALOIDS FROM ANTS AND OTHER INSECTS

207

G. BLATTARIAE (COCKROACHES) Uric acid (95) is found in many kinds of cockroaches in addition to pteridines (Table VI). It is stored in the utriculi majores of the accessory sex glands of the German cockroach, Blattella germanica (Blattelidae). Most of the uric acid (95) is eliminated during copulation by being poured over the spermatophore. Mating appears to be an important means of excretion in this cockroach (108). In addition, 5-hydroxytryptamine (5HT) (141) and dopamine (134) are contained in the nerve cord of the American cockroach, Periplanetu americuna (Blattidae) (Table VIII).

H. NEUROPTERA The secretion from the prothoracic glands of the lacewing Chrysopa oculatu (Chrysopidae) contains skatole (140) and tridecene (Table VIII) and offers some protection against invertebrate predators, such as ants. Uric acid (95) is stored as one of the excretory products of nitrogenous metabolism in fat bodies of the larvae of C . carnea (Table VI).

I. TRICHOFTERA (CADDISFLIES) The exocrine glands of the caddisfly Pycnopsyche scabripennis (Limnephilidae) secrete a defensive exudate which contains indole (138) and skatole (140) along with p-cresol (Table VIII). This secretion effectively repels invertebrate predators such as ants.

J. PHASMIDA (WALKINGSTICKS) The end products of tryptophan metabolism in the stick insect, Carausius morosus, are the ommochromes ommin and xanthommatin (58) in the epidermis, and kynurenic acid (53) in the feces. During larval development of this insect kynurenic acid (53) is the major end product of tryptophan metabolism (Table V) (109,110).Additionally, this insect contains five pteridines (Table VI), of which leucopterin (68), xanthopterin (65), and isoxanthopterin (67) are the origin of the yellow-white color of the insect (111).

K. ISOPTERA (TERMITES) AND OTHERINSECTS Uric acid (95) is found in various species of wood-eating termites (Isoptera, Termitidae) along with kynurenic acid (53) (Tables V and VI). Three catecholamines, adrenaline (132), noradrenaline (133), and dopamine (134), are found in the whole body of earwigs of the genus Forficula (Dermaptera, For-

208


ficulidae) (Table VIII), and two pteridines, ichthyopterin (71) and sepiapterin (81), occur in Panorpa japonica (Mecoptera, Panorpidae) (Table VI).

L. ARTHROPODS EXCLUDING INSECTS 1. Myriapoda

a. Diplopoda (Millipedes). The European small millipede, Glomeris marginata, has the characteristic habit of coiling into a tight sphere when disturbed, and in response to pinching, tapping, or prodding it discharges a defensive secretion, which oozes as single droplets from eight grandular pores spaced evenly in a row along the dorsal midline of the animal. The defensive secretion contains two crystalline alkaloids, glomerin (60) and homoglomerin (61) (Table V) (112). Another millipede, Polyzonium rosalbum, contains two alkaloids, polyzonimine (19) and nitropolyzonamine (49), in its defensive secretion (Tables I1 and IV). Polyzonimine (19) is repellent to such natural enemies as ants and might effect the deterrence of various insects by acting as a topical irritant (113). b. Chilopoda (Centipedes). The sting of the centipede, Scolopendra subspinipes, causes severe pain, swelling, edema, necrosis, and sometimes death. The venom contains histamine (136) and a histamine-releasingfactor. Histamine (136) contributes to the pain production caused by centipede sting (114). The venom of another centipede (S. oraniensis institania) also contains histamine (136), while S. viridicornis contains 5HT (141) (Table VIII). 2. Arachnida

a. Acari (Ticks). Guanine (93) is regarded as the main end product of nitrogen metabolism in arachnids such as scorpions, spiders, and ticks in contrast to uric acid (95) in insect excreta (Table VI). A tick assembly pheromone present in the excretory waste pr6duct of the soft tick, Ornithodoros porcinus porcinus, has been identified as guanine (93). It is nonspecific and attracts different life stages of the same species as well as other species, namely, Argus persicus nymphs, Amblyomma cohaerens larvae, and Rhipicephalus appendiculatus adults. Among various purines tested in the assembly bioassay, xanthine (91), hypoxanthine (92), and uric acid (95) have been shown to be active for A . persicus (115).

b. Araneae (Spiders). The gluelike substance which is spread over the sticky spiral thread of the web of the garden spider, Aranea diadema, contains, in addition to two inorganic salts, pyrrolidone (13), which hinders drying out the thread (Table 11) (96,116). Histamine (136) and 5HT (141) beside polypeptides


209

are present as smooth muscle active substances in the venoms of spiders in the generaLycosa and Phoneutria (118, 119). 5HT (141) is also found in the venoms of other five species (Table VIII). Since pain is absent for 15-20 min following the bite of black widow spiders (Latrodectus sp.), 5HT (141) may not serve a defensive role through induction of pain, but may facilitate the distribution and penetration of the toxic proteins (120). Spermine (112) is found in Atrax species (Table VIII) .

c. Opiliones (Harvestmen). The defensive secretion of the harvestman, Sclerobunus robustus, contains N,N-dimethyl-P-phenylethylamine(131), a new natural product, as the major component, in addition to nicotine (SO) (Tables I and VIII) (117). d. Scorpiones (Scorpions). 5HT (141) is present in the venoms of various scorpions (Leiurus quinquestriatus, etc.) (Table VIII). It can undoubtedly contribute greatly to the pain caused by a scorpion sting (121). M. TABULATION OF ALKALOID OCCURRENCES

Tables I through VIII summarize the occurrences of alkaloids from ants and other insects. Each table presents chemical structures as well as specific sources of particular types of alkaloids; e.g., Table I covers piperidines and pyridines, Table 11, pyrrolidines, pyrroles, and indolizidines.

210

ATSUSHI NUMATA and TOSHIRO IBUKA

TABLE I Occurrence of Pipendines and Pyridines Source Hymenoptera Fonnicidae (ants) Mynnicinae Solenopsis invicta (worker) S . invicta (alate queen) S . richteri (worker) S . richteri (alate queen) S . xyloni (worker) S. xyloni (alate queen) S . geminata (worker) S . geminata (alate queen) S . geminata (soldier) S . aurea S. eduardi (worker) S . saevissimu S. littoralis S . pergandei S . carolinensis Solenopsis sp. A (Puerto Rico) Solenopsis sp. B (Puerto Rico) S. conjuruta (worker) Aphaenogaster fulva A. tennesseensis Dolichoderinae Conomyrma sp. 1 (Wellborn, Texas) Conomyrma sp. 2 (Athens, Georgia) Iridomyrmex purpureus sensu stricta Coleoptera (beetles) Coccinellidae Cryptolaemus montrouzieri Staphylinidae Stenus comma Cafius xantholoma

Compound number"

lc, Id, le, If, lg, lh, 2a, 2b, 2c, 2d lc, Id lc, Id, le, If, 2a, 2b, 2c, 2d la, lb, lc, Id

Ref.

122-127 125 123-125.127 125.I28

lc, lc, lc, la,

Id, le, 2a, 7 Id Id, le, 2a lc, Id

123- I25 125 123,125,128 I25

lc, lc, lc, id, If Id, lb, 6

Id, le, 2a Id, l e Id le, If, 2a, 2b, 2d

125 124.127 I24 124 16 16 16 16

3c 3b

lb

16

la, lb, lc, 3a, 3b 8 8

I34 26 26

9a

51 7

9a

51 7

9a

129

4

87

5

94-96 130

9a

21 1


TABLE I (Continued) Source

Gabrius piliger Hesperus semirufus Philonthus politus Ph. fimetarius Ph. splendens Ph. sanguinolentus Ph. varius Ph. rectangulus Ph. temporalis Ph. carbonarius Ph. fuscipennis Ph. marginatus Ph. laminatus Ph. cephalotes Ph. cruenatus Ph. nigrita Arachnida Opiliones (Harvestman) Sclerobunus robustus a

Compound numbero

Ref.

9a 9a 9a 9a 9a 9a 9a 9a 9a 9a 9a 9a 9a 9a 9a 9a

130 131 130,131 130 130 130 130 130 130 130 130 130 130 130 130 130

50

117

Structures:

l a

n=

8 (cis)

1e

n= 1 2 (cis)

l b

n=

8 (trans)

1f

n= 1 2 ( t r a n s )

l c

n= 0 [cis)

1g

n= 14 (cis)

Id

n= 0 [trans)

1h

n= 1 4 (trans)

solenopsin A

2 a

n= 3 (cis)

2 b

n= 3(trans)

2 c

n=

2 d n=

solenopsin B

solenopsin C

dehydrosolenopsin B

5 (cis)

5(trans)

dehydrosolenopsin C

(continued)

212


TABLE I (Continued)

3a

n= 8

(cis)

3b

n= 8

(trans)

3 c

n= 10

(trans)

flyy N’

N’

8

9a

50

213


TABLE I1 Occurrence of Pyrrolidines, Pyrroles, and Indolizidines Source Hymenoptera Formicidae (ants) Myrmicinae Solenopsis fugax S . punctuticeps S . molestu S . texunas S . conjurutu (worker) Solenopsis sp. AA (queen) Monomorium phuruonis M . ebeninum M. lutinode M . subopucum Monomorium sp. near metoecus M. viridum

M . jloricolu M. minimum Monomorium new sp. near minimum Monomorium sp. near emersoni M . cyuneum Attu texunu A . cephulotes A . sexdens rubropilosu Acromyrmex octospinosus Diptera Trypetidae (flies) Cerutitis cupitutu Orthoptera Acrididae (locusts) Schistocercu greguriu Arachnida Aranae (spiders) Aruneu d i a d e m

Compound numbera

1oc (trans) 10a (trans), 1Oc (trans), lod, 12a, 12b, 12c, 12d 10b (trans) 10b (trans) 15a 17a 10a, 10f (trans), log, lob, 16a, ltib 10e, lOh, lOi, 12g, 12h 10a (trans), 1Oc (trans), l l a , 12e, 12f 10a (trans), 1Oc (trans), log, 12f 10e, lOh, lOi, l l b , 12g, 12h lOe, lOh, lOi, l l b , llc, 12g, 12h 10e lOi, l l c lOi, 10h

Ref.

18 132,133

133 133 134 134 20-23u, b, 135-137 16,25 16 16 25 25,138 25 25 25

10h, loi, l l b

25

10h, l l b 14 14 14 14

25 41 9,420,518 519 32 139

12i

102

12i

106

13

96,116 (continued)

214


TABLE I1 (Continued)

Compound numbera

Source

Ref

Mynapoda Diplopoda (millipedes)

P olvzonium rosnlhwm

a

19

113

Structures:

10 b

‘gH1 1

'5h13

10 c

C7H15

C4H9

10d

C7H15

‘ZH5

10 e

C9H19

R 1QR2 H

10 f

log

‘gHll C7H15

10h

CgH19

1Oi

CH3

(CH2)7CH=CH2

11a

C7H15

llb

CgH19

11c

'5h13 (CH2)4CH=CH2

M.111

(CH2)4CH=CH2

M.IV

(CH2)4CH=CH2

M.V

(CH2)4CH=CH2

C4H9 ( CH2)4CH=CH2

( C H2 ) C H=CH2 ( C

) 4CH=CH2

12a

C5Hll

C2H5

12b

C2H5

‘gHll

1 2 ~

C7H15

C2H5

12d

C2H5

C7H15

12e

C5Hll

C4H9

12f

C7H15

C4H9

12 g

( c H ~ ) ~ C H = C H(CH2)4CH=CH2 ~

12 h

( c H ~ ) ~ C H = C H(~C H 2 ) 7 C H = C H 2

12 i

H

H

215



0

H3C

C02CH3

H

H

13

14

G? CH3 R

19

** M = monomorine, configuration unknown Stereochemistry unknown. 1 5 a R = C2H5 16a R = C4H9

M-I

17a R = (CH,),CH, 1 8 * R = ( C H 2 ) 4 CH=CH 2

M.VI

216


TABLE 111 Occurrence of Pyrazines ~~

Source Hymenoptera Formicidae (ants) Ponerinae Anochetus sedilloti Brachyponera sennaarensis Hypoponera opacior Odontomachus hastatus 0. clarus 0. brunneus 0. troglodytes Odoniomachus sp. Ponera pennsylvunica Rhytidoponeru metallica Mesoponera castanea M . castaneicolor Myrmicinae Acromyrmex octospinosus Aphaenogasier rudis Atta sexdens rubropilosa Myrmica rubra M . ruginodis M. scabrinodis M. sabuleti M . ruglosu M . sulcinodis M . schencki M . lobicornis Tetramorium caespitum Wasmanniu auropunctata Formicinae Calomyrmex sp. Notoncus ectatommoides Polyrhachis sp. 2A.N.1.C Dolichoderinae Iridomyrmex humilis 1. purpureus sensu

stricta

Compound numbera

Ref.

20e, 20f, 20g, 21d, 21e, 21f 21d, 21g

36.144 36,141

20h 20h 20h, 21b 21b, 2112, 21d, 2lg 21b, 21d, 21g, 21i 21c, 21d, 21g, 2Ii 20h 20h, 201 20h 20h

38,141,464 35,37,141,464 35,37,141,464 35,37,141,464 36,141,464 35,141 38,141,464 142,464 41 41

20b,21b

139

23b 20b

464 32,141

20b 20b 20b 20b 20h 20b 20b 20h 20a, 20b 20h

522,523 522,523 522,523 522,523 522,523 522,523 522,523 522,523 33 40

20e, 20h, 20i 20h

39,141 143

20h

143

20c, 20h, 20j, 20k

141,144,145, 464 129

20b, 20c, 20d

217


TABLE 111 (Continued) Source Myrmeciinae Myrmecia gulosa Tiphiidae (wasps) Tiphia sp. (M&F)b Eumenidae (wasps) Ancistrocerus antilope (MI A. campestris (M&F) Eumenes fraternus (MW Euodynerus fuscus (MW Leptochilus acolhuus (F) Monobia quadridens Pachodynerus erynnis (MW Parancistrocerus fulvipes (F) P. rufovestis (M) P. perennis (F) Parancistrocerus sp. A (M) Parancistrocerus sp. B (F) Stenodynerus floridanus S. fulvipes Pseudodynerus quadrisectus (F) Sphecidae (wasps) Eremnophila aureonotata Ammophila fernaldi ( M ) A. procera (M) A. nigricans (M&F) A. urnaria (M) A. urnaria (F) Larridae (wasps) Tachytes guatemalensis Nyssonidae (wasps) Bicyrtes ventralis Argogorytes fargei (MW A. mystaceus (M&F) Nysson spinosus (M)

Compound numberu

Ref.

20c

146

20h

464

22b

45,464

20h, 21d 20h, 21h

464 464

20h. 21d

464

20d, 20h

464

21g 20c, 21c

464 464

20c, 20h, 21d, 21h

464

20h, 21d 20h, 21d 20h, 21d

464 464 464

20h, 21d

464

2oc, 21c 20e, 21h, 22b 20h

464 45,464 45

20d, 20h

464

20h 20h 20h 21c 21d

464 464,521 464,521 464,521 464,521

20d, 20h

464

20d, 20h 20h

464 520

20h 20h

520 520

(continued)

218


TABLE 111 (Continued) Source Philunthus triungulum

Compound number”

Ref

20c, 20h

520

21a, 22a, 23a 2fb

147 102

24b, 24c, 2 4

69

24b, 24d

69

24c, 24d

69

24a, 24b, 2 4

97

(MW Diptera Trypetidae (flies) Dacus cucurbitue Ceratitis capitutu Lepidoptera Nymphalidae (butterflies) Danuus plexippus Amatidae (moths) Amutu sp. Zygaenidae (moths) Zyguenu lonicerue Coleoptera (beetles) Lycidae Metriorrhynchus rhipidius a

Stmctures: R 20 a

H

20 b

Et

20 c

n-Pr

20 d

n-butyl

20 e

isobutyl

20 f

SeC-butyi

20 g

n-pentyl

20 h

isopentyl

20 i

2-methyibutyl

20 j

20 k

(Z)-styryl (E)-styryl

20 1

citronellyl

21a

Me

219



R

21 b

Et

21 c

n-Pr

21 d

n-butyl

21 e

isobutyl

21 f

sec-butyl

21 g

n-pentyl

21 h

isopent yl

21 i

n-hexyl R1

R2

22 a

Me

Me

22 b

H

isobutyl

23 a

H

H

23 b

n-Pr

24 a

Me

24 b

isopropyl

24 c

isobutyl

24 d

sec-butyl

* M&F, Males and females; M, males only; F, females only.

(E)-1-butenyl

TABLE IV Occurrence of Fyrrolizidines Source Lepidoptera Nymphalidae (butterflies) Danainae Lycorea ceres ceres Danaus gilippus berenice D. gilippus strigosus D. hamatus hamatus D. hamatus moderatus D. hamatus D. affinis ajjinis D. affinis albistriga D. affinis

Sex"

Locationb

Compound numberc

M M M M M M M M M

H

25 25 25 25, 26, 29 25, 26 29 25, 27 25, 27 29, 42 25, 27 26 25 25 25 29, 35, 36, 37, 42 29, 42 25 35, 36, 37 29, 35, 42 29, 42 35 29, 30, 32, 42, 43, 44 25, 27 42 29, 31, 32 29, 43, 44, 45, 46, 47 26, 29 26 26 29 29, 33, 43, 44, 45, 46,47 26, 28 29, 31, 34 26 26 29, 43, 44 29, 43, 44 29, 32, 43, 44 28 26 25

M

H H H B H H B H H H H H, B B H B B B B B

M F M F

H B B B

M M M M M

H H H B E

M F M M M F M M M M

H B H H B B B H H H

M D. pumilus hebridesius D. chrysippus petilea D. chrysippus dorippus D. chrysippus

D. limniace petiverana D. plexippus D. petiverana

D. formosa D. philene decipiens

D. juvenia sobrinoides

Euploea tulliolus tulliolus E. tulliolus E. sylvester sylvester E. sylvester E. nemertes polymela

E. nemertes E. treitschkei jessica E. treitschkei aenea E. boisduvalii fraudulenta E. lewinii lilybaea Amauris albimaculata

H

M M M M M F M M M F

F

w

220

Ref.

55,148a 59 59 66,148b 61 63 148b 61 63

64 61 61 149 56,158,150 63,65 63 149 65 63 63 63

64 64 64 64 64 66,1486 61 148b 63

64 64 64 61 61

64 64 64

64 61 149

TABLE IV (Continued) ~~

Source

Sexu

A . echeria A. niavius A . ochlea

Arctiidae (moths) Utetheisa pulchelloides U. lorrix U. ornatrix Creatonotos gangis C . transiens Nyctemendae (moths) Callimorpha jacobaeae C . jacobaeae Hymenoptera Farmicidae (ants) Mynnicinae Solenopsis xenovenenum Myriapoda Diplopoda (millipedes) Polyzonium rosalbum a b

c

Locationb

Compound numberc

Ref.

M M M M M F

H B H H B B

25 35 25 25 42 39. 42

149 63 149 149,151 63 63

M M M M M

C C C C C

26 26, 27 26 26 26

423 423 75 76 76

P B

35, 36, 38, 40, 41 35, 36, 38

152 152

48

430

49

153

M, Male; F, female. H, Hairpencil; C, coremata; B, body tissue of imago; P, pupae; W, wing pocket. Structures:

26 R=OH hydroxydanaidal

25 danaidone

27

R=H

1 2 29 R = H , R =Me

Me, ,R2

yH ,OH

28

danaidal lycopsamine

1 2 30 R = COCH3, R = Me

1 2 31R=H, R = H 1 2 32 R = H , R = E t Me

\ /

Me Me

YH ,OH C Ha 0C 0 y - CH ,

R?

Me

HO

OH Me 33

(continued)

22 1

222


TABLE IV (Continued) Me H OH 35 senecionine

R2 I

R1 I

F0

R =

R =

36 seneciphylline N

38 integerrimine

OH

Me H

Me

39 usaramine

R =

R =

Me H OH O**.C-CH2-C-C-' \: .Me

4o jacobine

\

2'

R '1=

R =

1 '

2\ R -

R -

OH Me,OH Me. \ Me

H-c-c:c..I

'1 R =

\

R 2\=

42 monocrotaline


TABLE IV (Continued) Me OH H,

Me

,C

I

I

=C-CH -CH-C.-. M e 2 1 A0 co I

37 rosmarinine

&

Me

48

C7H15n

49

223

TABLE V Occurrence of Quinolines, Xanthommatin, and Quinazolinones Source Hymenoptera Apidae (bees) Apis mellifera

Lepidoptera Nymphalidae (butterflies) Vanessa uriticae Pieridae (butterflies) Pieris brassicue Heliconidae (bumflies) Heliconius sp. Bombycidae (moths) Bombyx mori Phycitidae (moths) Ephestia kiihniella Diptera Drosophilidae Drosophila melanogaster Trypetidae Ceratitis cupitata Dacus oleae Calliphoridae Calliphora erythrocephala Protophormia terrae-novae Orthoptera Acrididae (locusts)

Locust migratoria cinerascens Dociostaurus maroccanus Gryllidae Gryllus bimaculatus Coleoptera (beetles) Dytiscidae Ilybius fenestratus Lycidae Metriorrhynchus rhipidius Phasmida Phasmidae Carausius morosus

Isoptera Temitidae (termites) Reticulitermes flavipes R . virginicus

Locationa

Compound numberb

Ref.

E H B, P

58 52 or 53 56

I54 I54 I55

S

58

156

L

58

I57

W

58

70

P

52, 54, 55

159,160

I

58, 59

I61

E B

52, 53, 58, 59 59

162-168 169

E E

58 58

170 I73

E B

58 52, 53, 58

171 172

E

58

174

54

I75

B, E

58

176

Pr

51

101

H

51

97

F, H I

53 58

109,I I0 I09,110,177

B B

53 53

178 178 (continued)

224

TABLE V (Continued) Source

Locationn

Coptotermes formosanus Marginitermes hubbardi Paraneotermes simplicicornis Cryptotermes cavifrons Mynapoda Diplopoda (millipedes) Glomerida Glomeris marginata

Compound numberb

Ref

B B B B

53 53 53 53

178 I78 I78 I78

S

60, 61

96,112,179-181

a E, Eye; H, hemolymph; P, pupae; I, larval integument; B, whole body; F, feces; Pr, prothoracic gland; S , secretion; L, larvae; W, wings. b Stuctures:

51

R1

R2

R3

COOMe

H

OH

methyl 8-hydroxyquinoline2-carboxylate

@LRl R3

52

COOH

OH

OH

xanthurenic acid

53

COOH

OH

H

kynurenic acid

54

H

OH

H

kynurine

55

H

OH

OH

4,8-dihydroxyquinoline

56

xanthurenic

57

acid 4,8-diglucoside

1-methyl-2 -quinolone

I

CH3 COOH I CHNH2

COOH

I

FHNH2

I

58

I CH3

xanthommatin

3

60

59

dihydroxanthommatin

d 1 CCI H 3 2 c H

glomerin

3 homoglomerin 61

225

TABLE VI Occurrence of Purines and Pteridineso ~~

Source Hymenoptera Fonnicidae (ants) Formicinae Formica rufa F . polyctena F. pratensis F . nigriccans F . cordieri Lasius flavus Raptiformica sanguinea Vespidae (wasps) Vespa orientalis V . crabro V . germanica V . vulgaris V . lewisi Apidae (bees) Apis mellifera Diprionidae (sawflies) Gilpinia hercyniae Lepidoptera Pieridae (butterflies) Appias nero Pieris brassicae

P . rapae crucivora P . napi Catopsilia argante C . crocale C . rurina C. statira Colias croceus C. eurytheme C . edusa C. helica Euchloe cardamines Gonepteryx rhamni Hebomoia glaucippe Prioneris chestylis Papilionidae (butterflies) Papilio xuthus P. protenor Nymphalidae (butterflies) Vanessa atalanta

Compound numberb

67, 63, 67 67, 67, 67 67

70, 76 67, 70, 72, 76 70, 76 70, 76

Ref.

182-1 84 182-185 I84 182,I83 183 I84 I84

65, 67, 70, 78, 92, 95, 96 65, 68 65, 68 65, 68 67

I90 I90 I90 155

62, 63, 67, 70, 72, 78

155,188

95

189

65, 67, 68, 73, 86, 94 65, 67, 68, 70, 73, 77, 81, 91, 92, 93, 94, 95, 96, 97 65, 67, 68, 73, 95 68,81,95 65, 68, 73, 86, 91, 94 63, 64, 67, 69, 73 91 91 62, 63, 65, 67, 68, 73, 80, 81, 86 65, 67, 68, 73, 81 65, 73 62, 65, 67, 68, 73, 81 65, 68, 73, 94 65, 68, 69, 73, 94 65, 68, 73 91, 92, 94, 95

190,192 50,157,190,192-199

95, 98 95, 98

95

226

186.187

53,190,191,200 190,I93 190,201-203 200 203 203 204-208 191,209 190 207 190 190 210 51

53.195 195

195

TABLE VI (Continued) Source Pyralidae (moths) Ephestica kuehniella

Galleria mellonella Plodia interpunctella Chilo suppressalis C. simplex Bombycidae (moths) Bombyx mori

Geometridae (moths) Ptychopoda sp. Noctuidae (moths) Heliothis virescens H. zea Spodoptera litura Mmestra brassicae Conistra vaccinii Leucania separata Trigonophora meticulosa Achuea janata Saturniidae (moths) Antheraea pernyi Philosamia ricini Attacus ricini Sphingidae (moths) Celerio euphorbiae Lasiocampidae (moths) Malacosoma americana Arctiidae (moths) Hyphantria cunea Diptera Drosophilidae Drosophila melanogaster

D. hydei Trypetidae Dacus oleue Ceratitis cupitata Calliphoridae Calliphora erythrocephala Lucilia cuprina Chrysomya rubifacies

Compound numberb

Ref.

65, 67, 70, 73, 74, 75, 76, 86 91, 92, 95, 98 62, 65, 67, 70, 73, 74, 75, 81, 82 95, 98 95, 98

211-214

62, 67, 78, 79, 81, 91, 92, 93, 95, 96, 98

80,223-236

86

214

91, 92, 95 91, 92, 95 95 95, 98 95 95 95 95

238 238 239 195,240 I95 241 I95 242

95, 98 95 95

236,237 243 244

95, 98

236

95

215

9598

I95

62, 65, 67, 70, 72, 73, 81, 82, 83, 87a, 87b, 88, 89, 90, 91, 92, 95 62, 65, 70, 81, 87a

42,50,105,165,166, 191.2&,245-256

81, 85 81, 84

173 I70

67, 81, 82 62, 67, 81, 95 67

50 257,258 184

215-219 220-222 82 I95

24 7

(continued) 221

TABLE Vl (Continued) ~~

Source Simuliidae Cnephia tredecimata Culicidae Aedes aegypti Glossinidae Glossina morsitans Piophilidae Piophila casei Orthoptera Acrididae (locusts) Locust migratoriodes L. migratoria cinerascens Schistocerca gregaria Gryllidae (crickets) Acheta domesticus Hemiptera Heteroptera F'yrrhocoridae Pyrrhocoris apterus Dysderus fasciatus Reduviidae Rhodonius prolixus Triatoma infestans Oncopeltus fasciatus

Lygaeidae Geocoris punctipes Miridae Lygus hesperus Homoptera Membracidae (treehoppers) Oxyrhachis taranda Oxyrhachis sp. Gargara contraria G. nigroapica Cercopidae Philaenus spumarius Aleyrodidae Aleyrodes proletella Aphididae (aphids) Anurophis roseus Brevicoryne brassicae Isoptera Termitidae (termites) Reticulitermes flavipes

Compound numberb

Ref.

62, 70, 81, 82

245

95

259-261

95

262

62, 67, 70, 81, 82, 85

263

65 65, 67, 81, 95 65, 81, 95

264 174,265-267 50,264,265,268

95

215

67, 69, 73, 78, 95 65, 73

107.269,270 50

62, 63, 65, 66, 67, 69, 70, 73, 75, 95 62, 63, 65, 66, 67, 69, 70, 73, 74, 75 62, 65, 67, 69, 70, 73. 95

271 -274 2 72 50,215,275,276

91, 92, 95

238

91, 92, 95

238

62, 65, 67, 70 65, 67, 70 65, 67 65

277 2 77 2 77 277

68

2 78

68

278

67, 68 65, 67, 68, 70

2 79 2 79,280

95

178

TABLE Vl (Continued) Source R. virginicus Coptotermes formosanus Marginitermes hubbardi Paraneotermes simplicicornis Cryptotermes cavifrons Blattariae (cockroaches) Blattidae Periplaneta americana Blattelidae Blattella germanica Parcoblutta pennsylvania Blaberidae Leucophuea maderae Coleoptera (beetles) Tenebrionidae Tenebrio moritor T. mauritanicus Tribolhm castaneum T. confusam Dermestidae Dermestes maculatus Bruchidae Caryedes brasiliensis Curculionidae Anthonomus grandis Sitophilus oryzae S. granarius Catopidae Bathyscini Anthrocharis querilhuci Speconomus sp. Boldoria sp. Trechini Trechus sp. Aphuenops sp. Neuroptera Chrysopidae Chrysopa carnea Phasmida Phasmidae Curausius morosus Mecoptera Panorpidae Punorpa japonica Arachnida Scorpiones (scorpions) Adroctonus australis A. amereuxi

Compound numberb

Ref.

95 95 95 95 95

i78 i78 178 178 178

65, 67, 76, 95

215.281-284

95 95

108 285

95

286

67, 70, 95 95 95 95

50,215,293,294 294 295 296

91, 92, 95

297

95

298

95 91, 92, 95 91, 92, 95

299 300 300

65, 68 65, 68 65, 68

301 301 301

65, 68 65, 68

301 301

95

302

62, 65, 67, 68, 76

I11,I 77,281

71, 81

303, 304

93 93

305 305 (continued)

229

TABLE VI (Continued) Source

Compound numberb

Araneae (spiders) Epeira diadema Acari (ticks) Argas (Persicargas) arboreus A. ( P . )persicus Ornithodoros ( 0 . )savionyi 0 . porcinus porcinus Hyalomma dromedarrii Haemaphysalis leporispalustris Rhipicephalus turanicus ~~~~~~~~~~~~~~~~

Ref

93

306,307

93 93 93 93 93 93 93

308,309 308 308 115 308 308 308

~

Additional ocurrences as follows: Pteridines occur in other Lepidoptera (204,310,311),Diptera (312), and Hemiptera (107,313,314),and other insects (50,315). Unc acid is found in other Drosophila species (253,316), other cockroaches (285,287-292), and other insects (317-321). Guanine occurs in other scorpions (322-324), spiders (322,325,326),and ticks (308,327). b Structures: R1 0

R2

pterin

62 H

H

63 C 0 2 H

H

64 H

C O H pterin-7-carboxylic acid 2

65 O H

H

66 OH

C O H xanthopterin-7-carboxylic acid 2

67 H

OH

68 OH

OH

69 O H 70 C H ( O H ) C H ( O H ) C H 3

CH3 H

7 1 CH(OH)CH(OH)CH3

OH

pterin-6-carboxylic acid

xanthopterin

isoxanthopterin leucopterin chrysopterin biopterin ichthyopterin

72 C H ( O H ) C H ( O H ) C H 2 0 H H

neopterin

7 3 OH

CH2COC02H

erythropterin

7 4 OH

CH2 C H ( O H ) C O Z H

ekapterin

75 O H

CH=C ( N H )~co2H

lepidopterin

R1

R2

R3

76 NHZ

OH

H

77 H

H

C O H pteridine-7-carboxylic

2-amino-6-hydroxypteridine 2

230

acid

TABLE VI (Continued)

R1

R2

78 H

0

violapterin

79 C O C H ( 0 H ) CH3

H2

7,8-dihydro-6-lactyllumazine

R

O

80

OH

81

COCH(OH)CH3

sepiapterin

82

COCH2CH3

isosepiapterin (deoxysepiapterin)

83

COCH3

&acetyl-7,8-dihydropterin

84

H

tetrahydropterin

85

CH(OH)CH(OH)CH3

tetrahydrobiopterin

H

86

87a 87b droso- and isodrosopterin

pterorhodin 88 neodrosopterin

R

89 aurodrosopterin

90 fraction e

R1

R2

R3

91

H

OH

OH

xant hine

92

H

H

OH

hypoxanthine

93

H

NH2

OH

guanine

94

H

OH

NH2

isoguanine

95

OH

OH

OH

uric acid

96

H

H

NH2

adenine

97

OH

OH

NH2

2,8-dihydroxyadenine

98

3-ribosyluric acid

23 1

TABLE VII Occurrence of Coccinellines and Adalines Source

Compound numbera

Coteoptra (beetles) Cantharidae Chauliognathus pulchellus Coccinellidae Coccinellinae Scymnini Cryptolaemus montrouzieri Hippodamiini Anisostica 19-punctata Hippodamia convergens H . caseyi Coccinellini Coccinella 5-punctata C . septempunctata C . 11-punctata C . 14-punctata C . cal$ornica C . transversoguttata Propylaea 14-punctata Myrrha Id-punctata Miraspis 16-punctata Cheilomenes propinqua Coleomegilla maculata Adalia bipunctata A. 10-punctata A. quadrimaculata A . pantherina Epilachna varivestis Structures:

H H Q

HQ H

100, 102, 104

328

108

87

102 101, 102 101, 102, 105, 106

86,329,330 86,329-331 332

99, 100 99, 100 99 99, 100 99 99, 100 104 103 100 99, 100 103 (or 100) 107 107

86,330 85,86,330,333 86,330 86,330 330 332 86,330,334 330 330 330 335,336 86,330,337,338 86,330,338 33 7 337 89

107 107 108

w vMe ??

H

Me 99 coccinelline

Me 100 precoccinelline

Ref.

H

H

101 convergine

102 hippodamine

Me 103 myrrhine

Q

H

Me 104 propyleine

105 hippocasine

106 hippocasine oxide

232

107 adaline

108 euphococcinine

TABLE VIII Occurrence of Acyclic Amines, Imidazoles, Catecholamines, and Indolesn ~

Source Hymenoptera Formicidae (ants) Ponerinae Mesoponera castaneicolor

M. castanea

Locationb

Compound numbere

B

114, 115, 116, 117, 118, 119, 120, 125, 126, 127, 128, 129 114, 115, 116, 117, 118, 119, 120, 125, 126, 127, 128. 129

B

Myrmicinae Atta sexdens rubropilosa Myrmica taevinodis Acromyrmex sp. Pheidole fallax Myrmecia gulosa M. pyriformis Dorylinae Neivamyrmex nigrescens Formicinae Lasius neoniger L. aliensus Acanthomyops claviger Formica rufa Vespidae (wasps) Vespa vulgaris V. crab0 _I

Ref.

41

41

M M M Po V V

139 139 139 140 136 136

34,339,340 340 340 44 524 341,525

Hd

140

43

Hd Hd Hd B

140 140 140 133

44 44 44 342

V

136, 141 110, 111, 112, 132, 133, 134, 135, 136, 141 136, 141 132, 133, 134, 136, 141 110, 111, 112, 135, 136, 141 133, 134, 141 141 132, 133, 134, 141 110, 111, 112, 134, 135, 136, 141 141 141 111, 112, 135, 136, 141 110, 111, 112, 133, 134, 135, 136

344 343,345-347

vs

V . cincta V . orientalis

V V

V . xanthoptera

vs

V . maculifrons V . maculata V . germanica Polistes rothneyi

V

Polybia rejecta Vespula lewisii

St, L P, B vs

Ropalidia maculiventris

vs

St V vs

348 347,349-35 I 343,352 349,353 354 347,349 343,355 354 354 343 343

(continued) 233

234


TABLE VIII (Continued) Locationb

Compound numberc

Eumenes arcuatus

vs

Rhynchium aruliferum

vs

Abispa splendida

VS

110, 111, 112, 134, 135, 136 110, 111, 112, 132, 133, 134, 135, 136 110, 111, 112, 134, 135, 136 132, 133, 134, 141 132, 133, 134, 141 141

Source

Paravespula germanica Dolichovespula saxonica Synoeca surinuma Pompilidae Batzonellus annulatus Hemipapsis ichneumusnea Cnemora adusta Apidae (bee) Xylocopa appendiculata Apis mellifera

vs V

St VS

vs vs vs

343 347 353 354 343 343 343

V

136

369

V

132, 133, 134, 136

343

136

3 70

136

370

SP SP SP SP

136 136 136 136

371 371 3 71 371

Hr Hr Hr Hr

136 136 136 136

3 71 3 71 3 71 79

Hr

136

79

VS

B

Scoliidae Megascoliu jlavifrons Sphecidae Sceliphron laetum Lepidoptera Saturniidae (moths) Dirphia sp. Megalopygidae (moths) Megalopyge sp. Limacodidae (moths) Monema jlavescens Latoia sinica L. lepida L. consocia Lymantriidae (moths) Euproctis subjlava E. pseudoconspersa E. similis E. chrysorrhoea Zygaenidae (moths) Batataea funeralis

343

343 343 349,356-365 342 366 367,368 343 343

B

Bumbus ignitus Amegilla macnamalae

135, 136 132, 133, 136 136

343

110, 111, 136 110, 111, 112, 136 133, 134, 136 133 141 132, 133, 134 110, 111, 112, 136 110, 111, 112, 134, 136

vs V

A. mellificu

111, 134, 111, 112, 134, 135, 134, 135,

Ref.

vs vs

235


TABLE VIII (Continued) Source Bombycidae (moths) Bombyx mori Nymphalidae (butterflies) Vanessa urticae Piendae (butterflies) Prioneris thestylis Diptera Culicidae Aedes uegypti Culex pipiens Muscidae Muscu domesticu Drosophilidae Drosophilu melunogaster Trypetidae Dacus cucurbitae D . tryoni D. neohumerulis Orthoptera Acrididae (locusts) Schistocercu greguriu Hemiptera Cimicidae Cimex lectutarius Coleoptera (beetles) Noteridae Noterus cluvicornis Dytiscidae Hyphydrus ovatus Coelumbus lernueus Gruptodytes pictus Hydroporus dorsulis Hygrotus inaequulis Potumonectes depressus Scurodytes halensis Stictonectes optutus Stictotursus duodecimpustulutus Hydroglyphus pusillus Lycidae Metriorrhynchus rhipidius Coccinellidae Hippodamiini Hippodumiu convergens Semiudaliu 1 I -notutu Adoniu vuriegata

Locationb

Compound number=

Ref.

109, 110, 111

106,372-374

133, 134

367

137

51

136 136

370

132, 133, 134

367

141

375,376

122, 123, 124 122, 123 122, 123

147 147 147

109, 110, 111

106

136

370

139

99

139 139 139 139 139 139 139 139 139

99 99 99 99 99 99 99 99 99

139

99

130

97

113, 121 121 121

378 3 78 3 78

3 70

~~

(continued)

TABLE VIII (Continued) Source Coccinellini Harmoniu 4-punctatu H . leis conformis Tenebrionidae Tenebrio moritor Scarabaeidae Melontha vulgris Dermaptera Forficulidae ForJicula sp. Blattariae (cochroaches) Blattidae Periplaneta americana Neuroptera Chrysopidae Chrysopa oculatu Trichoptera Limnephilidae Pycnopsyche scabripennis Arachnida Scorpiones (scorpions) Leiurus quinquestriatus Parabuthus hunteri Buthotus minax Vejovis sp. Opiliones (Harv6stman) Sclerobunus robustus Araneae (spiders) Phoneutria fera Lycosa erythrognata Latrodectus mactans tredecimguttantus Acanthoscurria atrox A. sternalis Pterinopelma vellutinum Atrax robustus Phoneutria fera Myriapoda Chilopoda (centipedes) Scolopendra subspinipes S. viridicornis S . oraniensis institania ~~

~

~~

Locationb

Compound numberc

B B

121 121

378 3 78

B

132, 133, 134

367,368

B

111

377

B

132, 133, 134

367

N

134, 141

379

Pr

140

380

E

138, 140

381

V V V

141 141 141 141

370,382,383 121 121 384

131

117

V V

136, 141 136, 141 141

118,119 118.119,354 120

V V V V

141 141 141 112

\I

141

354 354 354 385 3 54

T

114 354 370

136 141 136

V V V ~~~

Ref.

~~

~

Additional occurrences as follows: Biogenic mines are found in other Vespidae and Apidae (343,347,349,353,354,356,386).Indoleacetic acid occurs in other Dytiscidae (99). B, Whole body of adults; V, venom; Vs, venom sacs; St, sting apparatus; M, metathoracicgland; Po, poison gland; Hd, heads; Hr,hairs; Py, pygidial gland; L, larvae; P, pupae; Sp, spines; W, wings; S, secretion; N, nerve cord; E, exocrine gland; T, telson; Pr, prothoracic gland. Structures:

2837


TABLE VIII (Conrinued) ~

109

(CH3)2NH

dimethylamine 110

111 NH,(CH2),NH2

putrescine

HZN(CH2)4NH(CH2)3NH2

112

H2N(CH2)3NH(CH2)4NH(CH2)3NH2spermine

113

n -C8H17NH2

122

iso-C5H11NHCOCH3

114

iso-C5H11NHCgHlg

123

C2H5CH( CH3)CH2NHCOCH3

115

iso-C5H11NH 2 - C g H l 7

124

iso-C5Hl1NHCOCH2OCH3

116

iso-C5HI1N(CH3)CgHlg

125

iso-C5H11N(COCH3)CgHlg

117

iso-C5H11 N(CHO)CgHlg

126

CgHlgNHCOCM3

118

C7H15NHCgH19

127

iso-C4HgCONHCgHlg

119

(iso-C5H11)ZNCgH17

128

(iso-C5H11)2NCgHlg

120

iso-C5HllN(CgHlg)2

129

iso-C5H11N( C7H15 CgH19

121

H2NCH(CH3)(CH2)6CH=CH(CH2)8NH2 harmonine

130

PhCH2CH2CONH2

132

spermidine

131 PhCH2CH2N(CH3)2

adrenaline

1 3 3 noradrenaline

134 dopamine

135 tyramine

L -

CH=CHC02H

136 histamine H

H 138 indole

137 urocanic acid

H

H 139 3-indolacetic acid

H 140 s kat ole

H 141 serotonin ( 5 H T )

238


111. Structure and Synthesis

A. PIPERIDINES 1. 2-Alkyl-6-methylpiperidine The structure of 2-alkyl-6-methylpiperidine (1 and 2) from fire ant venom (Table I) has been assumed by mass spectroscopy and chemical reaction, and confirmed by direct comparison with synthetic compounds having known structure and stereochemistry (16,122,126). The mass spectra show a base peak at mlz 98 (152) resulting from a-cleavage of the alkyl group as well as M - 15, M - 1 and M ions, the last being often absent (16,122,126).Their secondary amine character is suggested by a positive spot test. Carbon-skeleton chromatography (387) gives only n-alkanes with the same carbon number as the parent compound, proving that the side chains are not branched. This and the IR spectrum between 2920 and 2980 cm- suggest 2,6-dialkylpiperidine rather than 2,sdialkylpyrrolidine .

1 or 2

152 m / z 98

Mass spectra of the cis and trans isomers of the two substituents are virtually indistinguishable, but the IR spectra allow easy differentiation in the region near 1320 cm- l . The relative stereochemistry of the natural alkaloids can be determined by comparison of gas chromatographic behavior with synthetic material of known stereochemistry, since the two isomers have different retention times. The position and geometry of the side chain double bonds can be determined by ozonolysis and a potassium permanganate-sodium periodate oxidation, as well as by the IR spectrum. Results have shown that the side chain double bonds are always Z (16,122,126). A number of syntheses have been reported for 2-alkyl-6-methylpiperidine (1 and 2). The first used synthetic route is the sodium-alcohol reduction of the corresponding pyridine derivatives, which are prepared by the alkylation of the lithium salt of 2,6-dimethylpyridine (153) with the appropriate bromoalkane (122,126). This reaction gives a mixture of the cis and trans isomers (85/15), from which (t)-solenopsins A (Id), B (If), and C (lh) can be separated. The catalytic hydrogenation of the corresponding pyridine (154a) with 5% rhodium on charcoal gives the cis isomer (lc) (Scheme 1). (+)-Dehydrosolenopsin B (2b) and C (2d) are synthesized along with their isomers by the sodium-alcohol reduction of the corresponding pyridine derivatives in the same manner (Scheme 2) (126).

239


154a (n= 10)

153

b ( n = 12)

c (n= 1 4 )

154a

iii

-

lc

SCHEME1 . Reaction conditions: i, CH3(CH2)n-1Br ( n = 10, 12, 14); ii, Na-EtOH; iii, 5% Rh-C.

I i H3C

?I!

(CH2)nC=C-(CH2)7CH3

2a

( n = 3) 3 part

2b

( n = 3) 1 part

2c

(n= 5 ) 3 part

2d

(n= 5 ) 1 part

155a (n= 3 ) b (n= 5 )

SCHEME2. Reaction conditions: i , CH3(CH&CH=CH(CH2),_ CH(CH3,- ,Br; ii, Na-EtOH.

10Ts or CH3(CH2),CH=

Improved synthesis by this method has been achieved in order to obtain solenopsin A (Id) more stereoselectively (388). A cis and trans mixture of pyridine derivative 158, obtained from 156 by the Wittig reaction, was reduced by Raney nickel catalyst in the presence of PtO, to yield the cis-piperidine (lc). The N-nitroso derivative 159, obtained from l c by treatment with isoamyl nitrite, was treated with potassium tert-butoxide and then subjected to hydrogenolysis over Raney nickel to give a mixture of (2)-solenopsin A (Id, 1 part) and its isomer (lc, I part) (Scheme 3). Some intramolecular aminations of olefins have been reported for solenopsin A (ld) and its isomer (lc) (389-392). The dimer (200) of methyl vinyl ketone was converted to the ketone (202) by a standard procedure. Borohydride reduction of 202, followed by acid-catalyzed cyclization, yielded an exof endo (60140)

240


lc

159

lc

SCHEME 3. Reaction conditions: i, PPh3-benzene; ii, NaH-CH2C1,; iii, decanal; iv, Raney NiPt0.2; v, isoamyl nitrite; vi, KOBuf-DMSO; vii, Raney Ni.

mixture of bicyclic derivative 203. A novel ketal fragmentation reaction of 203 with acetyl iodide gave a mixture of olefin 204 in favor of the trans-alkene. Treatment of 204 with hydroxylamine gave the oxime (205) which was reduced with molybdenum trioxide and sodium borohydride to afford the amine (206) (81%) and (+)-solenopsin A (Id) (10%).The latter can be also obtained from the former by mercuration (Scheme 4) (389). Another method by mercuration starts with keto alcohol 207 (390).The amino alcohol (208) obtained from 207 by reductive amination was protected by a standard procedure to afford the phthalimide (209). Successive treatment of 209 iv

i Me

Me

JQyc 10H 21n

0

200

202

201

vi

M

e 203

v-

0

vii

Q C l O H 2 ln-Me&C10H2P 204

SCHEME 4. Reaction conditions: i, C6HIINH2;ii, EtMgBr; iii, "C9HI9Br;iv, NaBH4; v, p-TsOH; vi, AcI; vii, NH20H.HC1, NaOAc; viii, Moo3, NaBH4; ix, Hg(OAc)2, NaBH4.

24 1


(a-

with Collins' reagent and Wittig reagent afforded a mixture of and (E)olefins (210). Hydrolysis of 210 yielded the amine (206), which was successively treated with mercuric acetate and sodium borohydrate to give (*)solenopsin A (Id, 4 parts) and its isomer, (+-)-isosolenopsin A (lc, 3 parts) (Scheme 5).

-

i

ii

iii

M e O O H

iv

208

207

O 209

206

\ B/

0

210

Id

IC

is, x

HgOAc

CV 2Me 211

212

Me CO ? M e 213-

SCHEME 5 . Reaction conditions: i, reductive amination; ii, protection of amino group; iii, Collins' reagent; iv, Ph3P=CHCIOH2,~; v, hydrolysis; vi, Hg(OAc)2; vii, N a B b ; viii, 1-decen-3-one;ix, ethanedithiol; x, Raney Ni; xi, HC1-EtOH.

Cyclization by amidomercuration has been reported (391). Reaction of Nmethoxycarbonyl-6-aminoheptl-ene (211) with mercuric acetate gave the organomercurial (212). Reductive coupling of 212 with l-decen-3-one in the usual way gave the cis and trans isomers (213). Successive treatment of 213 with ethanedithiol, Raney nickel, and ethanolic hydrogen chloride afforded (-+)-solenopsin A (Id, 2 parts) and its isomer (lc, 3 parts), which were separable by preparative gas chromatography (GC) (Scheme 5) (391). On treatment with benzeneselenenyl chloride two olefinic urethanes (214 and 217) underwent cyclization to afford piperidine derivatives (215 and 218, respectively) having the cis stereochemistry. Their reduction with triphenyltin hydride gave the same product (216). Removal of the blocking group from the nitrogen gave (-+)-isosolenopsinA (lc) (Scheme 6) (392). Application of the Mundy N-acyllactam rearrangement to 6-methyl-2piperidone (219) led to a synthesis of (+)-solenopsin A (Id), but it is not a

242


i

O c COOEt 1 l H 2 3

0

PhSe

‘11 H23 COOEt

1c

E; SePh 211

218

SCHEME 6. Reaction conditions: i, PhSeC1-silica; ii, Ph3SnH; iii, conc HCI-EtOH.

satisfactory route to the trans alkaloids. Pyrolysis of N-lauryld-methyl-2piperidone (220) over calcium oxide gave imine 221 in about 5% yield. The imine (221) was reduced with sodium borohydride to afford a 4 : 1 mixture of cis and trans isomers (lc and Id) (Scheme 7) (393). More recently, a new olefinic cyclization promoted by the Beckmann rearrangement of an oxime sulfonate has been developed (222 + 223) (394). Thus, successive reaction of the oxime methane sulfonate (224) with diethylaluminum chloride and diisobutylaluminum hydride afforded the tetrahydropyridine (225) as a mixture of cis and trans isomers. Subsequent catalytic hydrogenation yielded (&)-solenopsin B (If, trans) and its isomer (le, cis) (Scheme 8) (394). Another synthetic route via the Beckmann rearrangement, which is promoted by organoaluminum reagent along with alkylation, involves a new stereoselective reduction of the imino group. The starting oxime sulfonate (228) was synthesized from cyclopentanone (226) in three steps: Reaction of 226 with 1-undecene in the presence of silver oxide produced the a-undecylcyclopentanone (227) which on successive treatment with hydroxylamine and methanesulfonyl chloride-triethylamine gave the mesylate (228). Treatment of the oxime mesylate

219

220

lc

221

Id

SCHEME7. Reaction conditions: i, n-C, ,H23COCI-pyridine-benzene; ii, CaO, A; iii, NaBH,

243


N-OMS

3

c 13H 27

Me

n

N-OMS

224

222

223

-

...

111

M e 0 c 1 3 H 2 7 n H

Me

225

0

CuHnn

H le/lf

46/54

SCHEME 8. Reaction conditions: i, Et2A1CI; ii, DIBAH; iii, H2-Pd/C

(228) with trimethylaluminum resulted in the formation of I -piperideine (7)in 54% yield after workup by Nal-H,O. Reduction of 7 with a new reagent, LiAlH,-Me,Al, gave (+)-solenopsin A (Id, 95%) and its isomer (lc, 5 % ) (395).In a similar manner, (+)-solenopsin B (If, trans) was prepared with high selectivity (95% by GC assay) (Scheme 9) (395).

226

7

227

228

Id

lc

SCHEME 9. Reaction conditions: i, l-undecene, Ag20; ii, 130"C, 5 hr; iii, NH20H; iv, MsCIEt3N; v, Me,Al; vi, NaF-H20; vii, LiA1H,-Me3A1.

In addition, stereoselective synthesis of solenopsin A has been reported by four research groups. An approach utilizing the stereoselective reductive decyanation (396) starts with aminonitrile 229, prepared from 2-picoline. It was selectively hydrogenated in the presence of Pd-C, followed by alkylation with undecyl bromide, affording 231. Reductive decyanation of 231 with NaBH, in MeOH led to predominant (8 : 2) formation of the trans isomer (232) which was then debenzylated to (+)-solenopsin A (Id). The cis product (lc) was in turn prepared by treatment of 231 with sodium in liquid ammonia followed by debenzylation (Scheme 10). In the synthesis through the highly regioselective a-alkylation of a pyridinium

244


n

J vi

nlvi

SCHEME10. Reaction conditions: i, H2-Pd/C; ii, LDA; iii, C11H~3~Br; iv, NaBH,; v, Na-NH3; vi, debenzylation.

salt (398, N-methoxycarbonyl-2-methylpyridiniumchloride (235) was treated with Grignard reagent to give the a-alkylated 1,2-dihydropyridine (236). Controlled hydrogenation of 236 over 5% palladium carbon gave 1,2,3,4-tetrahydropyridine (237). Decarbomethoxylation of 237 afforded 1-piperideine (7) which was reduced with lithium aluminum hydride in the presence of trimethylaluminum to yield (+-)-solenopsin A (Id, 9 parts) along with a small amount of its epimer (lc, 1 part) (Scheme 11). In the synthetic route starting with enamidine (238) (398), its metalation followed by alkylation in the presence of TMEDA or pentynyl cuprate gave the

0i

Me

Me

/Q-

ii

M e O C S C - C gH 19n COzMe

c1- C O z M e 234

235

iv M e QCIl*23n60 2 M e 237

Me

iii

236

0

C 11H 23n

V

----

M e 0 ’ *H* C 1 1 H 2 3 n

7

SCHEME1 1 . Reaction conditions: i, ClCOOMe; ii, “C9Hl9--MgBr; ISiMe,; v, LiAIH4-Me3AI.

Id

iii, Hz-5% PdlC; iv,

245


238 239 SCHEME12. Reaction conditions: i, 'BuLi; ii, CH3Br, TMEDA, or pentynyl cuprate; iii, NH2NH2-AcOH; iv, LAH.

Me

I C02CH2Ph

i P h- C H 2 0 2 C'y&ScNL -N

MeQ'..C11H2: H

SMe

240

241

SCHEME13. Reaction conditions: i, S = C

Id

'SMe'

. ii, three steps.

forhamidine (239). When 239 was subjected to hydrazinolysis, the cyclic imine (221) was obtained and reduced with lithium aluminum hydride, producing (*)solenopsin A (la) and its isomer in a 9 : 1 ratio (Scheme 12). It should be noted that the cyclic imine (221) in this route has a reverse position of the alkyl group relative to the imine (7)of the synthetic route mentioned above. Cycloaddition reaction of the 1-acyl-l,2-dihydropyridinederivative 240 with methyl cyanodithioformate afforded adduct 241, which was converted by three steps to solenopsin A (Id) (Scheme 13) (399). This route constitutes a completely stereoselective synthesis of this alkaloid; however, details are not available. The structures of the N-methyl-2,B-dialkylpiperidines (3b and 3c), found in S. pergandei and S. carolinensis (Table I), are indicated by a base peak (242) of rnlz 112 as well as the parent peaks in their mass spectra. Structures were confirmed by their identity with authentic samples which were prepared by reductive methylation of the corresponding N-H piperidine with formaldehyde and formic acid (16).

CH3

242

246


2. 2-Methyl-6-(2-oxopropyl)piperidine The structure of cis-1-(6-methy1-2-piperidyl)propan-2-one (4), found in the ladybird C. montrouzieri (Table I), was assumed by the mass spectra and reduction, and confirmed by synthesis. A molecular ion at mlz 155, the intense fragment at M - 43 by loss of CH,CO, and the base peak at M - 57 by loss of CH,COCH, suggest an empirical formula and the nature of the side chain of the piperidine ring. A Wolff-Kishner reduction gave a product identical with dihydropinidine having a cis configuration (87). This alkaloid was prepared by acetylation of the lithium salt of 2,6-lutidine (153) with acetyl chloride, followed by reduction with Adams’ catalyst (Scheme 14) (87).

153

243

4

SCHEME14. Reaction conditions: i, CH,COCI; ii, H2. Adams’ catalyst

3. Stenusine An N-ethylpiperidine, stenusine (5), isolated from a staphylinid beetle, Stenus comma (Table I), indicated the molecular ion at mlz 183.1993 in the mass spectra, corresponding to the elemental composition C,,H,,N. The NMR spectrum shows the presence of an N-ethyl group and two methyl groups attached to methylene and methine groups; it gives no evidence for a double bond, showing a ring structure. In addition, explanation of the fragment ion (244) at mlz 113 in the mass spectrum, occurring by direct loss of a pentene moiety from the molecular ion, leads to the structure 5. This postulated structure was confirmed by synthesis. Thus the monoester of 2-methylbutylmalonic acid (245) was converted to ethyl 2-(2-methylbutyl)acrylate (246) by a Mannich reaction. Addition of ethylamine and subsequent Michael addition of the resulting secondary amine with ethyl acrylate gave the teritary amine diester (247). Dieckmann cyclization, saponification, and decarboxylation led to piperidinone (248), of which WolffKishner reduction provided 5 (Scheme 15) (94-96).

244

CH3

247

6. ALKALOIDS FROM ANTS AND OTHER INSECTS 0

0

245

246

247

5

248

SCHEME15. Reaction conditions: i, CH20, EtZNH; ii, EtNH2; iii, CH2=CHCOOEt; iv, Na; v ,

Wolff-Kishner reaction.

4. Piperideine The structure of the 1-piperideine (7), found in S . xyloni (Table I), was assumed by characteristic fragmentation ions (249 and 250) at rnlz 97 and I10 (base peak) in the mass spectrum and was confirmed by comparison with a synthetic sample. The mlz 97 peak results from allylic cleavage with hydrogen transfer to nitrogen, while the 110 peak arises from the loss of the side chain after transfer of two hydrogens. In contrast, the isomeric 6-piperideine (221), the nonnatural product, exhibits a base peak (253) at mlz 111 arising from a McLafferty rearrangement of the y hydrogen (123). Though the 1-piperideine (7) is prepared along with the isomeric 6-piperideine (221) by treatment of the corresponding piperidine (lc) with tert-butylhypochloride (Scheme 16) (123), it can

H3CO 7

249

m/z

C

C8H17

252

‘gH17

2 5 3 m / z 111 ‘gH17

2

250 m / z 1 1 0

97

CsH17

251

H

248


lc

221

7

SCHEME16. Reaction conditions: i, 'BuOCl.

be selectively prepared as the synthetic intermediate to solenopsin A as mentioned above (Schemes 9 and 11). Another 1-piperideine (6), found in Solenopsis sp. A (Puerto Rico) (Table I), exhibits in the mass spectrum the molecular ion at mlz 151 and the base peak (254) at mlz 97, suggesting an a-substituted 1-piperideine system. A terminal double bond was explained by the fragmentation ion (255) at mlz 110 arising via simple allylic cleavage in the mass spectrum and the characteristic ABC pattern of a terminal olefin in the 'H-NMR spectrum. The presence of a 1-piperideine system was confirmed by sodium borohydride reduction of natural material giving 2-(4-penten-1-y1)piperidine (16). Compound 6 was prepared by the Mundy rearrangement of N-(5-hexenoyl)-2-piperidone(257) which was prepared by acylation of piperidone (256) with 5-hexenoyl chloride (Scheme 17) (16). This method was far superior in ease of operation though it had been used to prepare a synthetic intermediate to 0-methylvalerolactim (400).

255

m / z 110

5. Anabaseine The structure of anabaseine (8), isolated from ants of Aphaenogaster species (Table I), was established by gas chromatography-mass spectrometry, the 'H-

Qo H

256

i_

0I

0

2 CA(CH2)3CH=CH2

O=C( CH2)3CH=CH2 257

6

SCHEME17. Reaction conditions: i, CH2=CH(CH2)-,COCI;

ii, CaO, A

249


0

0

0 +

0

Q k - O E i

I COPh

COPh 258

260

259

8

261

SCHEME 18. Reaction conditions: i, NaOEt; ii, conc HC1; iii, CaO, A.

NMR spectrum showing the presence of a 3-substituted pyridine with four nonequivalent methylene units in the substituent, and by its conversion to 2,3-bipyridyl with chloranil (26). Its synthesis was made by condensation of N-benzoylpiperidone (258) with ethyl nicotinate (259) followed by heating with concentrated hydrochloric acid, resulting in hydrolysis, decarboxylation, and ring closure (Scheme 18) (401). Application of the Mundy N-acyllactam rearrangement to N-nicotinoylpiperidone (261) has also led to a synthesis of anabaseine (8) (Scheme 18) (402). 6 . Actinidine

Actinidine (9a), found in an anal gland of dolichoderine ants and in the defensive secretions of rove beetles (Table I), was identified on the basis of gas chromatographic and mass spectral analysis and the UV spectrum. The mass

H 262 263

264

Yi 9a

SCHEME 19. Reaction conditions: i, PCI,, 100°C; ii, H2-Pd/C; iii, 2,4-DNPH; iv, HCI in AcOH; v, FeNH4(S04)*, A.

250


-

["r-]- Dc,

265

ii

A

266

261

T y 9b

SCHEME 20. Reaction conditions: i,

({) , 110°C; ii, NHzOH, A

spectrum exhibits fragmentation peaks at mlz 132 (M+ - CH,, 100%) and 117 (M+ - C,H,, 42%) as well as the molecular ion at mlz 147, It is likely that the absolute configuration is the same as that of actinidine from plants. Natural (-)-acthidine (9a) is prepared from nepetalinic acid imide (262) via dichloropyridine (263) (403) and from iridodial (264) via bis (2,4-dinitropheny1)hydrazone (404) or treatment with ferric ammonium sulfate (Scheme 19) (405). (+)-Acthidine (9b), the enantiomer of natural alkaloid, is synthesized from acid chloride 265, derived from (+)-pulegone, via vinylketone 267 (Scheme 20) (406). Racemic actinidine (9) is prepared by intramolecular cycloaddition of an acetylene across a pyrimidine ring in 5-(hept-5-yn-2-~1)-4,6dihydroxypyrimidine (268) followed by chlorination and hydrogenation (Scheme 21) (407). Since the biosynthesis of iridoid monoterpenes in insects has been shown to

269

ii iii+ 9 SCHEME 21. Reaction conditions: i, 200°C; ii, phosphoryl chloride, 195°C; iii, Hz-Pd/C.


25 1

follow the mevalonic acid route (408), it seems that the biosynthesis of 9a in insects also proceeds through this pathway, as in plants ( 4 ) .

B . PYRROLIDINES 1. 2,5-Dialkylpyrrolidines Isolation and structural elucidation of pyrrolidine and pyrroline alkaloids found in ants (Table 11) have been achieved in most cases by the use of gas chromatography-mass spectrometry techniques, owing to the small amount of available samples, and the structures have been confirmed by synthesis (16,18,23a,b,25,132,409). Mass spectra of 2,5-dialkylpyrrolidines (10) exhibit two intense fragment ions (270 and 271) resulting from &-cleavage of the side Their secondary chains as well as a weak molecular ion (16,18,23~,25,132,409). m i n e character is confirmed by the early elution of their acetates on the gas chromatography relative to the corresponding free bases. Carbon-skeleton hydrolysis over 1% Pd on Gaschrom P gave n-alkanes and pyrroles bonded with side chains, proving that the side chains are not branched and not located on the same (Y carbon atom of the pyrrolidine nucleus (16,132). The stereochemistry is established by direct comparison with synthetic isomers. The natural alkaloids of known stereochemistry are all of the trans configuration (16,18,25,133,138).

The technique of methoxymercuration-demercuration was utilized to determine the position of double bonds in the side chains. Since this method is not successful with the free alkaloids (272), the secondary amino groups must be protected as the N-heptafluorobutyramide. These amides are treated with mercuric acetate and methanol followed by reduction with sodium borohydride to yield the methoxylated compounds (273). The mass spectra of these compounds show a fragment ion (274) at mlz 59 indicating terminal double bonds in every case (Scheme 22) (16,25,410,411). Many synthetic methods have been reported for the pyrrolidine alkaloids, including procedures based on the Hofmann-Loffler reaction (132,412), the metal hydride reduction of pyrrolines (413,414), the a-alkylation of N-nitrosopyrrolidine (412,415), the catalytic hydrogenation of pyrroles (133), the reductive amination of 1,4-diketones (25,138),the direct alkylation of l-methoxycarbonyl-3-pyrroline (416), the versatile synthesis from the Lukes-Sorm dilac-

252


'' o(!::)m - (I,,),--CH

FH2 (CH

i, ii iii

Me

Me

Me

I

CH

CHOMe

(CH2)m

H

II

+OMe

COC3F7

272 273 274 Scheme 22. Reaction conditions: i, (C3F,CO)20; ii, H~(OAC)~-M~OH; iii, NaBH+

tam (418), and the chirospecific synthesis from glutamic acid (417).The Hofmann-Loffler reaction on the corresponding primary N-chloramines in concentrated sulfuric acid, using ferrous salts as initiators, gives 5-butyl-2-pentylpyrrolidine (monomorine 11) (10a) and 2-hexyl-5-pentylpyrrolidine (10d) (Scheme 23) (132,412). c ~ H ~ ~I ~ - c H i_ - R c ~ H ~ ~ I~ - c H - R NHCl NH2 275a R=C H d R=C6H13 ' n j

276a

R=C2H5

R=C H

d

' n R=C6H13

j

R=C2H5

c

~ nQR H

~

~

H

10a R=C H d R=C6H13 ' n j

R=C2H5

Scheme 23. Reaction conditions: i, 'BuOCI or NaOCI; ii, conc HZS04,(NH4)2Fe(SO,),, or UV.

Stepwise alkylation of I-nitrosopyrrolidine (277) via metalated nitrosoamine affords 5-ethyl-2-heptyl-I-nitrosopyrrolidine (279). Removal of the nitroso function gives an overall 33% yield of a 1 : 1 mixture of isomeric products (10d) (Scheme 24) (415). Following the same approach, 277 gives 5-butyl-2-pentylpyrrolidine (monomorine 11) (lOa), 2-hexyl-5-pentylpyrrolidine(lob), and 2-(5-hexenyl)-5-pentylpyrrolidine(monomorine 111) (100 (412). Catalytic hydrogenation of the unstable pyrroles (281a-c), which are prepared by heating the 1 ,Cdiketones (280a-c) with an excess of ammonium carbonate at 120°C, gives 2,5-dialkylpyrrolidines (10a-c) (cis : trans = 85 : 15, -85% conversion) (Scheme 25) (133). Reductive amination of 1,Cdiketones (282b,f,h,i) with ammonium acetate and sodium cyanoborohydride produces 2,5-dialkylpyrrolidines (10b,f,h,i) identical to natural products in 50-90% yields. Each pyrrolidine is an approximately 1 : 1 mixture of cis and trans isomers (Scheme 26) (25,138). 1) i , ii 2 ) i, iii

NO 277

-

iv

R G c 2 H 5 NO 278 R = H 279

R=C7H15

-

nC7H15 G

c 2 H 5 H

10d

n

SCHEME24. Reaction conditions: i, LDA-THF; ii, EtI; iii, 1-iodoheptane; iv, HCI

253


A highly attractive synthetic method is as follows. Alkylation of the in situ generated anion of 283 occurs with high regioselectivity at the a-position to afford the monoalkylated derivative (284), and sequential alkylation of 284 generates truns-2,5-dialkylpyrroline (285) with high regio- and stereoselectivity . Catalytic hydrogenation of 285 followed by demethoxycarbonylation gives the trans isomer of 5-butyl-2-pentylpyrrolidine (10a) in 40% overall yield. This synthetic route proceeds with a high degree of selectivity in establishing the trans stereochemistry of the dialkyl groups (Scheme 27) (416).

280a - c

281a-c

H 10a-c (cis) SCHEME25. Reaction conditions: i, (NH4)2C03, 120°C; ii, HZ-RhlA1203.

The Lukes-Sorm dilactam (287) can smoothly afford various 5-oxoalkyl-2pyrrolidones in high yield on treatment with Grignard reagents. This reaction has been applied to the synthesis of truns-5-butyl-2-heptylpyrrolidine(lOc), a repellent of ants. Reaction of 287 with methyl magnesium bromide afforded oxoalkylpyrrolidone (288), the dithioketal (289) of which was converted by hydrogenolysis with Raney nickel to alkylpyrrolidone (290a). Treatment of 290a with phosphorus pentasulfide gave thiolactam 290b which was converted by treatment with methyl iodide to the thioether (291). The thiomethyl group of 291 was replaced with a butyl group by reaction with butyl magnesium bromide in methylene chloride to yield pyrroline (292). Reduction of 292 with sodium borohydride afforded a 1 : 1 mixture of truns- and cis-5-butyl-2-heptylpyrrolidine ( ~ O C ) , separable by chromatography. The desired trans isomer is identical to the repellent of ants by spectral properties (Scheme 28) (418). Recently, both enantiomers each of cis- and truns-5-butyl-2-heptylpyrrolidine (1Oc) have been synthesized from glutamic acid by an excellent method with high diastereomeric and enantiomeric purity (417). The thiolactam (293) prepared from L-glutamic acid was reacted with benzyl 2-(trifluoromethylsulfony1oxy)octanoate to yield the rather unstable salt (294), which without purification was treated with triphenylphosphine and N-methylpiperidine to afford

254


R1 C5H11n

b

f

H

0

C6H13n

- ( CH2)4CH=CHz

-(CH2)7CH=CH2

-(CH2I4CH=CH2

0-

1 ) iv 2) v

nHgC4.:QR I

I

C02Me

nH9C4

CO2Me

284 R = H

283

10 b , f , h , i cis/trans= 1 / 1

282 b , f , h , i

- ( CH2)4CH=CH2

C5Hlln C9H19

h i

R2

285 R = C 5 H I 1

R 286 R = C 0 2 M e

n

lOa(trans) R = H

SCHEME27. Reaction conditions: i, LDA; ii, "BuBr; iii, C 5 H I I B r ; iv, H,-Pt0,-AcOH; Me3SiI.

$&J

L o s 4 o 0

287

290a

v,

288

x= 0

W

289

291

292

2 9 0 b X= S

1Oc (trans)

1Oc (cis)

SCHEME28. Reaction conditions: i, MeMgBr-CH2C12; ii, HSCH2CH2SH-BF,.Et20; iii, Raney Ni-H,; iv, P2S5-PhH; v, CH31; vi, n-BuMgBr-CH2C12; vii, NaBH4.

255


the vinylogous carbamate (295) as a 5 : 1 mixture of geometrical isomers. The carbamate (295) was transformed to cis-pyrrolidine (296) in a one-pot treatment with ammonium formate and 10% Pd-C in a mixture of MeOH and AcOH. Successive treatments of 296 with benzyl bromide-potassium carbonate and acetic acid gave the acid (298), which was treated with n-propyllithium to afford the ketone (299). Compound 299 was immediately reduced with NaBH, to the diastereomeric alcohols (300), which were converted to the secondary amines (301) by catalytic hydrogenolysis. Bisphenylsulfonylation of 301 followed by reduction with NaBH, in DMSO gave the sulfonamide (303). Finally, deprotection using 48% HBr or sodium in liquid ammonia gave (2S)-cis-S-butyl-2-heptylpyrrolidine (1Oc). (2R)-cis-lOc was prepared by a modification of this procedure. Alternatively, treatment of the cis acid (298) with POC1, followed by po-

293

294

296 R = H

298

R=OH

297 R = B n

299

R=C

3H7n ; 1 . . . Q . . C 7 H R 0

295

2 C4Hgn..

1;

x1

i 2

300 R 1 = H ,

n

3 1

1 303

R2=Bn

301 R 1 = R 2 = H

R=SOZPh

(2S)-lOc (cis) R= H

302 R 1 = R 2 = S O Z P h

HOOC

- 'o

'.C7Hl: Bn

xii

R Q-C7nl: Bn

C7H

C4Hg

H

steps

xiii, xiv

298

1t - Q''

304 305

R=CN R=COOH

(2s)-lOc {trans)

SCHEME29. Reaction conditions: i, nC6H,3CH(OTf)COOBn in CH3CH; ii, Ph3P and N-methylpiperidine; iii, HCOONH4, 10% Pd/C; iv, PhCH2Br-K&03; v, AcOH-H20-"PrOH; vi, "PrLi; vii, NaBH4; viii, H2-10% Pd/C; ix, phenylsulfonylimidazole and Me3+O-BF4-; x, NaBH4 in DMSO; xi, 48% HBr or Na-liq NH,; xii, POCL,; xiii, KCN; xiv, conc HCl.

256


tassium cyanide gave a mixture of cis- and trans-aminonitriles in favor of the trans isomer (304). This mixture was equilibrated in a silica gel slurry to produce a 1 : 9 cis : trans mixture. Hydrolysis with concentrated HCl followed by recrystallization of the resulting acid gave the pure trans acid (305), which was easily transformed to (2S)-truns-5-butyl-2-heptylpyrrolidine(10c) according to the procedure as described for cis-lOc from 298. (2R)-truns-lOc was prepared by the same method from D-glutamic acid (Scheme 29). Structures of N-methylpyrrolidines (11) are suggested by the mass spectra which exhibit the a-cleavage and parent ions increased by 14 mass units relative to those of corresponding N-H pyrrolidines. These structures are confirmed by reductive N-methyiation of N-H pyrrolidines with formaldehyde in formic acid (I6.25). 2. 2,5-Dialkylpyrrolines Mass spectra of 2,Sdialkyl- 1-pyrrolines (12) exhibit relatively more intense molecular ions and two diagnostic fragment ions (306 and 307) resulting from a McLafferty rearrangement of the y hydrogen and from an allylic cleavage relative to the C=N bond as well as an ion (308) at mlz 82 arising from a-cleavage of an alkyl group from the odd electron ion (306) (16,25,132,409).Reduction of these pyrrolines with sodium borohydride gives nearly equal amounts of cis- and trans-pyrrolidines, proving unequivocally that the pyrrolines are substituted in the 2,5 rather than the 2,2 position (132).

307

1-Pyrroline (129, found in the desert locust and the Mediterranean fruit fly (Table 11), has been identified by formation of the l-dimethylaminonaphthalene-5-sulfonyl (dansyl) derivative (106) or the colored adduct with o-aminobenzaldehyde, in addition to gas chromatography-mass spectrometry (102). The 1-pyrrolines (12) have been prepared by treatment of their parent pyr-

257


lOj

12a

12b

SCHEME 30. Reaction conditions: i, NaOCI; ii, NaOH

rolidines with sodium hypochlorite followed by heating the resulting N-chloropyrrolidines with aqueous alkali (16,133,138). Using this method, 5-ethyl-2-npentylpyrrolidine (l0j) gives a mixture of 2-ethyl-5-n-pentylpyrroline (12b) and its isomer (12a) (Scheme 30) (138). Reduction of the pyrroline mixture with sodium borohydride in methanol regenerates the pyrrolidines, in which the trans isomer predominates (133). 5-Ethyl-2-n-pentylpyrroline (12a) is also available as by-product in the Hofmann-Loffler reaction to prepare 5-ethyl-2-n-pentylpyrrolidine (lOj) (Scheme 23) (132). 1-Pyrroline (129 is prepared by heating a solution of (-t )-ornithine hydrochloride and ninhydrin or by the reaction of Nbromosuccinimide with (+)-ornithine hydrochloride (106). 3. Methyl 4-Methylpyrrole-2-carboxylate The trail-following pheromone, methyl 4-methylpyrrole-2-caboxylate (14), of the genera Attu and Acromyrmex (Table 11) is characterized by spectral data (419,420) and by comparison with an authentic synthetic sample, which had been prepared by methylation of the acid (310) resulting from the action of strong alkali on 3-ethoxycarbonyl-4-methylpyrrole-2-carboxylicacid (309) (Scheme 31) (421). The following synthesis from pyrrole (311) gives a better overall yield (30):Pyrrole (311) is treated with trifluoroacetic anhydride-dimethylaniline folLowed by hydrolysis to afford the acid (312). Diazomethane treatment and subsequent formylation with methoxydichloromethane and aluminum chloride give the aldehyde (313). Catalytic hydrogenolysis of 313 gave the pyrrole (14) in 83% yield (Scheme 32).

Me

COOEt

0

COOH

H

309

Me

Me

O C O O H

i iO

C O O M e

H

H

310

14

SCHEME 31. Reaction conditions: i, OH-; ii, CH2N2,

258


R1

0"" iii, iv

O

H

311

Me

R

z

L

QCOOMe H

H

1 2 312 R = H , R =COOH 1 2 313 R =CHO, R =COOMe

14

SCHEME32. Reaction conditions: i, TFAA-PhNMe,; ii, OH-; iii, CH2N2; iv, C12CHOCH3AIC13; V, H2-PdlC.

4. Polyzonimine Polyzonimine (19), isolated from a millipede secretion by preparative gasliquid chromatography (Table II), has been assigned the molecular formula

314

316

315

317 318

R=CHO R'CH:O]

(?)-19

0

+ j ? 319

323

320

R=COOEt

321

R=CHZBr

324

NC

OCH2Ph

322

(+)-19

SCHEME33. Reaction conditions: i, LiBr-HMPA; ii, morpholine; iii, AcOCH2CH2NOz; iv, ethylene glycol-H+; v, Hz-Raney Ni; vi, H 3 0 + : vii, (EtO),P(0)CH2COOEt-NaH; viii, AIH,; ix, PBr3-pyridine; x, L-benzoyloxyprolinol-KzC03-DMSO; xi, PhS03CH2CN; xii, (a) KOBuf-THFDMSO, (b) CuS04.5H20; xiii, CH3NOz-KOH-MeOH; xiv, MsCI-Et,N; xv, NaBH4-MeOH; xvi, 0,; xvii, Me$; xviii, ethylene glycol-triethyl orthoformate-H+; xix, H2-PtO,; xx, 10% HCITHF.


259

C,,H,,N on the basis of high-resolution mass spectrometry. The structure has been deduced from its spectra and an X-ray crystallographic analysis of the perchlorate, and confirmed by synthesis (113). The racemic polyzonimine (19) is prepared as shown in Scheme 33. The expoxide (314) is rearranged to the aldehyde (315) by refluxing with LiBrHMPA in benzene. Morpholine enamine (316) derived from 315 is condensed with nitroethylene, generated in situ from 2-acetoxynitroethane, to afford the nitroaldehyde (317). Ethylene acetalization, reduction over Raney nickel, and subsequent deacetalization give (*)-polyzonimine (19) in 22% overall yield from the epoxide (314) (113). Natural (+)-polyzonimine (19) has been synthesized by a reaction sequence using the asymmetric [2,3]sigmatropic rearrangement of the ammonium ylide to generate the chiral intermediate. The Homer-Emmons reaction of the ketone (319) gives the ester (320) accompanied by two isomers. Reduction of the ester (320) with aluminum hydride followed by bromination gives the bromide (321), which is aminated with L-benzoyloxyprolinol to afford an amine. This amine is converted to the quaternary salt (322) by treatment with cyanomethylbenzenesulfonate. Treatment of 322 with potassium tert-butoxide followed by hydrolysis with CuSO,.SH,O affords the optically active olefin aldehyde (323), the optical purity of which is estimated to be 68% enantiomeric excess. Condensation of 323 with nitromethane followed by dehydration affords the nitroolefin (324) which is readily converted to ( )-polyzonimine (19) by standard reaction sequences (Scheme 33) (422).

+

C. PYRROLIZIDINES

1. Danaidones Four dihydropyrrolizines and many pyrrolizidine ester alkaloids have been found in danaid butterflies and arctiid moths (Table IV). The first isolation of danaidone (25), an important pheromone of hairpencils or coremata, has been carried out by chromatography of the hairpencil extract on a silicic acid column and vacuum sublimation of the resulting crystalline compound (14th). After this isolation, two other dihydropyrrolizines (26 and 27) were identified by thin-layer or gas-liquid chromatographic comparison with authentic compounds, in conjunction with specific color reactions with Ehrlich's reagent (61,64,14Bb,423). Nonvolatile alkaloid 28 can be seen in gas chromatograms only after trimethylsilylation (64). Identifications of pyrrolizidine esters are made by using combined gas chromatography-mass spectrometry and by comparison and cochromatography with authentic samples (63,64). The structure of danaidone (25), namely, 2,3-dihydro-7-methyl- 1H-pyrrolizin-1-one, has been inferred from the IR (v 1681 cm-') and UV ,A[ 288

260


nm (log E 4.22)] spectra suggesting a conjugated carbonyl group, the mass spectrum (M m/z 135, a base peak) indicating the molecular formula C,H,ON, and the 'H-NMR spectrum suggesting one methyl group (6 2.2, s), a pair of methylene (6 2.84, 4.13, t, J = 6.5 Hz), and two coupled aromatic protons (6 6.09, 6.69, d, J = 2.5 Hz) (55,148~).Synthetic confirmation of structure 25 is obtained as follows. Cyanoethylation of 3-rnethylpyrrole (325) using Triton B as base gives N-cyanoethyl-3-methylpyrrole(326). Cyclization of 326 with hydrogen chloride followed by hydrolysis via the imine (327) gives danaidone (25), identical to the natural alkaloid (Scheme 34) ( 1 4 8 ~ )Danaidone . (25) can also be easiIy obtained in high yields from ethyl 3-methyl-1H-pyrrole-2-carboxylate (328) via Dieckmann reaction of the N-propanoate derivative (329) (Scheme 35) (424). +

H 325

326

327

R

25

H CHZOH

N 331

26b

SCHEME34. Reaction conditions: i, CHFCHCN, MnOz.

332 R= OH 333 R= H

26a 27 R= H

Triton B; ii, dry HCI; iii, H2O-AcONa; iv,

In contrast to the achiral pheromones (25 and 27), hydroxydanaidal (26) possesses an asymmetric carbon atom (C-7),but the absolute configuration has not yet been determined. The coremata of the male arctiid moth, Creatonotos gangis, have recently been shown to produce (R)-(-)-hydroxydanaidal (26a) both from heliotrine (330, 7 s ) and from monocrotaline (42, 7R) (Table IV), when the larvae are raised on a diet incorporating either 330 or 42. This fact indicates that the (7s) alkaloid is inverted at C-7 in its biosynthetic conversion to 26 and suggests the possibility that the natural hydroxydanaidal (26) has the (R) configuration (425). (R)-(- )-Hydroxydanaidal (26a) can be prepared by oxidation of retronecine (332) with manganese dioxide. In a similar manner, heliotridine (331) affords @)-(+)-26b (75,423,426).Supinidine (333) is similarly oxidized by manganese dioxide to afford danaidal(27), identical with the natural product (Scheme 34) (423,427). Recent synthetic studies on the potential anti-

26 1


328

ii

___)

329

r

~

C

0

2

E

j

-

&

25

SCHEME 35. Reaction conditions: i, Br(CH2)2C02Et;ii, Dieckmann condensation.

tumor agents derived from pyrrolizidine alkaloids and their derivatives have been reported (428). Me, ,Me

yH

,OMe CH20COC-C\H I

OH Me 330

heliotrine

2. 3-Heptyl-5-methylpyrrolizidine

(5Z, 8Q-3-Hepty1-5-methylpyrrolizidine(48), from a cryptic thief ant S . xenovenenum (Table IV), shows in the mass spectrum a molecular ion at mlz 223 and two diagnostic fragment ion peaks (334 and 335), at mlz 208 (M+ - Me) and 124 (M+- C,H,,), corresponding to the loss of the alkyl side chains from carbons adjacent to nitrogen. In addition to this fragmentation pattern, a molecular formula of C,,H,,N and an absence of double bonds suggest a 3 5 disubstituted pyrrolizidine ring system (430). H

H

H

-c 7H 1 5 ’ m / z 208

m l z 223

Me m / z 124

334

48

335

The overall carbon-nitrogen framework was confirmed by synthesis. Reductive amination of the triketone (336) (429) with sodium cyanoborohydride and ammonium acetate formed a mixture of four isomeric pyrrolizidines. Pure sam-

262


ples of each isomer were obtained by preparative gas chromatography. The naturally occurring alkaloid (48) has a gas chromatographic retention time identical with that of the major synthetic 5Z,8E isomer (48) by direct comparison (Scheme 36) (430). The selective synthesis of the enantiomer of 48 started with the ally1 alcohol (338). Oxidation of 338 by the Sharpless procedure (431)gave the chiral epoxide (339) which was reduced with bis(2-methoxyethoxy)aluminuminum hydride to yield the 1,3-diol (340). Monobenzoylation of 340 and subsequent treatment with phthalimide by employing the Mitsunobu condition (432) gave an imide. Successive treatment of the imide with potassium carbonate in methanol and hydrazine hydrate gave the amino alcohol (341). The amino alcohol (341) was converted to the imine (342) by treatment with aqueous perchloric acid. Reduction of 342 with sodium cyanoborohydride gave a mixture of the pyrrolizidines (343a; R 1= H, R2 = OH, and 343b; R' = CN, R2 = OH). The cyano group in 343b could be reductively eliminated by sodium borohydride or by sodium in ammonia-ethanol to afford the pyrrolizidine (343a). Oxidation of 343a and Wittig reaction of the resulting aldehyde with pentylidenetriphenylphosphorane led to a mixture of (2)-and (E)-olefins. Catalytic hydrogenation afforded (-)-[(3~)-(3~,5~,8cu)]-3-heptyl-5-methylpy~olizidine (343c; R 1 = H, R2 = C5Hlln) [(33)-48](Scheme 36) (433).

Me

0 336

v,

-

Yt

. NH2

341

-

C7H1jn

337

'f

'OH

342

x, xi

Me

343

5 R2

SCHEME36. Reaction conditions: i , 'BuOOH-Ti(O'Pr)4, (+)-L-diethyltartarate; ii, (MeOCH2CH20)2AIH; iii, PhCOC1-Et3N; iv, phthalimide, Ph3P; v, K2C0,-MeOH; vi, NH,NHz.H,O; vii, aq HC1O4; viii, NaBCNH3-THF-MeOH-20% AcOH; ix, DMSO oxidation; x, Me(CH2)2CHZCH=PPh3; xi, H2-Pt02.

263


344

19

49

SCHEME 37. Reaction conditions: i, I-(CH&NO*; ii, Py, reflux.

3. Nitropolyzonamine Nitropolyzonamine (49) (Table IV) can be isolated as colorless crystals from the secretion of the millipede, P. rosalbum, by preparative gas chromatography or as its crystalline perchlorate from an ethereal solution of the crude defensive secretion. The structure and stereochemistry have been determined by an X-ray analysis of the base perchlorate (153). Racemic nitropolyzonamine (49) can be synthesized from polyzonimine (19). Treatment of polyzonimine (19) with 3nitropropyl iodide gives a crystalline salt (344) which is readily cyclized to racemic nitropolyzonamine (49) in boiling pyridine (Scheme 37) (153).

D. INDOLIZIDINES 1. Monomorine I The structure of monomorine I (16a), isolated from the extract of workers of the thief ant, Monomorium pharaonis, by gas-liquid chromatography (Table 11) , has been revealed to be 3-butyl-5-methyloctahydroindolizidine on the basis of mass and 'H-NMR spectra. The mass spectrum shows characteristic peaks at mlz 180 (345; M - CH,) and rnlz 138 (346; M - Bu, a base peak), indicating the presence of methyl and butyl group attached to the a carbons of an amine, in addition to a molecular ion at rnlz 195. The fact that the (M - I) peak is higher than the M peak indicates a cyclic amine. The 'H-NMR spectrum shows two methyl groups (triplet at 6 0.88, C€I,-CH,; doublet at 6 1.18, C€I,CH-N) and three methines adjacent to nitrogen (6 2.13, 2.27, and 2.52). Structure 16a, assumed on the basis of these spectral data, was confirmed by

m/z 345

180

m / z 195

m / z 138

16a

346

264


comparison with a synthetic stereoisomeric mixture. The synthesis was carried out by condensing diethyl 3-oxoglutarate (347), acetaldehyde (348), and 4aminooctanal diethylacetal (349). The resulting oxooctahydroindolizine (350) was subsequently saponified, decarboxylated, and reduced to yield a stereoisomeric mixture of 3-butyl-5-methylindolizidine (16) (Scheme 38) (21,23a). COOEt

CH(0Et)

COOEt

CHO COOEt

Me

347

348

Me C4Hgn 350

349

Me C4Hgn (i)-16

SCHEME 38

The stereochemistrywas determined by evaluation of biological assays of four stereoisomers of monomorine I prepared by Sonnet and Oliver (434,435). The natural monomorine I was the all-cis isomer, namely, (SZ,9Z)-3-n-butyl-S-methylindolizidine (16a), having both attractant and trail-initiating activity (22,236,427).Racemic synthesis of the four stereoisomers by Sonnet starts with 2,6-lutidine (351). Successive treatments of 351 with n-BuLi and hexene- 1-oxide gave an alcohol (352). Cyclization of 352 with triphenylphosphine dibromide gave the quaternary base (353), which on reduction yielded the indolizidine (16a), racemic monomorine 1, as a sole product. Alternatively, catalytic hydrogenation of 352 yielded the amino alcohol (359, and successive treatments of 355 with triphenylphosphine dibromide and triethylamine gave an isomeric mixture of indolizidines (16a and 16b), which could be separated by spinning-band distillation. Similarly, trans-amino alcohol 354 can be transformed to a separable mixture of the indolizidines (16c and 16d) (Scheme 39) (434,435). Similar synthetic routes starting from 2-butylpyrrole (356), cis-amino alcohol 355, and trans-amino alcohol 354 have also been reported (Scheme 40) (434-436). The conformation of the four stereoisomers(16a-d) of monomorine I was investigated by ‘H- and 13C-NMRspectroscopy (436). The stereoisomers 16c and 16d have also been prepared by a [3 + 31-type annelation between a,a’-dimethoxylatedamides and allyltrimethylsilane (363). Compound 366 was synthesized by ring formation with 363 and 365, prepared by methoxymethylation of 364, in the presence of TiC1,. Hydrogenation of 366 followed by butylation with n-BuLi and reduction with sodiumborohydride gave a mixture of stereoisomers 16c and 16d (Scheme 41) (437). A stereocontrolled synthesis of racemic monomorine I (16a) has been accomplished by Stevens and Lee (438). An ally1 alcohol obtained by reaction of acrolein with the Grignard reagent of the chloroacetal(367) was oxidized to yield the enone (368). The Michael addition of 1-nitropentaneto 368 was catalyzed by tetramethylguanidine to yield the nitroalkane (369). Reductive cyclization of 369

265


oMe i , ii

__c

Me

351

Me

HO 353

C4~gn

(+)-16a

Me.. HO

HO

354

355

Me (+)-16a

C4Hgn

(+)-16b

L&J + @ iii

Me

C4Hgn

(f)-16~

Me

C4Hgn

(?)-16d

SCHEME39. Reaction conditions: i, “BuEi; ii, hexene-I-oxide; iii, Ph3P.Br2-Et3N; iv, Hz-PtOz; v, Na-EtOH.

357

358

(f) -16b 355

359

Me

C4Hgn

(t)-16d

SCHEME40. Reaction conditions: i, RMgX; ii, 5-methyl-2-oxotetrahydrofuran; iii, HZ-RO2; iv, PhsP.Br2-Et3N; v, Cr03; vi, HClOk; vii, LiAIH4.

266


C H 3 0Q

O

L CH30

H CH30

364

A

CH3

365

...

111

O

i

v

V

c1

& dH3

366

4Hgn

+

k4Hgn

’CH3

(+)-16~

(+)-16d

SCHEME41. Reaction conditions: i, NaH, CH3CH60CH3; ii,Hz, Raney Ni, KOH; iv, “BuLi; v, NaBH4, AcOH.

Si(CH,), (363), TiC14; iii,

gave the amine (370), which on sequential treatments with aqueous acid and sodium cyanoborohydride yielded (*)-monomorine I (16a) (Scheme 42). Furthermore, two other stereoselective syntheses of (2)-monomorine I (16a) have been reported by the groups of Natsume and co-workers (439,441) and Kawanishi et aE. (440). Acetal372 prepared from the dihydropyridine derivative (371) was successively treated with p-toluenesulfonyl chloride-pyridine and DBU in toluene to afford acetal 373. Compound 373 was treated with aqueous hydrochloric acid to afford an aldehyde which on reaction with the anion of diphenyl(1-phenylthiopentyl)phosphine oxide gave the thioether (374) as a mixture of the cis and trans isomers. Hydrolysis of 374 with aqueous hydrochloric acid in methanol gave a ketone and subsequent reductive cyclization gave (*)monomorine I (16a) as a sole product (Scheme 43) (439).On the other hand, the pyridinium salt of a-picoline (375) was treated with Grignard reagent to give the a-alkyl- 1,2-dihydropyridine (376). Catalytic hydrogenation of 376 followed by

368

367

370

369

Me

64Hgn

(+)-16a

SCHEME 42. Reaction conditions: i, Mg-THF; ii, CH,=CHCHO; iii, MnOz; iv, 1-nitropentane; v, H2-Pd/C, NazS04; vi, H 3 0 + ; vii, NaBCNH3.

267


Me

+

Me Cbz

Cbz 372

371

Me Cbz

Me

374

373

(+)-16a

SCHEME 43. Reaction conditions: i, TsCl-Py; ii, DBU-toluene, 100°C; iii, aq HC1-DME; iv, v, aq HCl-MeOH; vi, H,-10% Pd/C. Li

deprotection afforded cis-2,6-dialkylpiperidine (377) which was transformed to the ketal(378) on successive oxidation and protection. Decarbomethoxylation of 378 and subsequent cyclization gave (t)-monomorine I (16a) in 60% yield (Scheme 44) (441). The racemic stereoisomer (16b) of monomorine I has been stereoselectively synthesized (416). Thus, successive bis-alkylations of 1 -methoxycarbonyl-3pyrroline (379) gave truns-2,5-dialkylpyrroline(381) as a I : 1 mixture of 4’bromopentane isomers. N-Decarbomethoxylation gave the bicyclic compound

375

& H *H.., &

376 ,..H

r

C 0 2 Me

OH

C02Me

377

P

O

378 A

.H ___)

viii (+ )-16a

SCHEME44. Reaction conditions: i, CIC0,Me; ii, BrMgmCH(CH2)3CH,; iii, H2-F’VC; iv,

I 0 THP

H + , MeOH; v, CrO3, aq HzS04; vi, HOCHzCHzOH, P-TsOH, PhH; vii, KOH, NHzNHz, HOCHzCHZOH;viii, Pd/C, aq HCl, MeOH.

268


0- 0

.

1,

...

Ill

Bun

i, ii

COOMe 379

Me 6OOMe 381

COOMe 380

iv, v

"BU

vi

Me

4f.) "Bu Me (f)-16b

382

SCHEME45. Reaction conditions: i, LDA; ii, "BuBr; iii, 1,4-dibromopentane; iv, TMSI; v, Na2C03-MeOH; vi, H2-Pt02.

(382) as a 1 : 1 mixture of C-5 methyl isomers. Catalytic hydrogenation afforded a single product (16b) (416). This highly interesting reduction phenomenon does appear to be general, occumng with related 3,5-dialkyl- 1,2-dehydroindolizidine alkaloids (Scheme 45) (416,442). The first asymmetric synthesis of (-)-monomorine I, an enantiomer of the natural alkaloid, by Husson and co-workers starts with the chiral 2-cyano-6oxazolopiperidine synthon (385) prepared from (-)-phenylglycinol (384), glutaraldehyde (383), and KCN (443). Alkylation of 385 with an iodo ketal led to the formation of a single product (386). The cyano acetal (386) was treated with silver tetrafluoroborate and then zinc borohydride to afford a 3 : 2 mixture of C-6 epirnenc oxazolidine (387) having the (2s) configuration. Reaction of 387 with

385

Me 390

CqHg

386

Me

C4Hgn

(-)-16a

SCHEME46. Reaction conditions: i, KCN, pH 3-4; ii, LDA-THF; iii, ethylene ketal of 1iodoheptane-3-one; iv, AgBF4-THF; v, Zn(BH4)2; vi, MeMgI; vii, H2-PdIC, 1% 1 M HCi-MeOH.

269


methylmagnesium iodide afforded a 4 : 1 mixture of the desired cis-alcohol (389) and its trans isomer (388). The major cis-alcohol (389) was reductively cyclized in the presence of aqueous acid to yield (-)-monomorine I (Ma) after the usual column chromatographic separation from its isomer (Scheme 46). Since the absolute configuration of synthesized (-)-monomorine I [16a*HCl,[ c ~ ] ~ ~ - 6 9 . 2 ~ (MeOH)] is (3S,5R,9R), the natural monomorine I (dextrorotatory) (20) should have the (3R, 5S,9s) configuration (443). 2. Other 3-Alkyl-5-methylindolizidines Structures of 3-alkyl-5-methylindolizidines, found in thief ants, Solenopsis species (Table II), arrived at by gas chromatographic and mass spectral analysis were confirmed by coinjection and direct comparison with the synthetic sample. U ~ U characteristic peaks at mlz 152 (M Indolizidine 15a from S. C O ~ ~ K ~exhibits CH,) and 138 (M - C,H,, a base peak) as well as aparent peak at mlz 167 in the mass spectrum. It corresponds to an isomer of 3-ethyl-5-methylindolizidine (15) which was prepared as a mixture of four stereoisomers by reductive amination of triketone 391 with ammonium acetate-sodium cyanoborohydride and sodium borohydride (Scheme 47). In order to assign the stereochemistryof the isomers, indolizidine preparations from 2,6-lutidine (351) by Sonnet (134,435) were employed. The hydroxyalkylpyridine (392) obtained from 351 was catalytically reduced to afford

v i , vii

391 i

M e QMe

viii Me

5

15 iii;'i>

H

...

+ Me

351

Me

OH

H

111

Me

393

Me 15a

Me

392

n

H

395

17a

I

OH 394

SCHEME47. Reaction conditions: i, "BuLi; ii, octene-1-oxide; iii, H2-Pt02; iv, CrO,-AcOH; v, HCIO,; vi, NH40Ac-NaOH, NaBCNH,; vii, NaBH,; viii, butene-1-oxide.

270


cis-2-methyl-6-(3-hydroxypentyl)piperidinewhich on oxidation with chromium tnoxide-acetic acid followed by treatment with perchloric acid gave the iminium salt (393). Catalytic hydrogenation of 393 gave as a sole product (52,92)-3ethyl-5-methylindolizidine (15a), which had an identical gas chromatographic retention temperature with the natural alkaloid (Scheme 47) (134). (5Z,9Z)-3-Hexyl-5-methylindolizidine(17a) from a Solenopsis sp. exhibits characteristic peaks at mlz 208 (M - CH,) and 138 (M - C,H,,, a base peak) as well as a parent peak at mlz 223 in the mass spectrum. The stereochemistry has been determined by synthesis. Racemic (5Z,9Z)-3-hexyl-5-methylindolizidine (17a) was prepared by the above-mentioned methodology, using octene- 1-oxide instead of butene-1-oxide (Scheme 47) (134). Monomorine VI (lS), 3-(5-hexenyl)-5-methylindolizidine,has been isolated from M . phuruonis workers (Table 11), but its stereochemistry is unknown and synthesis has not yet been conducted (22,238). E. QUINOLINES A predominant toxin (51) from water beetles of the genus Zlybius (Table V) shows a UV absorption corresponding to hydroxyquinoline or hydroxyisoquinoline. The 'H-NMR spectrum exhibits, beside signals of methyl ester and phenol, signals of five aromatic protons as both ABC and AB systems, the latter indicating two protons at C-3 and C-4 in quinoline. Since electron pyrolysis of 51 gives radioactive 8-hydroxyquinoline, its structure is identified as methyl 8hydroxyquinoline-2-carboxylate (51) and confirmed by synthesis from xanthurenic acid (52) (Scheme 48) (101).The precursor of this alkaloid was shown to be tryptophan (444). The structure of 1-methyl-2-quinolone (57), from the aposematic beetle in the genus Metriorrhynchus (Table V), was expected from the mass spectral data and was confirmed by comparison with an authentic sample (97).

F. XANTHOMMATIN Xanthommatin (58) and dihydroxanthommatin (59) are well-known representatives of the tryptophan metabolite, ommatine. Xanthommatin (58) shows a c1

OH

...

OH

OH

52

OH

396

397

R= H

51

R= CH3

SCHEME 48. Reaction conditions: i, P0Cl3; ii, H,-Pd; iii, HCl/CH30H.

27 1


COOH

YOOH

CHNHZ

CHNH2

1

I

I

CH

COOH

COOH ___t

398

399

58

SCHEME49. Reaction conditions: i, aq AcOH, A.

characteristic redox behavior: the yellow-brown pigment (58) is converted by treatment with sulfurous acid or sodium dithionite to the red pigment, dihydroxanthommatin (59), which is reoxidized by oxygen in air. Basic degradation of 58 by treatment with 0.5 N sodium hydroxide solution yields xanthurenic acid (52) via 3-oxykynurenine (398). The enzymatic reaction of 58 with kynureninase affords alanine. On the basis of this evidence structure 58 was proposed, and confirmed by total synthesis, which was accomplished by condensation of 3oxykynurenin (398) with quinolinequinone (399) (Scheme 49) (445).Xanthommatin (58) was also demonstrated to be synthesized from 3-oxykynurenin (398)

in vivo. G. PAPILIOCHROMES One of the papiliochromes, papiliochrome I1 (142), isolated from Pupilio butterflies, is actually a pair of optical isomers, papiliochromes IIa and Ilb. Compound 142 is hydrolyzed by treatment with 10W3 N HC1 to afford Lkynurenine and a new catecholamine (400) (71). Results of acid hydrolysis of the latter with 1 N HC1 and the mass and 13C-NMR spectra suggest that the structure of 400 is N-P-alanylnoradrenaline, which was proved by chemical synthesis. The 13C-NMR data indicate that papiliochrome I1 is represented as structure 142 in which the nitrogen of aromatic amino group of kynurenine is bonded to C-5 of the side chain of N-P-alanyldopamine. The existence of optical isomers, IIa and

5178

+

C H - C Hz-N H - CO- C HZC HZN Hz

77

HO 400

HO

H H 142

6 H H

272


Ilb, is explained by rotation of the catechol ring about the axis C-5 and p-OH to the opposite side.

H . COCCINELLINES 1. Structure The isolation of eight defensive alkaloids (99-106) (Table VII) from the ladybug (Coccinellidae) and the soldier beetle (Cantharidae) was carried out by partitioning the methanol extract between aqueous methanol and n-pentane followed by chromatographic separation (alumina) of the aqueous methanol extract (85,328,330-332,334). The mass spectrum of coccinelline (99), purified by recrystallization, shows a characteristic peak at mlz M - 16, diagnostic of an Noxide, as well as a molecular ion at mlz 209, indicative of a molecular formula C,,H,,NO. Compound 99 shows only end-absorption in the UV spectrum, and its 'H-NMR spectrum shows the absence of olefinic protons. It is optically inactive, and the 13C-NMRspectrum affords strikingly simple signals (only eight signals). This evidence indicates that 99 is a tricyclic amine oxide possessing a plane of symmetry (85,333). The structure and stereochemistry have been established by an X-ray analysis of coccinelline hemihydrochloride (446).Reduction of coccinelline (99) under mild conditions (ferrous sulfate or catalytic hydrogenation) gives precoccinelline (loo), which is therefore a free base of 99. Propyleine (104) is an enamine with one olefinic proton and a secondary methyl group, as assumed from the IR and 'H-NMR spectral properties. Catalytic hydrogenation of 104 gives precoccinelline (100). There are three possible dehydroprecoccinellines(336).Propyleine (104) is devoid of the UV absorption typical of enamines, indicating that the lone pair on nitrogen cannot be parallel with the n-electron system of the double bond. An enamine, which in addition to this condition can lead to 100 on catalytic hydrogenation, could only be 104a of the three possible dehydrococcinellines (334,336).

Convergine (101) and hippodamine (102) are an N-oxidelfree base pair, since monoperphthalic acid oxidation of 102 gives convergine (101) and 101 can be reduced with lithium aluminum hydride to yield 102. The structure and absolute configuration of 101 and 102 have been established by X-ray diffraction analysis

213


99

401

103

100

SCHEME50. Reaction conditions: i, Ac20 or CIC0,Et; ii, catalytic hydrogenation.

of convergine hydrochloride and by chemical correlation between the two alkaloids (329). The structure and absolute configuration of hippocasine (105) and hippocasine oxide (106) have been determined by X-ray analysis of hippocasine oxide hydrochloride and by chemical correlation between both alkaloids. Pyrolysis of 106 gives 105, whereas oxidation of 105 with hydrogen peroxide affords 106. This indicates that 105 is the free base of 106 (332). Myrrhine (103) shows in its IR spectrum the Bohlmann bands ( 4 4 3 , possible only for an all-trans fusion of the three rings. The structure was confirmed by chemical correlation between 99 and 103, using the Polonovski reaction. Thus, treatment of coccinelline (99) with acetic anhydride or ethyl chloroformate gave an unstable enamine (401), which was reduced by catalytic hydrogenation to yield a 9 : 1 mixture of myrrhine (103) and precoccinelline (100) (Scheme 50) (330,448). 2. Synthesis Extensive synthetic studies on ladybug defensive alkaloids have been carried out by Ayer and co-workers starting from pyridine derivatives and culminating in total synthesis of several alkaloids (336,449,450).Collidyllithium generated from collidine (402) was alkylated with P-bromopropionaldehydedimethylacetal to give the acetal (403). Subsequent treatment of 403 with phenyllithium and acetonitrile provided, after an aqueous workup, the ketone (404) which was isolated as its bis(ethy1ene) acetal (405). Reduction of 405 with sodium in isoamyl alcohol yielded the all-cis piperidine (406) as the major product. Hydrolysis of 406 with a diluted acid gave a crystalline hemiacetal (407) which yielded a tricyclic ketone (408) on treatment with p-toluenesulfonic acid. The ketone (408) possessing the myrrhine stereochemistry was unstable and immediately converted to the thioketal(409), which was desulfurized with Raney W-2 nickel to yield myrrhine (103) in approximately 40% yield from the tricyclic acetal(407). When hemiacetal 407 was treated with AcOH-pyrrolidine, a mixture of the ketones (408 and 410) was obtained. Thioketalization of the mixture followed by Raney nickel desulfurization provided a mixture of myrrhine (103) and hippodamine (102) separable by preparative thin-layer chromatography (449). The hippo-

274


damine framework would arised from iminium ions A, B, and C (Scheme 51) (336,449).Oxidation of hippodamine (102) yielded convergine (101). In a similar manner, coccinelline (99) and precoccinelline (100) have been synthesized from 2,6-lutidine (351) (336,450).Thus, treatment of the monolithium derivative (153) of 351 with p-bromopropionaldehyde dimethylacetal gave an acetal, which was converted to the keto acetal (412) by treatment with phenyllithium and acetonitrile. Reaction of 412 with ethylene glycol and p toluenesulfonic acid followed by reduction with sodium-isoamyl alcohol gave the cis-piperidine (413). Hydrolysis of 413 with 5% HCl gave the tricyclic acetal (414) which was transformed to a separable 1 : 1 mixture of the ketones (415 and 416) by treatment with pyrrolidine-acetic acid. Reaction of ketone 416 with methyllithium followed by dehydration with thionyl chloride afforded the rather unstable olefin (417) which on catalytic hydrogenation over platinum oxide in methanol gave precoccineIline (100). Oxidation of 100 with m-chloroperbenzoic acid yielded coccinelline (99) (Scheme 52) (336,450). Another elegant synthetic method to obtain ladybug defensive alkaloids, starting from perhydroboraphenalene (451), has been reported by Mueller and co-

U

407

Me

Me

408

R= 0

103

409

R=:gJ

Me

Me

0

R A

B

C

H

410 R= 0 ; 1 0 2 R= H2 411 R=CS] S

SCHEME51. Reaction conditions: i, PhLi-Et20; Br(CH2)2CH(OMe)2; ii, PhLi; MeCN; H 3 0 + ; iii, (CH20H)2,p-TsOH; iv, Na-isoamyl alcohol; v, aq 5% HCl; vi, p-TsOH; vii, (CH2SH)2; viii, Raney W-2 Ni; ix, AcOH-pyrrolidine.

275


&-

412

v o & +

HO

vi

__c

0

:o Me

& 413

H

H 414

415

Me

Me

H

H

H

416

Me

417 100 99 SCHEME52. Reaction conditions: i, BICH,CH2CH(OMe)Z, PhLi, MeCN, H30+ ; ii, ethylene glycol, p-TsOH; iii, Na-isoamyl alcohol; iv, aq 5% HCl; v, AcOH-pyrrolidine; vi, MeLi; SOCI,; vii, HZ-PtO2-MeOH; viii, m-CPBA.

workers (452-458). Hydroboration-oxidation and equilibration of 1,5,9cyclodecatriene (418) gave perhydroboraphenalene (419) which was oxidized with ruthenium and sodium periodate to afford the triketone (420). Reductive amination of 420 yielded the all-cis amine (421). A next step involves the inversion of stereochemistry at one of the carbon atoms adjacent to the nitrogen atom. Oxidation of 421 to the known enamine (422) (455,456,459)was accomplished with mercuric acetate. Hydrocyanation of 422 gave the aminonitrile (423) which was converted to the amide (424) by fuming sulfuric acid. Reaction of 424 with mercuric acetate gave the tetracyclic amide (426) via the quaternary base (425). Catalytic hydrogenolysis of 426 afforded the amide (427) which was converted by treatment with phosphorus oxychloride to the nitrile (428) admixed with the enamine (429). Reaction of the borane (419) with N-chloro-0-(2,4dinitropheny1)hydroxylamine and subsequent oxidation with hydrogen peroxide in aqueous sodium hydroxide gave the amino alcohol (430) (452), which was converted to the enamine (429) by oxidation. On the other hand, treatment of amino alcohol 430 with p-toluenesulfonic acid gave the amine (431) which on oxidation with mercuric acetate or by the modified Polonovski reaction on its Noxide gave the enamine (422). Enamine 429 has the appropriate stereochemistry for conversion to all the ladybug alkaloids except myrrhine (103) (Scheme 53).

276


418

419

420

421

H

H

-

422

H

VL

VLll

"R

H"

423 R= CN 4 2 4 R= CONH,

425

426

427 R= CONH2 428 R= CN XI1

..

HQ E H Q H

422

422

431

429

1

I XI

HQH2H 419

430

SCHEME53. Reaction conditions: i, BH3.MezS; ii, RuOz-NaI04; iii, NH3-Hz-Pd/C; iv, Hg(0Ac)z-EDTA; v, KCN, H + ; vi, HZSO4.SO3;vii, Hz-Pd/C; viii, POCl,-F'y; ix, ClN(H)ODNP; x, H202-NaOH; xi, CrO,; xii, p-TsOH; xiii, H202; xiv, T F A A - E t 3 N .

Hydroboration-oxidation of 429 yielded a separable 3 : 1 mixture of two alcohols (432 :433 = 1 :3), and subsequent oxidation of alcohol 433 gave the ketone (434). Reaction of 434 with the Bredereck reagent gave the enamino ketone (435) which was reduced to the unstable amino ketone (436) using lithium bronze. Catalytic hydrogenolysis of 436 over palladium on carbon gave the methyl ketone (437). Wolff-Kishner reduction of the ketone (437) gave a 2 : 1 mixture of hippodamine (102) and its axial methyl isomer (significant epimerization occurred during hydrazone formation). However, reduction of the derived thioketal with lithium in ethylenediamine gave hippodamine (102) as a sole product (453). Reaction of 102 with peracid gave the hydrated form of the N oxide of 102, convergine (101) (Scheme 54) (453). Conversion of ketone 437 to hippocasine (105) was accomplished by Bomford-Stevens reaction via the following reaction sequence. Successive treatments of 437 with hydrazine, p-toluenesulfonyl chloride, and then lithium tertbutylamine gave hippocasine (105). The reaction occurred exclusively in the desired direction. Treatment of hippocasine (105) with methanolic hydrogen peroxide gave hippocasine oxide (106) (Scheme 54). Propyleine (104) also is derivable from ketone 437. Reduction of 437 with LAH gave the equatorial alcohol (438) which was converted into the corresponding mesylate (439). Clean elimination was effected by heating 439 with potassium carbonate in dimethylsulfoxide to yield a 3 : l mixture of propyleine (104) and isopropyleine (440) (Scheme 54) (455). Coccinelline (99), precoccinelline (loo), and myrrhine (103) have been syn-

277


H

H

W o n 429

435

432

436 437

n

n

U

U

H

\/**OH 433

R= CHZNMe2 R= Me

434

102

101

H 105

106

438

439

R= n R= Ms

104

440

SCHEME 54. Reaction conditions: i, BH,; ii, H@-NaOH; iii, Cr03; iv, MeOCH(NMe2)2; v, LiNH+BuOH; vi, H*-Pd/C; vii, 1 ,Z-ethanedithiol, BF3-Et20; viii, Li-ethylenediamine; ix, rnCPBA; x, NH2NH2; xi, p-TsC1; xii, 'BuNHLi; xiii, LiAIH4; xiv, MsCI; xv, K2CO3; xvi, H202.

thesized from enamine 429. Epoxidation of the allylic amine (441), derived from 429, with trifluoroperacetic acid in trifluoroacetic acid gave the epoxide (442) which was reduced with lithium in ethylenediamine to afford the axial alcohol (443).Oxidation of 443 gave the ketone (416), previously prepared by Ayer and Furuichi (450)and Stevens and Lee (460).Wittig reaction of 416 and subsequent isomerization of the double bond with p-toluenesulfonic acid gave the allylic amine (417). Catalytic hydrogenation over palladium-carbon gave precoccinelline (loo), oxidation of which afforded coccinelline (99) (Scheme 55) (455). Myrrhine (103) differs significantly from all other ladybug alkaloids in that it possesses the thermodynamically favored all-cis stereochemistry to the nitrogen atom. Hydroboration-oxidation of 422 followed by Jones oxidation afforded the ketone (445)(455).Reaction of 445 with the Bredereck reagent gave an enamino ketone which was treated with thiobutanol to yield the thiomethylene compound 446. Reduction of 446 with lithium aluminum hydride followed by treatment with aqueous acid gave the aldehyde (447). Reduction of 447 with lithium gave a good yield of aldehyde 448 along with its epimer in the thermodynamic 85 : 15 ratio. Conversion of the mixture of the aldehydes to the alcohols by hydride reduction permitted purification of the desired equatorial hydroxylmethyl com-

27 8


N

-

-

Q

H

iii

H

H

Q /

),

429

CHZ

444

-

442

Me

Me

-

-

N

-

,,i,

H 0 416

Me

Me

100

99

''H

xviil

0

H"

*.H

XIS

CHO

CHSBu 446

445

- H Q

OH 443

417

422

v 1N

H

v

0

441

-

H

Q

iv

-

H

H

R 448 R= CHO

447

449 R= C H 2 0 H 103 R= M e

SCHEME55. Reaction conditions: i, MeSO3F; ii, LDA-THF; iii, EtSLi-DMF; iv, CF3C03HCF,C02H; v, Li-ethylenediamine; vi, Cr03; vii, Ph3+CHz; viii, p-TsOH, xylene, reflux; ix, HzPd/C; x, BH3.MezS; xi, H2O2-NaOH; xii, Cr03; xiii, MeOCH(NMe2)2;xiv, BUSH-p-TsOH; xv, LiA1H4; xvi, H 3 0 + ; xvii, Li-NH3; xviii, MsCI-Et3N; xix, LiBHEt,; xx, m-CPBA.

+ CH2=CHCH0

i

iii

7MeOZC

CH(OMe)2

Me02C

Me0 2C

CHOMe I

OMe

450

451

CH(OMel2 0

iv

_?)

CH(OMe)2

p H ( O M e ) 2

"'

CH(OMe)2

CH(0Me) 2

CH (OMe)

452 H

2.-

453

454 H

H viii

H MeOZC

0 455

0

416

Me 100

Me 99

SCHEME56. Reaction conditions: i, NaOMe; ii, CH(OMe),, H + ; iii, NaCl, wet DMF; iv, NaH, DME; v, AcONH,-NaB(CN)H3; vi, dimethyl 3-oxoglutarate, pH 1; vii, Ph3P=CH2; viii, H2-Pd/C; ix. m-CPBA.


279

pound (449) by crystallization. Subsequent mesylation of 449 followed by reduction with lithium triethylborohydride completed the synthesis of myrrhine (103) (Scheme 55) (455). A stereospecific synthesis of (*)-coccinelline (99) and (?)-precoccinelline (loo), using the classical Robinson-Schopf reaction, has been reported (460). Thus, reaction of dimethyl malonate with acrolein afforded an aldehyde which was protected by treatment with trimethoxymethane in the presence of an acid catalyst to yield the acetal (450). Decarbomethoxylation of 450 under neutral conditions followed by self-Claisen condensation afforded the 6-keto ester (452) via the acetal ester (451). Decarbomethoxylation of 452 gave the keto diacetal (453) which was reductively aminated to afford the amino diacetal(454). Hydrolysis of 454 with hydrochloric acid at pH 1 followed by addition of dimethyl 3oxoglutarate gave the tricyclic keto diester (455) as a single isomer. Decarbomethoxylation of 455 afforded the known ketone (416), and subsequent reaction of 416 with the Wittig reagent gave an olefin which was catalytically reduced to afford (?)-precoccinelline (100). (+-)-Precoccinelline (100) was converted to crystalline (*)-coccinelline (99) by oxidation with rn-chloroperbenzoic acid (Scheme 56) (460).

3. Biosynthesis The framework of coccinelline-type alkaloids may be generated by linear combination of seven acetate units, as illustrated in Scheme 57 (330,336). An intermediate such as 456 would explain the existence of the different ladybug alkaloids. Support for the polyketide origin has been provided by feeding experiments (14CH,COONa and CH, 14COONa) with Coccinellu septempunctutu (330).

7 CHQCOOH

p-0 - & CH3

456

SCHEME51

280


I. ADALINES 1. Structure

A defensive alkaloid of ladybugs in the genus Adaliu, adaline (107) (Table VII), C,,H,,NO (M+ mlz 209), isolated by alumina column chromatography of the extract, contains a carbonyl and an N-H group, as indicated by IR bands at 17 10 and 3330 cm- I . The IH-NMR spectrum shows the presence of one methyl group attached to a methylene group and one proton a to the nitrogen atom. These data suggest a bicyclic aminoketone (337). The complete structure including the absolute configuration was established by X-ray analysis of the base hydrochloride (337) and by optical rotatory dispersion measurement (338), as described by formula 107a. H

On the other hand, a defensive alkaloid in ladybugs of the genus Cryptolaemus and Mexican bean beetles of the genus Epilachna, euphococcinine (108) (Table VII), is isolated by preparative gas chromatography or successive gel filtrations of the extract (87,89). It is resistant to catalytic reduction and contains a carbonyl group, as shown by formation of a dimethylhydrazone. The empirical formula C,H,,NO (M+ mlz 153) indicates three degrees of unsaturation and thus suggests a bicyclic aminoketone. The general resemblance of the mass spectrum to that of the adaline (107) shows 108 to be a C, lower homolog of adaline (107), namely, l-methyl-9-azabicyclo[3,3,l]nonan-3-one(87). This alkaloid (108) is identical with the known plant alkaloid from Euphorbia atoto (88). 2. Synthesis The well-known Robinson-Schopf reaction has been applied to the synthesis of dl-adaline (107) from ketoglutaric acid (457), ammonium chloride, and ketoaldehyde (458) (Scheme 58) (3382. The second synthesis of dl-adaline (107) starts with nitrone 459 (462). Reaction of 459 with pentylmagnesium bromide gave a hydroxylamine (460) which was oxidized to yield a mixture of nitrones 461 and 462. Without separation of the nitrones (461 and 462), successive treatments with allylmagnesium bromide and then mercuric oxide gave a mixture of desired nitrones 466 and 467 and by-product 468. Nitrones 466 and 467 are capable of 1,3-dipolar cycloaddition and, on heating in chloroform, 466 and 467

28 1


were converted to the isoxazoline derivative 469. dl-Adaline can be obtained from 469 in a straightforward way via amino alcohol 470 (Scheme 58) (462). The third synthetic route reported by Husson and co-workers (140) is as follows: Amino nitrile 472 obtained from the ketal (471) was converted to the 2,6-dialkylpiperidine (473) by catalytic hydrogenation followed by alkylation with lithium diisopropylamide and pentyl bromide. Refluxing a solution of 473 in methanol containing hydrochloric acid led to the formation of 9-benzyladaline (475) in 90% yield. Debenzylation of 475 gave dl-adaline (107) in nearly quantitative yield (Scheme 59) (140).

+

NH4C1

+

COHO

-

0 A

457

107

458

459

&J

‘C5Hlln

C5Hl?

460

461

462

463

464

465

466

467

468

OH

A

-

0

iV

H . @C5HI;

469

fC5H11 470

v_ 107

SCHEME 58. Reaction conditions: i, “C5HI ,MgBr; ii, HgO; iii, allyl-MgBr; iv, Raney Ni; v, PCC.

282


Asymmetric synthesis of adaline has been reported by Hill and Renbaum (461). The 1,Caddition of pentylmagnesium bromide-copper iodide reagent to dienone 476 followed by treatment with phenylselenyl bromide gave the ketone (477). Oxidation of 477 with hydrogen peroxide-pyridine gave a dienone (478) via selenoxide. Double Michael-type addition of (R)-(+)-a-methylbenzylamine gave a separable diastereoisomeric mixture of the adduct (479). After separation, each of the diastereomers can be hydrogenolyzed to (+)- or (-)-adaline. The synthesized (-)-adaline (107) was found to be identical to the natural alkaloid (Scheme 59) (461). Euphococcinine (108) has been prepared by the groups of Husson and Hill according to the method described above.

rPh

r Ph

472

471

474

473

107

475

is

( + ) - a d d i n e (107) ( - ) -adaline

(107)

479

SCHEME 59. Reaction conditions: i, H2-Pd/C; ii, LDA-THF; iii, “C5H, ,Br; iv, 10%HCI; v , H2Pd/C-HCI-EtOH; vi, C,H, ,MgBr-CuI; vii, PhSeBr; viii, H202-Py; ix, (R)-(+)-a-methylbenzylamine.

3. Biosynthesis Biosynthesis of adaline (107) may be carried out via intermediate 456 from polyketide origin. A possible biogenetic interrelationship between adaline (107) and the coccinelline-type alkaloids (Scheme 57), suggested by Tursch et al.

283


(330,337) and Ayer and Browne (336), is supported by the presence of the monocyclic alkaloid 4, a key intermediate of the biosynthetic scheme, in the genus Cryptoluemus (Table I) (87).

J. PYRAZINES 1. Structure

Isolation and identification of pyrazine alkaloids (Table 111)have been achieved in most cases by a combination of gas chromatography and mass spectrometry (35,36,38,69,97,142). Methyl-, 2,3,6-trimethyl-, and tetramethylpyrazines (23a, 21a, and 22a) from the melon fly are identified by utilizing a solid sampling technique in conjunction with gas chromatography-mass spectroscopy (147). Methylpyrazines show the molecular ion as a base peak. Fragmentation proceeds mainly by the loss of HCN or CH,CN from the molecular ion (141). Eth-

____)

.. CH +

rnlz 135

20b R 1=R 2=Me,

R 3=H

480a R 1=R 2=Me, R 3=H

21b R 1=R 3=Me,

R 2 =H

b R1=R3=Me, R 2 =H

yldimethylpyrazines (20b and 21b) exhibit an intense peak for the (M - 1) ion owing to loss of the f3-hydrogen (32,141). The primary carbonium ion (480) would be stabilized by the pair of electrons on the nitrogen (141). 2,5-, 2,6-, and 2,3-Dimethylpyrazines having a side chain alkyl group of three or more carbons exhibit a characteristic and diagnostic peak (484, base peak) at mlz 122 resulting . from a McLafferty rearrangement (35,45,141,142,145). +

+

CH2

R1 ,>C=CH2 R

H

mlz 122 481 R 3=R 5=Me, 3 4 482 R =R =Me,

R4=H 5 R =H

3 5 4 484a R =R =Me, R =H 3 4 5 b R =R =Me, R =H

483 R 4=R 5=Me,

R 3=H

c R4=R5=Me, R 3=H

284


Since the mass spectra of the 3-alkyl-2,6-dimethylpyrazines (482) are almost identical to those of the 2,5 isomers (481), it is necessary to compare gas chromatographic retention times with authentic samples. The retention times of the 2,5 isomers (481) are significantly shorter than those of the 2,6 isomers (482) under isothermal conditions. Further confirmation of the 2,5 and 2,6 isomers is obtained by quaternization of one nitrogen with methyl iodide, followed by reduction of the ring with sodium borohydride to give N-methylpiperazines. 3Alkyl-2,6-dimethylpyrazines(482) are alkylated preferentially on the nitrogen not surrounded by both methyl groups, while the 2,5 isomers (481) are alkylated on the nitrogen not surrounded by the methyl and large alkyl groups. The monornethylpiperazine (485) from 2,6-dimethyl-3-n-pentylpyrazine(21g) exhibits a base peak at mlz 128, while the monomethylpiperazine (486) from 3-isopentyl-2,5-dimethylpyrazine (20h) has its base peak at mlz 72 (399,463). Me

H I

Me Me 72

Me M & Me i 1 : 485

B 486

The mass spectrum of 3-citronellyl-2,5-dimethylpyrazine(201) exhibits a parent peak at mlz 246 and a normal base peak (484a) at mlz 122, indicative of a dimethylpyrazinehaving an unsaturated C,, alkyl chain without branching at the a-methylene group. The pyrazine is identified by direct comparison with the compounds synthesized on the assumption that the alkyl chain is isoprenoid (142). The (a-and (E)-styrylpyrazine structures 20j and 20k were assigned on the base of the mass, NMR, and UV spectral data. The mass spectrum of Z isomer (20j) shows a base peak (the molecular ion) at mlz 210 with a peak at mlz 133 formed by the loss of a phenyl group from 20j. The 'H-NMR spectrum shows the presence of five aromatic and two olefinic protons in addition to one heteroaromatic proton and two methyl groups attached to the heteroaromatic nucleus. Ozonolysis of the Z isomer (20j) yields 3-formyl-2,5-dimethylpyrazine(487) and benzaldehyde, confirming the styryl moiety in 20j. The (E)-styryl derivative (20k) is readily isomerized to the Z isomer (20j) on exposure to sunlight (Scheme 60). Extraction of the pyrazines from I . humillis in the dark indicates that E isomer 20k is the naturally occurring product (144,145). 2 4 l-Butenyl)-5-methyl-3-n-propylpyrazine (23b) has a base peak at mlz 133 (M - 57) as well as a parent peak at m / z 190. This is reduced catalytically (Pt and H2) to give a mixture of two compounds (489 and 490) with molecular weights of 192 and 198, respectively. Compound 489 shows the normal


487

2Oj

20k

285

SCHEME60.

McLafferty rearrangements: mlz 164 (loss of ethylene), 150 (loss of propylene), and a double-Mclafferty loss to 122. Compound 490 exhibits two major fragments at mlz 100 and 98 in accordance with the fragmentation of piperazines. An assumed structure was confirmed by synthesis (464).

23b

489

490

3-Alkyl-2-methoxypyrazinesexhibit a base peak at mlz 124 in the mass spectrum. The peak corresponds to a molecular ion in 2-methoxy-3-methylpyrazine (24a) and to a fragment ion, resulting from a McLafferty rearrangement of an alkyl group, in 3-isopropyl-2-methoxypyrazine(24b) and 3-sec-butyl-2-methoxy pyrazine (24d) (97). 2. Synthesis Alkylpyrazines are prepared by two main procedures, (1) self-condensation of a-amino carbonyl compounds and (2) alkylation (or acylation) of pyrazines at nuclear or side chain carbons. Condensation of aminoacetone hydrochloride (491) in the presence of the corresponding aldehyde gave the 3-n-alkyl-2,5dimethylpyrazines 20e and 20g (Scheme 61) (36). 2,5-Dimethylpyrazine 20a was prepared from hydroxyiminoacetone (493) by reduction with tin and hydrochloric acid (Scheme 61) (145). 3-Ethyl-2,6-dimethylpyrazine(21b) was prepared along with 20a and 495 by condensation of aminoacetone hydrochloride (491) with 2-aminopentan-3-one hydrochloride (494) in the presence of sodium ethoxide (Scheme 61) (36). The alkylation of either 2,5- (20a) or 2,6-dimethylpyrazine (496) with the appropriate alkyl lithium at a nuclear carbon atom affords various dimethylpyrazines (20b-20d, 20g-204 201, 21b-21d, 21g-21i) (Scheme 62) (35,36, 142,145). The procedure involving the alkylation or acylation of dimethylpyrazines (496, 20a) gives 2-( l-butenyl)-5-methyl-3-n-propylpyrazine (23b) (Scheme 63) (464). The (2)-and (E)-2,5-dimethyl-3-styrylpyrazines(20j and 20k) are pre-

286


+

+ RCHO

-

, Z C H 3 *QC CH2R 2 0 e R= iso-Pr

492

491

2 o g R= n-Bu

493

OH

20a

or -n”r kN\Y + +

ii

N’

H2N 491

494

21b

SCHEME 61.

N’

20a

495

Reaction conditions: i, Sn-HC1; ii, NaOEt.

pared by replacement of the halogeno substituent of 3-chloro-2,s-dimethylpyrazine (505)by either an alkenyl or an alkynyl group (Scheme 64) (465).

3. Biosynthesis A hypothetical biosynthetic sequence has been proposed for the 3-alkyl-2,6dimethylpyrazines (482)from various species of Odontomachus ants, as shown in Scheme 6.5. The acyloin (507),prepared by condensation of the pyruvate with “active” acetate, or the derived dione (508)may condense with the amide (509) of alanine, ultimately giving the 3-alkyl-2,6-dimethylpyrazines(482)(141). A separate biogenesis is envisaged for the 3-alkyl-2,5-dimethylpyrazines(481) such as 3-isopentyl-2,S-dimethyl(20h)and 2,5-dimethyl-3-styrylpyrazines (20j,

20a

497

496

498

SCHEME 62. Reaction conditions: i , RLi.

500

23b

20a

501

503 23b

504

SCHEME63. Reaction conditions: i, LDA; ii, EtBr; iii, CH3CH2CH=CHLi; iv, n-PrLi; v, EtCOZEt; vi, NaBH4; vii, TsC1,A .

x:Lph-

AZKCI- 111

...hP&i y )

CEC-Ph

505 506 SCHEME64. Reaction conditions: i, PhCH=CHZ, Pd(PPh3),, CH,COOK; Pd(PPh&, CH3COOK; iii, H,/Pd-CaCO,; iv, LiA1H4.

20j

20k

ii, Ph-H,

COOMe

R

I

I

C

+

%J

H3C’

507

R

H N 2 \c=o

\,/OH

‘c=o

I ,c=o

H3 508

I

FN

I -

CH H ~ N / \ C H ~

H3C

509

1 decarboxylation,

1 +

482

etc

Oxidation

H N

x,%,,

‘c=o

I

CH H ~ N / \ C H ~ 509

SCHEME65

I

reduction

288


20k) from I . humilis. It seems likely that the precursors to the 3-isopentyl and 3styryl substituents in these pyrazines may be introduced into a symmetrical intermediate arising via dimerization of alanine (141,145).

K. ACYCLICAMINES 1 . Hannonine

A new aliphatic diamine, harmonine (121) (Table VIII), has been isolated as a diacetate (510) from ladybugs in the genera Hippodamia and Harmonia. Its structure has been identified as (Z)-1,17-diaminooctadec-9-eneon the basis of various spectroscopic analyses of diacetylhannonine (510) and the mass spectrum of the epoxide (511) of 510. The high-resolution mass, IR, and IH-NMR spectra suggest that 510 is a C,, long chain aliphatic bearing two acetylamino groups at C-1 and C-17 beside a double bond. The geometry and position of the double bond can be determined from the IR spectrum of 510 and the mass spectrum of the epoxide (511), respectively. This structure has been proved from the fact that oxidative cleavage of 510 by treatment with NaIO, in the presence of catalytic amounts of KMnO, followed by CH,N, esterification gave methyl 8acetylaminononanoate and methyl 9-acetylaminononanoate (378). 2. Amines from Ants Twelve volatile acyclic amines and amides (114-120, 125-129) (Table VIII) from ponerine ants in the genus Mesoponera have been identified by gas chromatography-mass spectrometry and mass spectral comparison with authentic synthetic samples (41).The major aliphatic amine, N-isoamylnonylamine (114), shows a molecular ion at m/z 213, a-cleavage fragments at miz 156 (M - C,H,) and 100 (M - C,H,,), and an ion at m/z 44 (CH2=NHCH3+) resulting from cleavage and rearrangement with hydrogen transfer, typical of alliphatic secondary amines. 3. Amides from Flies and Beetles

Two of amides from melon flies of the genus Dacus (Table VIII) have been identified as N-isoamylacetamide (122) and N-(2-methylbutyl)acetamide (123) by comparison of their mass spectra and chromatographic properties with those of authentic samples (103). The third amide, previously reported neither as a component of an insect secretion nor as a synthesized derivative, was assigned as N-isoamyl-2-methoxyacetamide (124) from the mass spectrum, showing a molecular ion at mlz 159 and fragment ions at miz 129 (M+ - CH,O) and 102 (M+ - C,H,), and its structure was confirmed by comparison with a synthetic au-


289

thentic sample. It has been suggested that the N-isoamyl and N-2-methylbutyl amine moieties originate from leucine and isoleucine, respectively (104).The 2methoxyacetamide component (124) may arise from the sequential hydroxylation and methylation of the acetamide (122) or via a route involving glycolic acid. 3-Phenylpropanamide (130), from the aposematic beetle (genus Metriorrhynchus) (Table VIII), has been purified by gas chromatography from the methanol extract. Its structure is presumed from mass spectral data and was confirmed by comparison with a synthetic sample (97). The co-occurrence of amide 130 and 1-methyl-2-quinolone (57) in this beetle suggests a common pathway of biosynthesis and that they may be derived from the amino acid phenylalanine. 4. Other Amines

Dimethylamine (109), putrescine (lll),and spermidine (110), isolated from various insects (Table VIII), were obtained as p,p’ -nitrophenylazobenzoyl, p phenylazobenzenesulfonyl, and 1-dimethylaminonaphthalene-5-sulfonyl(dansyl) derivatives and picrates or were detected by high-performance liquid chromatography (HPLC) using the ion-exchange resin (106,343). N,N-Dimethyl-Pphenylethylamine (131) from spiders of the genus Sclerobunus (Table VIII) has been identified by mass spectral comparison with a synthetic sample (117).

L. PEDERIN 1. Structure

Pederin (147) contains two hydroxyl, four methoxyl, and four methyl groups and a secondary amide. It is hydrolyzed on gentle heating in aqueous solution to yield pseudopederin (148) (466),in which a hydroxyl group replaces a methoxyl group in pederin (147). Reduction of pederone (149) with lithium aluminum hydride shows it to have a ketone instead of a hydroxyl group as in pederin (147) (93). The structures of pederin (147), pseudopederin (148), and pederone (149) were initially proposed by Cardani and co-workers (93,466), based primarily on the structures of degradation products, pederolactone and meropederoic acid, which were obtained from 148 on treatment with barium methoxide in an oxygen atmosphere. On the basis of detailed NMR spectral analysis, however, Matsumoto and co-workers (467) suggested that the structure for pederin was better represented as 147, which has a hydroxyl group at C-13 instead of C-12 in tetrahydropyran ring. This was confirmed by two independent X-ray crystal analyses of a di-p-bromobenzoate of pederin (147) (468,469), which also established the absolute configuration. The structures of pseudopederin and pederone are therefore represented as 148 and 149, respectively (470).

290


w% OCH3

R1

Y OCH3 O C H ,

l3

OH

1 2 3 1 4 7 R = OCH3, R = O H , R = H 1 2 3 148 R = R = O H , R = H 1 2 3 1 4 9 R = OCH3, R = R = 0

..14

R3 'R2

2. Synthesis of (*)-Pederamide Pederamide (512), an acid hydrolysis product of pederin (147) (467),has been synthesized by two research groups. In one approach (471) to 512, cis-dimethylbutyrolactone (513) was converted to the dihydroxyalkynyl ester (516) by

no-no-z H

i

ii

iii

P

OH

G ; 514% '

513

515

H

. .

*' vi

@C02Me

-

-

OH

vii

'CO-Me

L

516

517

OMe F

C

0

2

518

OMe M

e

w

C

0

2

OMe

-

M

R~ R~

OH

e

519 R= OH

C

O

N

H

2

OAc

ix

R

520 R= SePh

m

523 I

1

2

521 R = O H , R = H 2 522 R1= H , R =OH

OMe

512

SCHEME66. Reaction conditions: i, LDA, CH==CCH2Br; ii, LiAIH,; iii, DHP-TsOH; n-BuLiCIC02Me; TsOH-MeOH; iv, Et,N; v, m-CPBA; vi, PhCOCI-Py; 1 N HCI-THF; PhCOCl-Py; MeON-AcC1; MeONa-MeOH; vii, TsCl; phenylselenolate anion; viii, H202-THF, Et3N; ix, MeOH-H20-Et,N, AqO-Py, 6-chloro- I-@-chlorobenzenesulfonyloxy)benzotriazole-Et,N-NH~; x, NH,MeOH.

29 1


alkylation with propargyl bromide, lithium aluminum hydride reduction, and carbomethoxylation (Scheme 66). Internal Michael addition of the unsaturated ester gave a Z-E mixture of the vinylidene furan (517) which was transformed to the bicyclic ketal (518) by oxidation with rn-chloroperbenzoic acid. The tetrahydrofuran ring of 518 was opened with hydrochloric acid, using the benzoyl protecting group, to yield the tetrahydropyran (519). The primary alcohol of 519 was selectively selenated to give 520. Oxidative elimination of the selenide to form the exocyclic double bond afforded methyl pederate (521) together with its epimer (522) at C-2. The methyl pederate (521) yielded racemic pederamide (512) on basic hydrolysis of the ester, acetylation, amidation with a benzotriazole derivative, and deacetylation. A second approach (472) to 512 started with trans-2-butene epoxide (524) (Scheme 67). Opening of the epoxide ring of 524 with lithium acetylide gave an acetylenic alcohol, which was converted to the acetylenic acid (525) by carboxylation with gaseous carbon dioxide. Partial hydrogenation of 525 followed by lactonization afforded the ol,P-unsaturated lactone (526) which was transformed to the nitrolactone (527) by a Michael addition reaction of nitromethane. The Nef reaction of 527 gave the tetrahydrofuranyl acetal (528) which was converted to

o L+ y

P

...-

*-

524

528 X

526

CH2N02 527

To

C02Et

vi

C02Me

vii

531 R= C(Me)20Me 529

532 R= H

x

>6

O

o

C02H

525

QoMeL

iv

T

iii

H

X

q

C

0

CHO 533

2

E

?

T C 0 2 ' > C H 2 9 3 534 N02

~

0

2

E

t

A 512

535

SCHEME 67. Reaction conditions: i, C H s L i ; n-BuLi-COz; ii, 5% Pd-BaS04, A; iii, CH,NO,Triton B; iv, NaOMe; H2S04-MeOH; v, HCI gas-HSCH2CHzSH; vi, LDAMeOC(Me)20CH2C02Et (530), HCI; vii, acetone-P205, HgO, HgCI2; viii, NaBH4; o-NOzPhSeCN-n-Bu3P; ix, H202; x, NH40H; HC1-MeOH.

292


the dithiolane lactone (529) by treatment with ethanedithiol. Lactone 529 afforded adduct 531 on treatment with the lithium enolate of 530. The alcohol protecting group was removed to give hemiketal alcohol 532 as a mixture of epimers. The dithiolane ring of the acetonide of 532 was cleaved by oxidative hydrolysis, using mercuric oxide and mercuric chloride, to yield the aldehyde (533). After sodium borohydride reduction 533 was converted to the aryl selenide (534) which afforded the exocyclic olefin (535)on oxidation with hydrogen peroxide. Olefin 535 was transformed to the corresponding amide which was treated with hydrochloric acid in methanol to yield pederamide (512). 3. Total Synthesis of Pederin

Many approaches to the synthesis of pederin have been tried (473,474). Total synthesis of (+)-pederin (147) was finally accomplished by two research groups (475-477) on the basis of a method joining pedamide, the right-hand half of pederin, and a pederic acid derivative, the left-hand half. In the first total synthesis by Matsumoto and co-workers (475,476), (+)benzoylpedamide (536) (478,479) was prepared through a new, remote-controlled asymmetric induction (Scheme 68). An optically active acetal ketone

1 2 537 R = R = O 1 2 538 R =OH, R = H

Ph 539 R1= R2 = 0 1 2 540 R = O H , R = H 1 2 541 R = OMe, R = H

542 R = CH2Ph 543 R = H

byom -

vii HO

M

_ j

0 e

~

OMe

~ OMe

O M 2 ~ x,xi

R OMe

1

~

viii, i x

OH 544

R 545 546

1

6COPh

R 2

R = R = O 1 2 R = H , R = OH

1 2 547 R = C 0 2 M e , R =H 1 2 548 R = H , R = C 0 2 M e (+)-536 R 1= C O N H 2 , R 2 = H

SCHEME 68. Reaction conditions: i, LiAlH4, ii, PhCH,Cl-'AmONa; m-CPBA; NaOMe-MeOH; Collins oxidation; iii, Li( +Bu0)3A1H; iv, MeI-NaH-PhH; v, 3 N HC1-acetone; CHFCHCH2BrMg; vi, Na-liq NH3; vii, m-CPBA, p-TsOH-HzO-PhH; viii, Jones oxidation, CH2N2;ix, NaBH,; x, PhCOC1, i-PrzNLi-THF, HOAc; xi, Et3N-HzO-MeOH, SOCl2; NH3.

~

O

293


(537) from (-)-(2R, 3R)-2,3-butanediol was reduced with lithium aluminum hydride to give the (+)-alcohol (538) having the desired (15R) configuration. Alcohol 538 was converted to a dialkoxy ketone (539) by protection of the C-15 hydroxyl group, oxidation of the double bond, opening of the epoxide group employing sodium methoxide, and Collins' oxidation. Reduction of 539 with lithium tri-tert-butoxy aluminum hydride followed by methylation of the new hydroxyl group afforded a (-)-acetal (541) having the desired (17s) configuration. Acetal541 was converted to an olefinic diol (543) by removal of the acetal group followed by Grignard reaction with allylmagnesium bromide and removal of the benzyl protecting group. Oxidation of the double bond with rn-chloroperbenzoic acid and subsequent acid treatment gave a tetrahydropyran (544) which was transformed to the (13R)-alcohol (546) by Jones oxidation followed by esterification and reduction with sodium borohydride. After protection of the hydroxyl group, stereocontrol at C- 1 1 bearing the methoxycarbonyl group was effected by enolization and subsequent kinetically controlled protonation to give the desired ester (547) and its epimer (548) in 4 : 1 ratio. The (+)-ester'(547) was converted to (+)-benzoylpedamide (536) by hydrolysis of the methoxycarbonyl group, acid chloride formation, and amidation. Pedamide 536 was converted by treatment with trimethyloxonium tetrafluoroborate to methyl pedimidate (549) (475), which was connected by the reaction sequence shown in Scheme 69 to (+)-acetylpederic acid (550), prepared via a route similar to that to the racemic pederamide (536) from (-)-(2R, 3R)-2,3butanediol. The ratio of the resulting (+)-pederin (147) to (+)-10-epipederin (551) was 1 : 3. This ratio can be inverted to 60 : 14 by a stereocontrolled synthesis (476) including connection of methyl pedimidate (549) and (+)-selenoacid (552)

536

i

Me0 H N % T O M e OMe OCOPh 549

WO~H - wNk yOMe oMe0

OMe

H

ii, iii

OAc

R1R2

iv

OMe

OH

6H

550 (+)-147 551

R 1= OMe, R 2= H 1 2 R = H , R = OMe

SCHEME69. Reaction conditions: i, Me30BF4; ii, SOCL-Py; iii, 549-Et3N; iv, NaBH,; 1 N

LiOH .

294


prepared through a similar route to (+)-acetylpederic acid (550), selective conversion of the resulting (+)-dihydro-10-epipederin derivative (554) to a (+)-dihydropederin derivative (553) by an acid-catalyzed double alkoxy exchange reaction, and generation of the exo double bond at a later step. ?Me T

C

0

2

OAc SePh

0

b'voMe

R1 R2

H OCOPh

OMe

SePh

6COPh 2 5 5 3 R = OMe, R = H

1

552

5 5 4 R'=

H , R'=

OMe

In the second synthesis to (+)-pederin (147) by Oishi et ul. (477), (+)benzoylpedamide (536) (480) was prepared by using recently developed general methods for the synthesis of both 1,3-syn-and 1,3-unti-polyols (481) (Scheme 70). Treatment of aldehyde 555, prepared from (S)-(-)-malic acid, with iPrC0,Et afforded P-hydroxy ester 556, which was converted into &-lactone557 by deacetonization, silylation, and lactonization. After protection of the hydroxyl group of 557 as the ethoxyethyl ether, the lithium enolate of tert-butyl acetate was treated to give hemiacetal 558 which was transformed to a mixture of the desired 4P-alcohol (559) and 4a-isomer (560) by acetalization and removal of the ethoxyethyl protecting group. Treatment of 559 with ethanedithiol in the presence of Lewis acid caused acetal-thioacetal interchange at C-6 and subsequent lactonization between the 4P-hydroxyl group and the tert-butyl ester to give &-lactone 561. The liberated hydroxyl groups in 561 were methylated by treatment with CH,N, in the presence of silica gel to give dimethoxy lactone

562. 6a-Alcohol 565 was stereoselectively prepared by the method used in the 1,3-anti-polyol synthesis involving DIBAH reduction of 562, treatment with BrCH,OMe and i-Pr,NEt, dethioacetalization with NBS, and LiAlH, reduction of 564. The benzoate (566) of 565 was converted to a mixture of 8P- and 8anitriles (568) by acid treatment followed by acetylation and treatment with Me,SiCN and Lewis acid. Treatment of 568 with TiC1, produced predominately the 8P-amide (536). The synthesis of (+)-benzoylselenopederic acid (569) (477)(Scheme 71), the left-hand half of pederin (147), began with (+)-P-keto imide 570, which was subjected to the recently developed syn-directing Zn(BH,), reduction (482) to give syn-a-methyl-P-hydroxy acid derivative 571. Imide 571, after protection of the hydroxyl group as the THP ether, was reduced with DIBAH, and the resulting aldehyde was treated with lithium enolate of tert-butyl acetate to give the P-

295


Aop Ph

-!+

f&CHO 555

556

6H

R 561 562

R= H R= Me

viii

O-(i-tBu

__L

Ph

iii

557

6R

563 R= SCH2CH2S

565

R= H

564 R= 0

566

R= COPh

-

- .MO* "

is

(+)-536

OCOPh 567

R= OAc

568

R= CN

SCHEME70. i, LDA-Me2CHCOOEt; ii, p-TsOH-MeOH; rBuPh2SiC1-imidazole; CSA-PhH; iii, CH2=CHOEt-PPTS; LDA-'BuOAc-THF; iv, CSA-CH(OMe)3; v, HSCH2CH2SHBF,.Et20, CH2N2-silica gel; vi, DIBAH, MeOCH2Br-'Pr2NEt, NBS-AgN03-Na2C03; vii, LiA1H4,PhCOCI; viii, 6 N HCI, Ac20, Me3SiCN-BF3; ix, TiC1,-aq AcOH.

hydroxy ester (572). After removal of the protecting group, 572 was converted by treatment with p-TsOH to the a,P-unsaturated lactone (573) which on Michael addition of nitromethane gave nitromethyl lactone (574). The nitro group of 574 was converted to aldehyde with TiCl, and Et,N, producing bicyclic lactone (575) which was isomerized to more stable lactone (576) with HC1 treatment. The treatment of 576 with ethanedithiol afforded thioacetal lactone (577), which was converted to the a-keto ester (578) by introduction of a glycolic acid moiety, conversion of the resulting hemiacetal to the methyl ether, deprotection of methoxy isopropyl ether, and Moffatt oxidation. Zn(BH,), reduction of 578 gave the desired 7;IP-alcohol (579). After benzoylation 579 was transformed to the selenoester (582) by dethioacetalization followed by

296


TH PO

ii

1

570

571

M

e ?Me p

ix

Me

OR

s\

-

COOMe Me

580

Me 572

'

H

y me^ OMe COOMe Me

/s

R= C OPh

OMe

OOH

d

x , xi Me

u 579 R= H

Me

OR1xii

R2 1 2 581 R = C O P h ; R = OH 1 2 582 R = COPh; R = S e P h

O CO Ph SePh

(+)-569

SCHEME71. Reaction conditions: i, Zn(BH4)2; ii, DHP-p-TsOH; DIBAH-PhMe; LDA-rBuOAc; iii, p-TsOH-MeOH, p-TsOH-PhH; iv, MeNO,-Triton B; v, TiClrEt3N; vi, conc HCICH2C12; vii, HSCH2CH2SH-BF3.Et20; viii, LDA-MeOC(Me,)OCH,COOMe, CSA-CH(OMe)3, DMSO-DCC-F'y-CF~COOH-Et20; ix, Zn(BH4)2, PhCOC1-DMAP-Py; x, HgO-HgCb-aq MeCN; Zn(BH4)2; xi, PhSeCN-Bu3P; xii, PrSLi-HMPA.

Zn(BH,), reduction and phenylselenation. The methyl ester of 582 was selectively hydrolyzed by PrSLi treatment to yield (+)-selenoacid (569) (Scheme 7 1). The total synthesis of (+)-pederin (147) from (+)-536 and (+)-569 was accomplished in a manner similar to Matsumoto's. 4. Biosynthesis

Pederin (147) has been considered to be derived via polyketide biosynthesis, based on the result of feeding experiments with [ l-14C]acetateand [2-14C]acetate in Puederus fuscipes (483). M . ISOXAZOLES

Compound 150, one of two isoxazolinones first found in the defensive secretion of chrysomelid beetles, Chrysomelu tremulue, shows a UV spectrum (A,,


297

260 nm, E = 6500) characteristic of an N-substituted 3-isoxazolin-5-one system and diagnostic peaks for the 3-isoxazolin-5-oneheterocycle, namely, two doublets (J = 3.5 Hz) at 6 8.42 and 5.31 ppm, in the ‘H NMR spectrum. The presence of a glucose moiety in 150 was indicated by acid hydrolysis followed by GC analysis and fragment peaks at mlz 331, 211, 169 and 109 in the CI-mass spectrum of the tetraacetate of 150. Compound 150 was shown from this evidence to be 2-(~-~-glucopyranosyl)-3-isoxazolin-5-one, previously isolated from Lathyrus odoratus seedlings. The general features of the various spectra of the other compound (151) are very similar to those of 150 except that two characteristic CH, signals coupled to each t, J = 6 Hz) and 3.01 ppm (CO-CH,, t, other appear at 134.70 ppm (CH,-NO,, J = 6 Hz) in the ‘H NMR of 151 and the 13C-NMR signals appear at 174.50 (C=O), 73 (CH,NO,) and 33.70 ppm (CH,CO), showing the existence of a 3nitropropanoyl moiety. Acylation shift in the 13C-NMR spectrum demonstrates that the primary hydroxyl group at C-6 of the glucose is acylated by the 3nitropropanoyl group. Thus, 151 is identified as 2-[6’-(3”-nitropropanoyl)-P-~glucopyranosyl]-3-isoxazolin-5-one (98).

HO

151 R= F - C H 2 C H 2 N 0 2 0

N . QUINAZOLINONES On the basis of studies by two research groups on various spectra and electron pyrolysis, structures 60 and 61, respectively, have been proposed for glomerin and homoglomerin which have been isolated from the defensive secretion of a small millipede, Glomeris marginata (Table V) (112,181,484,485). A search of the literature showed that both glomerin (60) and homoglomerin (61) had been synthesized in connection with a study of Indian medicinal plant alkaloids such as arborine, originally isolated from Glycosmis arborea (486).The two alkaloids (60 and 61) were synthesized by reacting N-methylanthranilic amide (583) with either acetic or propionic anhydride (486) (Scheme 72). Two similar syntheses have been reported by Ziegler and co-workers (487)and Kametani et al. (488,489). Reaction of N-methylisatic anhydride (584) with thioacetamide afforded glomerin (60) in 58% yield (487). The other synthetic route is as follows: The sulfinamide (585), prepared from N-methylanthranilic anhydride and thionyl chloride, was treated with acetamide and propionamide to afford glomerin (60) and homoglomerin (61), respectively (Scheme 72) (488,489). Feeding or injecting 14C-labeledanthranilic acid (586) to Glomeris marginata

298

ATSUSHI NUMATA AND TOSHIRO IBUKA 0

H

Me

60 R= Me

583

6 1 R= E t

QyJo-Q-f-JMe

Qo02 KJR

0

Me

Me

584

60

0

0

Me

Me

585

60

R= Me

61

R= E t

Me

586

60

R= Me

61

R= E t

587

SCHEME72. Reaction conditions: i, (CH3C0)20; ii, (CH3CH2C0)20; iii, CH3CSNH2; iv, CH3CONH2; v, CH3CH2CONH2; vi, Glomeris marginata; vii, 2 N NaOH, 100°C.

resulted in the biosynthesis of the radioactive glomerin (60) and homoglomerin (61). Radioactive homoglomerin (61) gave N-methylanthranilic acid (587) by an alkaline hydrolysis. From these facts, anthranilic acid has been suggested as a common biosynthetic precursor (Scheme 72) (490).

0. PTERIDINES AND PURINES 1. Guanine and Hypoxanthine Since chemistry of pterines and purines has been already reviewed (42,48,491), only recent studies will be described here. Guanine (93) was prepared by reaction of 4-hydroxy-2,5,6-triaminopyrimidinesulfate (588; see Scheme 73) with HCONH, with removal of H,O from the reaction system in an excellent yield (492). Also, irradiation of oxygenated aqueous solutions of 6-mercaptopurine with near-UV light gave hypoxanthine (92) as a minor product (Y&%

3 p?i$hkb>~? X&~h m h t p~&a,N\A ws pmva tb

correspond to the racemic form of natural (-)-norargemonine. Reduction of 41, on the other hand, supplied another benzyltetrahydroisoquinoline, (&)-pseudolaudanine, and also the positional isomer of norargemonine, isonorargemonine (ll),which was found in an optically active form in nature 3 years later (35).

b. Bischler-Napieralski Procedure. A different synthetic sequence was proposed for the preparation of (&)-norargemonine (13) (102)where the required appropriately substituted benzylisoquinoline was synthesized by a multistep process starting from benzylvanillin (43) (Scheme 3). The amidic intermediate 44 was cyclized by the well-known Bischler-Napieralski procedure. Subsequent reduction afforded the benzyttetrahydroisoquinoline 45. This material was subjected to catalytic dehydrogenation to afford the isoquinoline 46, which had undergone undesired debenzylation in the process. Rebenzylation was carried out prior to the application of the classical procedure (quaternization, partial reduction, acid-catalyzed cyclization) to 47 to obtain the expected (%)-norargemonine. The above sequence has also been utilized in constructing the requisite isoquinoline for a synthesis of (+)-bisnorargemonine (6) (103).

335

7. PAVlNE AND ISOPAVINE ALKALOIDS

BzO

BzO

44

BzO

""C NaBH4

no

BzO

NH

/NH.

CI

BzO

OMe

45

1. M e 1

2. N a B H 4 3. H +

no

13

SCHEME3

c. Pictet-Gams Modifications of Bischler-Napieralski Procedure.

In

order to preclude debenzylation during dehydrogenation, Pictet-Gams modification of the Bischler-Napieralski reaction was applied to the construction of the required isoquinoline for the syntheses of ( t)-bisnorargemonine (6) and its isomers (1,99). (2)-Caryachine (7) and (2)-isocaryachine (139) were synthesized by the same Pictet-Gams approach (104,105) in order to differentiate between the two possible structures proposed for (-)-caryachine. Racemic eschscholtzidine (8) was also synthesized following the above sequence to confirm the structure previously deduced by chemical and spectral analyses of the natural levorotatory compound (106). Scheme 4 exemplifies the Pictet-Gams approach as applied to the synthesis of (+-)-eschscholtzidine (8) (106).

d. Pavinan Synthesis via Reissert Compounds. Total synthesis was used for the structure confirmation of the 2,3,7,8-tetrasubstitutedpavine bases, (-)-

336

BELKIS GOZLER

POCI3

3.

I

H+

8

SCHEME 4

platycerine (14) (107)and (-)-munitagine (12) (108), where a different approach was used to obtain the required isoquinoline (Scheme 5). The Schiff base 50, prepared by condensation of 2,3-disubstituted benzaldehyde 48 and aminoacetaldehyde dialkyl acetal 49, was converted to 7,8-disubstituted isoquinoline 51 by a series of reactions depicted in Scheme 5 . Treatment of 51 with potassium cyanide and benzoyl chloride afforded the Reissert compound 52, which was then converted to the desired benzylisoquinoline 53, using the appropriately substituted benzyl halides. Successive quaternization, partial reduction, and acid-catalyzed cyclization furnished (+)-platycerine or (2)-munitagine. The trisubstituted pavine base, (+)-2-hydroxy-3,8-dimethoxypavinan(10) was also synthesized by a parallel route (26).

e. Double Cyclization of Benzylaminoacetaldehyde Dialkyl Acetals. A conventional method, where isopavines are obtained by an acid-catalyzed double cyclization of benzylaminoacetaldehyde dialkyl acetals 54 under nonreductive conditions, is known to produce pavines as well (Scheme 6). The initial cyclization affords the 4-hydroxybenzyltetrahydroisoquinoline intermediate 55 (109). Two processes compete at this stage, one involving an intramolecular nucleophilic substitution at C-4 by the C-1 benzyl group to afford isopavine 56, and the second involving a dehydration to the 1,2-dihydro compound 57, furnishing pavine 58 on intramolecular cyclization. This method has been used by Dyke and co-workers (110) to synthesize the isopavine alkaloid reframoline (29) in the racemic form, while the corresponding

337

7. PAVINE AND ISOPAVINE ALKALOIDS

48

49

50

51

3 . H+

12: R = H

53

14: R=Me

SCHEME5

RO OR

OR

'

54

RO ROW

\

Y

R

Row

Ra 50

OR

'

NR

,

OR

58

SCHEME 6

338

BELKIS GOZLER OE t

1

CN

Q 0J0

J

SCHEMEI

pavine base, (+-)-caryachine (7) was obtained as a by-product (Scheme 7). This route was also adapted to a preparation of the isomeric isopavine base (?)-146, so far unknown as a natural product, while the by-product was the unnatural pavine alkaloid, (&)-isocaryachine (139) ( I 10). It has been emphasized that either pavines or isopavines can be obtained selectively depending on the choice of acid conditions used in the aforementioned cyclization process (111). It is also apparent that acid-catalyzed cyclization at room temperature results almost solely in the production of isopavines, whereas application of heat at this stage, which promotes dehydration of the 4hydroxy intermediate, affords a mixture of pavine and isopavine alkaloids in varying ratios (110,112).

2. Synthesis of Optically Active Pavines

a. Resolution of Racemates. Enantiomeric forms of pavines were initially obtained by resolution of the racemic bases constructed by total synthesis (20,113-116). Attempts to synthesize optically active pavines using enantiomers of the I ,2-dihydrobenzylisoquinolineintermediates were unsuccessful ( I 15). b. Enantioselective Total Synthesis. In 1977, Dyke and co-workers (I 12) successfully resolved the properly substituted 1,2-diarylethylamines 59 using (+)-dibenzoyltartaric acid to obtain the (+) enantiomer in crystalline form. This

339

I . PAVINE AND ISOPAVINE ALKALOIDS

could in turn be converted to its acetal60 without racemization. Acid treatment of the optically active acetal yielded (-)-caryachine (7) as well as the isopavine base, (-)-reframoline (29), in almost equal but relatively low overall yields (Scheme 8). This instance represents the first total synthesis of an optically active pavine alkaloid. A more recent synthesis of optically active pavine bases has been reported by Brossi’s group (Scheme 9) (I 17). The readily available (S)-( -)-N-norreticuline (61) (118) was converted to the dextrorotatory carbamate 62 which was then treated with DDQ in methanol to furnish quinone methide 63. This reactive intermediate underwent 1,6-addition of methanol in situ to afford the stable ( +)-4-methoxy-N-carbethoxybenzyltetrahydroisoquinoline64. Thermolysis of 64 resulted in loss of methanol to furnish (+)-1,2-dihydro analog 65. Cyclization was achieved using chlorosulfonic acid in acetonitrile. Reduction of the tetracyclic product 66 by lithium aluminum hydride gave (-)-bisnordrgemonine (6), which was readily converted to (-)-argemonine (5) through methylation. The racemates of these pavine bases have also been prepared from racemic N-norreticuline, following an analogous course of synthesis ( I 1 7 ) .

1. C i C O O E t

Me0 Bzo&NHMe

2. L i A l H q

bO)

NH,

I

59

I

0

OEt

(+I-

Dibenzoyltartarlc acid

(+)-59

B f orno a c

elai

-

-

bO) HCI

0

(+)-6O

SCHEME8

(-1-7

(14%)

and

[-)-29

(19%)

340

BELKIS GOZLER

Me0 no%*H

ClCOOEt

*

M

:

:

".*

s

OH /

/

OMe

(-1 -61

OMe

1

(+) - 6 2

I

.

no \ \

M eOH

OH OMe

(+) - 6 4

63

'

OMe

therrnolysis

CIS0 H

3 HO OH

(-1 - 6 6

OMe

(+) - 6 5 LiAlH4

(-1 - 5

(-1 - 6 SCHEME9

3. Novel Routes

In a novel synthetic route involving the transformation of a tetrahydroprotoberberine nucleus to a pavine skeleton (Scheme 10) (119), canadine methiodide (67), was subjected to Hofmann degradation to yield styrene 68. This compound was successively oxidized with osmium tetraoxide-sodium periodate and the

34 1


Hofmann deg.

OMe

OMe

68

67

I

OMe

OMe

69

72

71

73 SCHEME10

product reduced with sodium borohydride to furnish benzyl alcohol derivative 69. Treatment of 69 with methanesulfonyl chloride gave the methomesylate 70, which rearranged in the presence of phenyllithium to afford the unnatural pavine base 71. Cleavage of the methylenedioxy group by boron trichloride followed by methylation furnished (&)-0,O-dimethylmunitagine (72), so far unknown as a natural product. Another product of the base-catalyzed rearrangement was reported to be the tetracyclic base 73.

342

BELKIS GOZLER

Racemic argemonine (5) has been synthesized from the readily available tetrahydr0-6,12-methanodibenz[c,jlazocine(74) (120-122) through a sequence involving a Stevens rearrangement and in an overall yield of 53% from 74 (Scheme 11) (123). Hofmann degradation of 74 furnished the em-methylene compound 75 (120,122). An oxidative ring expansion of 75 afforded ketone 76, which was then reduced to secondary alcohol 77. A transannular reaction, effected by acetic acid-acetic anhydride, resulted in the formation of the tetra-

74

75

TIC104

OMe

Me0

L I A I H ~

meO

OMe

77

I

OMe

Me 76

Meo

ACOH -AcpO

Me

m a

Me0

OMe

Me

QX

80

70

1

I . qualerniza Iron

BuLi

Me0

M

e

o

~

o

M4m 2. ButOK

'MO M e eMM e 0 + , e 0

3

Me0

81 N M e ,

5

I

1. H Q ( O A C ) ~Z,. T E D A

NaBH4

OMe

Me0

5 79

SCHEMEI 1

343

I . PAVINE AND ISOPAVINE ALKALOIDS

cyclic quaternary salt 78 ( X = OAc). Treatment of 78 (X = Cl) with butyllithium gave two products, the spiroindoline 79 and (&)-argemonine(5) in overall yields of 18 and lo%, respectively. In an alternate route designed to improve the yield of argemonine (5), 78 (X = CIO,) was subjected to Hofmann elimination. The resulting compound 80 was quaternized and allowed to react with potassium tert-butoxide to generate dimethylamino compound 81. An internal dimethylaminomercuration-demercuration procedure followed by N-demethylation then provided ( 2)-argemonine in 53% yield (123). 4. Synthesis of Analogous Structures The synthesis of a new class of compounds possessing the general structure 4,4,8,8-tetraalkyl-2,3 : 6,7-dibenzo-9-azabicyclo[3.3. llnonane- 1,5-diol(84) deserves mention since the basic skeleton is analogous to that of the pavines (Scheme 12) (124-129). Oxidation of a series of indeno[2,1-a]indenes 82 with chromic acid yielded dibenzocyclooctanediones 83. Treatment of these diketones with various amines resulted in a transannular reaction to afford species 84 in good yields.

82

83

84

SCHEME12

Brief reference should also be made to indolopavine derivatives 85 which were synthesized as illustrated in Scheme 13 (130). Since the utilized process, which is the classical route leading to pavines, also represents the probable biosynthetic sequence for the natural pavine alkaloids, it has been suggested that the future discovery of naturally occurring indolopavines is not an unlikely possibility (130).

B. SYNTHESIS OF ISOPAVINES In 1955, Guthrie and co-workers (131) erroneously assigned pyrroline structure 87 to the crystalline compound obtained by treating aminoacetal 86 with sulfuric acid (Scheme 14). The structure assignment was revised by Battersby and Yeowell (69)to 35, who named it isopavine, since the structure had already been proposed but eliminated for the isomeric compound pavine (34) (95,97). The Battersby structure was conclusively confirmed through a study of the chem-

344

M Re

BELKIS GOZLER

o

q

N

-

H

Pd , c y m e n e

R

H

1. L i A I H 4 2. R ’ X

I

H

1

H

85

SCHEME13

ical and UV spectral characteristics of the Hofmann degradation products (69). This structural revision was also reached independently by Waldmann and Chwala (132). 1. Classical Routes to Isopavines

a. Double Cyclization of Aminoacetaldehyde Dialkyl Acetals. The method of Guthrie, further developed by Battersby and Yeowell, has since become a OEt

Me0 Raney NI

Me0

87 /

86

35

SCHEME14

345

7. PAVINE AND ISOPAVME ALKALOIDS

traditional approach to the synthesis of isopavines. It involves an acid-catalyzed double cyclization of an appropriately substituted benzylaminoacetaldehyde dialkyl acetal 88 under nonreductive conditions (Scheme 15). Originally it was postulated that the reaction proceeded via 1 ,Zdihydro- and tetrahydroisoquinoline intermediates, 89 and 90 (132). However, it has now been established that the cyclization initially affords the acid-sensitive 4-hydroxytetrahydroisoquinoline 92 via the aldehyde 91 (132a). The key intermediate 92 then undergoes rapid internal nucleophilic displacement of the hydroxyl group by the 3,4-dialkoxylated aromatic ring to afford the tetracyclic skeleton 93. The confirmatory evidence for the proposed mechanism was provided by the isolation of 4-hydroxy intermediates from the reaction medium (109,1324. Even in instances where these key intermediates were not easily isolable, they were claimed to be present by conversion to 1,2,3,4-tetrahydroisoquinols(109,133). Following the initial cyclization to the 4-hydroxy intermediate, a competing mechanism may operate depending on the reaction conditions utilized to afford a 1,2-dihydro derivative through dehydration. This will eventually lead to a pavine skeleton (Section 111,A). As mentioned previously, temperature is one of the

QOR

OR

91

92

111 H+

93

SCHEME15

346

BELKIS GOZLER

controlling factors in the fate of the reaction, where elevated temperatures promote the dehydration process and consequently pavine formation. Both pavines and isopavines are produced simultaneously, but in varying ratios when heat is utilized during cyclization, whereas cyclization at room temperature furnishes almost solely the isopavine derivatives. It has also been shown that variations in acid conditions may have definite effects on the nature of the products, and either a pavine or an isopavine may be obtained selectively depending on the choice of acid (111).Attempts have been made to develop milder conditions where preferential formation of isopavine bases could be achieved through this classical route. Treatment of the intermediate acetal with chlorosulfonic acid at very low temperatures gave only the isopavines in high yields (134). The isopavine bases, (k)-amurensinine (25) (81,135), (?)-O-methylthalisopavine (26)(136), (+)-reframidhe (27)(77), and (*)-reframhe (28) (77) were synthesized by the above-mentioned classical route, where deoxybenzoins were utilized as starting materials. In some cases, some modification to the method has been introduced, particularly involving the formation of the requisite benzylaminoacetals (77,110). The synthesis of (+)-thalisopavine (30) was undertaken along parallel lines to confirm the structure of the naturally occurring base (53). Moreover, both (5)-reframoline (29) and its positional isomer (+)-146were synthesized in an attempt to establish the position of the phenolic hydroxyl (110). The synthesis of (+-)-reframhe (28)from the properly substituted deoxybenzoin 94 has been outlined in Scheme 16 as a typical example (77).

b. Hydroboration and Oxidation of 1,2-Dihydroisoquinolines. An alternate approach to the key 4-hydroxy intermediate and subsequently to the desired isopavine has involved the hydroboration and oxidation of a properly substituted 1,2-dihydroisoquinoline,as exemplified in the synthesis of (+-)-O-methylthalisopavine (26)from 1,2-dihydropapaverine (96)(Scheme 17) (77).In an attempt to establish the position of the phenolic hydroxyl, (?)-amurensine (24) and (+)-isoamurensine (100)were prepared along parallel lines, where the requisite isoquinolines 98 leading to 1,2-dihydro derivatives 99 were obtained via the Reissert compounds 97 (Scheme 18) (72). The same route has been utilized to confirm the structure of (-)-thalidine (21) through the total synthesis of the racemic base (82). The corresponding dihydro compound was obtained by N-methylation and subsequent partial reduction of the Bischler-Napieralski product. The following steps leading to racemic thalidine were similar to those presented in the foregoing examples. c. 4-Acetoxytetrahydroisoquinolinesas Intermediates. Since 4-hydroxytetrahydroisoquinolines cyclize to isopavines in relatively low yields, Hoshino and co-workers (137) described a method where the properly substituted 6hydroxybenzyltetrahydroisoquinolines of type 101 were subjected to lead

347


meorno Me0

I

Me0

I

H,NCH2CH(OMe),

NaEH4

Me0

94

Me0

conc. HCI

Me0

1.

HCHO

2.

NaEH4

95: norreframine

28

SCHEME16

OH

96

Me0

26

SCHEME1 1

348

BELKIS GOZLER

0

24: R*=R3=Me

: R 1 =Bz ; R4:H

100: R J = R 4 = M e ; R2=Bz ; R 3 = H

SCHEME 18

tetraacetate oxidation to afford 4-acetoxy derivatives 102 (Scheme 19). Acidcatalyzed cyclization of species 102 afforded the isopavine bases in improved yields. Thus, (+)-reframoline (29) and (&)-reframhe (28) were obtained by this route with overall yields of 54 and 40%, respectively. (+)-O-Methylthalisopavine (26) and the unnatural isopavine (2)-147 were also synthesized through this sequence (137). In further studies by the same group (138,139), the C-8 position of the 7hydroxybenzyltetrahydroisoquinoline was blocked with chlorine to promote the

349

I. PAVINE AND ISOPAVINE ALKALOIDS OAc

101

102

28

29

SCHEME 19

formation of isopavines at the expense of aporphines, which were previously shown to be the sole products when 8-nonsubstituted substrates were used (140142). As illustrated in Scheme 20, lead tetraacetate oxidation of species 103 afforded p-quinol acetate 104. Subsequent treatment with trifluoroacetic acid yielded the corresponding isopavine 106 via the transitory quinone methide 105 in low yields. Also obtained, however, were the related aporphine 107 and morphinandienone 108, both in relatively low yields. It was, therefore, concluded that the blocking of the C-8 cite was not effective in directing the course of the reaction. 2. Enantioselective Synthesis of Isopavines

The first synthesis of an optically active isopavine, (-)-reframoline (29), has been achieved by the acid-catalyzed double cyclization process described previously. The properly substituted diarylamine 109 was resolved using (+)-dibenzoyltartaric acid to afford the (+) enantiomer. Conversion to the acetal 110 was accomplished without racemization. Subsequent acid-catalyzed cyclization yielded the levorotatory alkaloid 29 (Scheme 21) (112). It has already been mentioned that a novel synthetic process furnished racemates and optically active forms of pavine bases via unstable quinone methide intermediates (Section III,A) (11 7). In this process, isopavine formation has also been achieved by the proper choice of reaction sequence. Racemates of thalidine (21) and 0-methylthalisopavine (26) were efficiently obtained by the abovementioned route (11 7). Moreover, the sequence provides a convenient route to

*

P b ( O A c )4

/

CF3COOH

103 0W

OR

M

OR 104

e

Me0

105

0 108

i

RO

::woIR

OR

107

CI

106

SCHEME20

OEt

Bz 0

NHMe

(+)-dibenzoyl-

-(+)-log-

bromoacetal

t a r i a r i c acid

109

(-1-29

SCHEME21

Me0

35 1


optically active isopavines when the starting material is (S)-( -)-N-norreticuline (61), now readily available by optical resolution of racemic N-norreticuline (118,143).Scheme 22 illustrates the synthesis of the optically active forms of the aforementioned isopavine bases, 21 and 26. Thus, phenolic N-carbethoxybenzyltetrahydroisoquinoline 111 was subjected to DDQ oxidation to afford the quinone methide intermediate 112. 1,6-Addition of methanol furnished species 113. Cyclization of 113 under mildly acidic conditions supplied the corresponding N-carbethoxy-N-norisopavine114. Hydrazinolysis then gave rise to the N -

ClCOOEt

-

MHOe o W C O O E t

-..H

OMe

(-1 - 6 1

[+)-Ill

MeOH P

OH D

O

OMe H

-

(+) 1 1 3

11 2

/

(-) - 11 4

(-)- 2 1

CH2N2

MMe 0

e

o

(-)

- 26

SCHEME22

~

o

~

~

e

352

BELKIS GOZLER

norisopavine in high yield, whereas diborane reduction proved to be the preferential method for the conversion into the N-methylated analog, (-)-21. Diazomethane 0-methylation of (-)-21 gave (-)-26 (117).

3. Novel Routes Kametani and co-workers used a previously demonstrated ring expansion method to construct the isopavine skeleton (144,145). The method was successfully applied to the synthesis of (+-)-reframidine (27) (Scheme 23) (145).Treatment of the 3-aryl-3,4-dihydroisoquinoliniumiodide 115 with diazomethane furnished aziridinium iodide 116. On standing in 6 N hydrochloric acid, crude 116 underwent a one-step ring expansion-ring closure to afford (+-)-reframidhe in 20% yield. The same product could be obtained via benzazepine 118 depending on the reaction conditions. It has been postulated that the aziridinium iodide 116 may have formed a transitory quinonoid intermediate 117 which is attacked

115

116

27

SCHEME23

I. PAVINE AND ISOPAVINE ALKALOIDS

(%o)

2.

PC13

\ '

0

H

119 ClCOOEt

HgO - H C 1 0 4

124

SCHEME24

353

354

BELKIS GOZLER

either intermolecularly by a methoxyl group to afford a 3-benzazepine 118 or intramolecularly by the 3-alkoxyphenyl group to generate the isopavine framework (145). In a more recent study, another novel route for the total synthesis of (*)reframidine (27) was described (Scheme 24) (146). The requisite aziridine derivative 120 was obtained from deoxypiperoin (119) in three steps. Treatment of 120 with ethyl chlorocarbonate furnished 121 through a ring opening of the reactive quaternary aziridinium salt. Reaction of the urethane 121 with mercuric oxide-perchloric acid gave 122 and 123, the former of which could be converted to the latter in good yield by passing through an alumina column. Successive reduction and Swern oxidation gave 124, which on treatment with acid cyclized to furnish (*)-reframidine with an overall yield of 18%. A facile acid-catalyzed double cyclization of N,N-dibenzylaminoacetaldehyde dialkyl acetals of type 125 has been known to generate 1-azadibenzo[c,Jlbicyclo[3.3.l]nona[3,6]dienes126 in high yields (120,121,147). A novel and convenient synthesis of (*)-amurensinine (25) and (*)-reframhe (28) (Scheme 25) proceeds from the quaternary salt 127, where proper choice of base and reaction OEt

125 126

128

127

I

ButOK

28

25

SCHEME25

355


conditions results in preferential production of either isopavines or species 128, the latter shown to be the intermediate en route to pavine bases (Section 111,A). Thus, the doubly cyclized product 126 obtained from N-(3,4-dimethoxybenzyl)-N-(3,4-methylenedioxybenzyl)aminoacetaldehyde diethyl acetal 125 was quaternized to afford 127, which was in turn heated with potassium tertbutoxide in dioxane to furnish the isomeric isopavine alkaloids, (-+)-ammensinine and (2)-reframine (147).

OMe

VOF3

*

MM e0

e

o

w

o

:

:

e

129

26

SCHEME 26

A novel route to (*)-0-methylthalisopavine (26) involves the oxidation of the properIy substituted tetrahydro-3-isoquinoloneof type 129 with vanadium oxytrifluoride to furnish bridged lactam 130. Compound 130 was then reduced to the racemic isopavine alkaloid 26 in an overall yield of 4.4% (Scheme 26) (136).

OMe

‘OH

132

133

I

Meor

MeO

35

SCHEME 21

- H2S04

I.

NaN3

2.

thermolysis

356

BELKIS GOZLER

A recent endeavor at the total synthesis of isopavines describes a promising novel route to these bases via functionalized dibenzocyclooctadienes (Scheme 27) (148). Dibenzocyclooctadienylether 132, formed from homoveratraldehyde (131) by a double Friedel-Crafts alkylation, is converted to dibenzocyclooctatrienol 133. Treatment with hydrazoic acid, followed by thermolysis and reduction, supplies (*)-isopavine (35) in good overall yield (53%). Subsequent attempts to prepare pavine bases by this approach have proved to be unsuccessful (148).

0%

Polyphosphoric

acid

*QpJJ

/

135

134

SCHEME28

An isopavine having a methyl group at C-5, 135, was obtained as the major product when the acetylenic derivative 134 was heated in polyphosphoric acid (Scheme 28) (149).

IV. Unnatural Pavines and Isopavines

A number of pavine and isopavine bases hitherto unknown as natural compounds were encountered in the course of our literature survey. These compounds had been obtained as intermediates or by-products during synthetic studies which were designed primarily for the structural elucidations of natural compounds and for the improvement of methods or yields en route to synthetic target compounds. The resolution of racemates or alternatively successful stereoselective syntheses furnished enantiomers of known optically active alkaloids. In this section, the aforementioned compounds are compiled under the heading ‘‘Unnatural Pavines and Isopavines,” the term specifically denoting racemic or optically active compounds not yet found in nature and optical antipodes of optically active natural pavine and isopavine alkaloids. The coverage is restricted to compounds of which natural occurrences are probable with regard to biosynthetic considerations. The references related to their syntheses and physical and spectral data presented in Tables VIII-XI1 may prove useful in the event of the future isolation of any of these compounds or their close analogs from natural sources.

TABLE VIII Unnatural Pavine Alkaloids

Alkaloid

Molecular formula

Molecular weight

R1

RZ

R3

R4

References

R5

~

(*)-2,8-Dihydroxy-3,9-dimethoxy-N-

19HZ 1 N04

327

OH

OMe

H

OH

OMe

i

C19H21N04

321

OMe

OH

H

OMe

OH

i

C18H17N04

311

M H 2 4

H

OH

OH

31

339

OMe

OMe

H

119

325

H

OH

OMe

104,105,I 10, 150,I51

340

H

OH

OMe

29

methylpavinan (136)

(*)-3,9-Dihydroxy-2,8-dirnethoxy-Nmethylpavinan (137)

(*)-8,9-Dihydroxy-2,3-methylenediox y-N-methy lpavinan (138) (*)-7 ,b-Dimethoxy-2,3-methylenedioxy-N-methylpavinan (71)

(*)-8-Hydroxy-9-methoxy-2,3-methylenedioxy-N-methylpavinan (139) [ = (t)-isocaryachine] (*)-8-Hydroxy-9-methoxy-2,3-methylenedioxy-N,N-dimethyl pavinium salt (140) (*)-2,3,8,9-Tetrahydroxy-N-methylpavinane (141) (-)-2,3,7,8-Tetramethoxy-N-methylpavinan (142) [= (-)-O,O-dimethylmunitagine] *)-2,3,7,8-Tetramethoxy-Nmethylpavinan (72) [= (2)-O,O-dimethylmunitagine]

C21H25N04

299

OH

OH

H

OH

OH

1

355

OMe

OMe

OMe

OMe

H

25,35,37,42

355

OMe

OMe

OMe

OMe

H

119

TABLE IX Unnatural N-Norpavine Alkaloids

w

Molecular formula

Molecular weight

(?)-2,9-Dihydroxy-3,8-dimethoxy-

C1gH19N04

313

pavinan (143) [= (*)#norbisnorargemonine] (?)-9-Hydroxy-8-methoxy-2,3methylenedioxypavinan (144)

c 18H17N04

31 1

(?)-2,3,8,9-Tetrarnethoxypavinan

C20H23N04

34I

m VI

Alkaloid

(34) [= (*)-pavine]

RI

OH

R2

R3

OMe

OMe

OH

117

OMe

OH

112

OMe

OMe

90,91,92, 93,95, 97

M H 2 4

OMe

OMe

R4

References

TABLE X Unnatural Isopavine Alkaloids

Akaloid

(+)-2,9-Dihydroxy-3,8-dimethoxy-N-methylisopavinan (145) [ = (+)-thalidine] (*)-2-Hydroxy-3-rnethoxy-8,9meth y lenedioxy-N-methylisopavinan (146) (*)-3-Hydroxy-2,8,9-trimethoxyN-methylisopavinan (147) (+)-8-Hydroxy-9-methoxy-2,3methylenedioxy-N-methylisopavinan (100) [= (*)-isoamurensine]

Molecular formula

Molecular weight

Rl

R2

R3

1gH2 1N04

321

OH

OMe

OMe

1gH1 gN04

325

OH

OMe

341

OMe

OH

C2&3N04 1gH 1gN04

325

M H Z 4

R4

OH

References 143

110

O-CH2-0

OMe

OMe

137

OH

OMe

72

TABLE XI Unnatural Quaternary Isopavine Alkaloids

Alkaloid

Molecular formula

Molecular weight

Rl

R2

R3

R4

References ~~

W o\ 0

( -)-2,3,8,9-Dimethylene-

dioxy-N,N-dimethylisopavinium salt (148) (+)-2,3,8,9-Dimethylenedioxy-N,N-dimethylisopavinium salt (149) (?)-2-Hydroxy-3-methoxy-8,9methylenedioxy-N,N-dimethylisopavinium salt (150) (+-)-3-Hydroxy-2-methoxy-8,9methylenedioxy-N,N-dimethylisopavinium salt (151) (+-)-2,3,8,9-Tetramethoxy-N,Ndimethylisopavinium salt (152)

338

0-42H2-4

M H Z 4

76

C20H20N04 +

338

M H Z - 4

0-42H24

77

CzoHz2N04

340

OH

OMe

W H 2 - 4

110

CZOHZZN04+

340

OMe

OH

M H 2 4

137

C2zHzsN04 +

370

OMe

OMe

C20H20N04

+

+

OMe

OMe

69

TABLE XI1 Unnatural N-Norisopavine Alkaloids

Alkaloid

(-)-2,9-Dihydroxy-3,8-dimethoxyisopavinan (153) [= (-)-PInorthalidine] (+)-2,9-Dihydroxy-3,8-dimethoxyisopavinan (154) [= (+)-Nnorthalidine] (+)-2,9-Dihydroxy-3 ,g-dimethoxyisopavinan (155) [= ( t ) - N northalidine] (+)-2,3-Dimethoxy-8,9-methylenedioxyisopavinan (95) [= (? )-N-norreframine] (*)-2,3,8,9-Dimethylenedioxyisopavinan (156) [= (+)-N-norreframidine] (*)-2,3,8,9-Tetrahydroxyisopavinan (157) ( +)-2,3,8,9-Tetramethoxyisopavinan (35) [= (*)-isopavine]

Molecular formula

Molecular weight

Rl

1gH 1gN04

313

c1sH 19N04

R2

R3

R4

OH

OMe

OMe

OH

143

313

OH

OMe

OMe

OH

143

laH 1

313

OH

OMe

OMe

OH

117,143

19H1gN04

325

OMe

OMe

C18H15N04

309

285

OH

OH

OH

OH

143

34 1

OMe

OMe

OMe

OMe

69,117, 120,131, 132,134, 136,148

MHZ--O

References

77

362

BELKIS GOZLER

V. Spectral Properties References relevant to the spectral analyses of naturally occurring pavine and isopavine bases are presented in Tables XI11 and XIV. An exhaustive numerical compilation of spectral data of these alkaloids may also be consulted (11).

A. MASS SPECTRO~COPY A base peak corresponding to a 6,7 (or 7,8)-disubstituted isoquinolinium ion is the prime criterion in considering a pavine or an isopavine structure. In the case of a pavine, the presence of the expected peaks may only confirm the structure deduced by other spectral and chemical means. In isopavines, however, mass spectroscopy is an exceptionally powerful tool in differentiating this group from the pavine alkaloids, as well as from other related isoquinoline bases.

1. Pavine Alkaloids Pavines which are identically substituted on rings A and D display a single isoquinolinium ion (a), formed by cleavage of the benzylic bridge on the rearranged molecular ion (Scheme 29) (24,25). The molecular ion M + and the accompanying (M - 1) ion may be of variable intensity depending on the inlet system (24). Pavines which have nonidentical substituents on rings A and D furnish two different isoquinolinium ions through the same fragmentation mode, as ex+

M+

r e a r r a n g e d Mi

RO

RO

OR

RO I

ca)

( M - 1 )+

(100%)

SCHEME 29

OR

OR

TABLE XI11 References for Spectral Properties of Naturally Occumng Pavine Alkaloids

uv

Alkaloid

IR

'H NMR

Mass

ORD, CD, and Abs. Conf.

18,45,117, 123,154

112,115,153, 155- 160

32,35

32,153

35 1,23,25,33

35 1,25,33,50, 113

115,I53

29,31,104, 110,l I2 29 29,30,41,52, 104,106 29,32

104,110,112

112,115

29 I54

29 115,153

24,31

24,54,154

Argemonine ( 5 )

18,24,25,37, 152a,153

14,37,45, 152a

Argemonine N-metho salt (15) Argemonine N-oxide (20) Bisnorargemonine (6)

13,3291

35

18,24,25,29, 30,34,41, 45,123 29,32,35

13,27,33,50, l52c, 153,

35 13,50,152c

110

-

165

Caryachine (7) Caryachine N-metho salt (16) Eschscholtzidine (8) Eschscholtzidine N-metho salt (17) Eschscholtzine (9) Eschscholtzine N-metho salt (18) Eschscholtzine N-oxide (20a)

31 104,110, 112 29 52,104,106, 153 32 ~

24,31,51,54, 152d,153 54,152e

29 -

-

31,152d

-

-

152e

-

2-Hydroxy-3,8-dimethoxy-

32a 26

26

32a 26

pavinan (10) Isonorargemonine (11)

42

22

1,22,25,42

32 115,153

32a 26

-

32a

-

42 (continued)

TABLE XI11 (Conrinued)

uv

Alkaloid

4,8,9-Trirnethoxy-2,3-rnethylenedioxypavinan (3) Munitagine (12) Norargemonine (13) Platycerine (14) Platycerine N-rnetho salt (19)

27 25,108 13,34,37,50, 102,1526. 153,165 37,42,152f 47

'H NMR

IR

-

Mass

27

27

25 14,22,37,50, 102,1526

25 1,22,25,34

25,108 34,50,71

37,152f 47

35,42

35 47

-

ORD, CD, and Abs. Conf. -

115

115,153

42 -

365

I. PAVINE AND ISOPAVINE ALKALOIDS TABLE XIV References for Spectral Properties of Naturally Occurring Isopavine Alkaloids

uv

Alkaloid Amurensine (24) Amurensinine (25)

IR

67,85,86,88, 67,152g 152g,I 64 67,80,81,85, 67 86,88,165 81 81

Amurensinine N-metho salt (31) 0-Methylthalisopavine (26)

53

Reframidine (27) Reframine (28) Reframine N-metho salt (32) Reframoline (29) Thalidicine (23) Thalidine (21) Thalisopavine (30)

76,86 76 75 76,110,112 84 82 53

76 76

76, 10,137 84 53

'H NMR

Mass

ORD, CD, and Abs. Conf.

67,70

71

67,70,86, 147 81

71,85,86,88, 67,70,160 89,147

53,77,78

53,78,I 17, 136 77,86,162 147,162

77,145 77,147 74,75 110,112,137 84 82 53

112,160,161

-

-

110,112,162 12 84 82,117 82 53

-

-

emplified by the mass spectra of caryachine (7) (29) and eschscholtzidine (8) (Scheme 30) (154). The abundances of these ions in these species are relatively close (26,27,29,34,71) and sometimes of equal magnitude (110,112). On the other hand, in platycerine (14), the mlz 190 peak is only 30% of the mlz 204 peak. This exceptional situation has been interpreted as due to the lesser contribution of the o-quinonoidal fragment (a) to the stability of the mlz 190 ion (Scheme 31) (35). Mass spectroscopy does not generally provide assistance in differentiating between isomeric diphenols, because the relative locations of hydroxyl and methoxyl groups do not significantly alter the fragmentation pattern (29). The mass spectrum of a pavine N-oxide displays a low intensity molecular ion peak from which an oxygen is readily expelled. The remaining pattern is superimposable with that of the corresponding tertiary base (32a,35).The N-metho salts of pavines exhibit mass spectra nearly identical with those of their tertiary bases. The halogen anion is detected at mass units which match the corresponding halogen halides and methyl halogenides (29,32,35,47). 2. Isopavine Alkaloids

The isopavines display only one isoquinolinium ion in their mass spectra, as do the symmetrically substituted pavines. This isoquinolinium ion is also the base peak and is formed directly from the ionized molecule as confirmed by the presence of the relevant metastable ions (162). Moreover, the molecule is

366

BELKIS GOZLER

0 M+

\

/

:I:&

% (OMe

'

/*NMe

OMe

r e a r r a n g e d M+ rearranged

I

1 M

e

N

a

M+

I

I

: C

rn/z 204

m

N Me

m / z 188

SCHEME30

cleaved in such a manner that it is possible to differentiate between the substituents on rings A and D, which greatly facilitates structural elucidation. The molecular ion is relatively abundant (30-50%), as is the (M - l ) + ion. The latter may be represented as either (a) or (b) (Scheme 32). The clue which points out unequivocally to an isopavine nucleus is the presence of the (M 43) ion in intensities varying from 30 to about 60%. It is formed by the retroDiels-Alder condensation of the molecular ion, resulting in loss of a CH,=NCH, unit. This particular ion is practically absent in the spectrum of a pavine (71). An additional peak of moderate intensity is associated with the (M - 86) ion which is formed by a subsequent loss of a methyl radical and carbon +

+

+

M Me0

e

o

:NMe w O

/M

e

___)

\

/NMe

m i z 204

m / z 190

14 Mi

Me'mNM

Me0

M

e

N

a

ta)

SCHEME31

o

M

e


367

RO r e a r r a n g e d M+

RO RO

CH,. ( 1 00 O h )

SCHEME32

monoxide from the (M - 43)+ ion (71,162). The sequence is confirmed by metastable ions (71) and also by the absence of this particular peak in the spectrum of reframidine (27) which lacks a methoxyl substituent (162). An unexpectedly encountered peak in the spectrum of reframidine (27)is due to the (M + 14)+ ion, formed by the transfer of a methyl radical from one molecular ion to another, followed by hydrogen expulsion (77). Furthermore, an (M - 16)+ peak has been spotted in the spectrum of amurensine (24), being attributable to the elimination of a methyl radical from the (M - 1)+ ion (71). The presence of a rather unusual (M - 17)+ peak in the spectrum of amurensinine (25) remains unexplained (71).

B . 'H-NMR SPECTROSCOPY 1 . Pavine Alkaloids The 'H-NMR spectra of pavines can provide appreciable assistance in structural elucidation. The oxygenation pattern of a pavine may be deduced from a careful examination of the methine (Ha,J and methylene (Hb,c,e,f)proton absorptions (lc). In the case of 2,3,8,9 substitution, the abc and def protons furnish two superimposable ABX patterns. A doublet integrating for two protons at the lower field end of the system at approximately 6 4.0 represents the bridgehead protons, H, and H,. At 60 MHz, it appears as if these protons are coupled to only one of the neighboring protons (J = 6 Hz) (18,20,25). Furthermore, the geminal hydrogens couple to each other with a coupling constant of 17 Hz (18,20).On

368

BELKIS GOZLER

ic

the other hand, in the 'H-NMR spectra of pavines bearing 2,3,7,8 substituents, the Ha and H, protons are represented by two doublets at about S 4.0 and 4.4, where the latter is assigned to H, which is proximal to one of the oxygen functions positioned on ring D (25). In the C-7 phenolic species, platycerine (14) and munitagine (12),the bridgehead protons will be shifted upfield by approximately 0.2 ppm on acetylation (163). Some generalizations can be made regarding the aromatic region of pavine bases. In alkaloids with 2,3,8,9 symmetric substitution, the aromatic protons are paired into two singlets, each integrating for two protons ( I ,18,20,25), whereas asymmetric substitution, as in bisnorargemonine (6),results in four well-defined singlets (23).In a 2,3,7&tetrasubstituted pavine, H-9 and H-10 are expected to appear as an AB quartet. However, they may collapse into a singlet of two protons as exemplified by the spectrum of O,O-dimethylmunitagine (72) (25). The chemical shifts of the aromatic protons of some pavine bases have been amply summarized (25,29).A complementary and additive relationship has been formulated into a set of rules for the chemical shifts of aromatic protons in an Nmethylpavine system (1,29,105,112).The determining factor has been stated to be the inductive effect of the bridgehead C-N bond, causing deshielding and consequently downfield shifting of H-1 and H-7 ( I ) . However, it has been justifiably pointed out that it is rather the anisotropic shielding by the aromatic rings which results in the upfield chemical shift of H-4 and H-10 (112). In symmetrical pavines, the C-2 and C-8 methoxyls will appear as a singlet of six hydrogens just as the C-3 and C-9 methoxyls. The former pair, which is proximate to the bridgehead, will appear more downfield by about 0.07-0.1 ppm with respect to the latter (1,25). The methylenedioxy protons center around 6 5.8-5.9 as an AB quartet (J = 1-1.5 Hz). The N-methyl protons appear almost invariably between 6 2.49 and 2.57 in CDCl, solutions and at 6 2.35 in DMSO solutions. Conversion to phenolates coupled with NMR analysis has been used in determining the relative locations of the hydroxyl and methoxyl groups in phenolic pavines (I ,25). Moreover, changes in chemical shifts of neighboring aromatic protons when going from a CDCl, solution to a DMSO solution had been useful in assigning the correct position of the phenol (25,112).


369

The general absorption pattern of quaternary pavines strongly resembles that of the tertiary analogs with the exception of the expected downfield shifts for each of the protons. In particular, the bridgehead protons will move downfield by about 1-1.5 ppm (32,35).N,N-Dimethyl protons will be observed as a singlet between 6 3.3 and 3.7 (29,32,35).The set of empirical rules deduced for aromatic proton chemical shifts in a tertiary system has been shown to apply also to the quaternary system (29). A listing of aromatic proton chemical shifts of some quaternary pavine bases has been presented as a reference for future studies on similar compounds (29).

2. Isopavine Alkaloids The aromatic protons of isopavine alkaloids generally appear between 6 6.45 and 6.80 in CDC1, solutions as either four or three singlets. In case of the latter, it is always the most downfield absorption peak that integrates for two protons. The chemical shifts of aromatic protons are mostly reported without specific assignment to positions, because no set of rules have yet been formulated for the chemical shifts of these protons due to the asymmetrical nature of the isopavine ring system (222). Similarly, methine and methylene protons are usually reported as an unresolved complex pattern between 6 2.2 and 3.9. It has been reported, however, that the H-12 absorption appeared as a triplet at 6 3.8-3.9 ( 6 3 , moving downfield by about 1 ppm in quaternary species to display a triplet at 6 4.8 (J = 6 Hz) (82). The two N-methyl groups in a quaternary isopavine alkaloid display two different chemical shifts, explained by the nonsymmetrical nature of the molecule (74,75). The C-9 methoxyl group absorbs at a higher field (6 3.77-3.78 ppm) as compared to the C-10 methoxyl (6 3.83-3.86) ( 5 3 , 6 3 . Despite the various criteria summarized above for the 'H-NMR spectra of isopavine bases, it should be emphasized that it is difficult to assign an isopavine ring system to a compound based only on the NMR data.

C. 13C-NMR SPECTROSCOPY Only the 13C-NMR spectrum of argemonine (5) has been reported so far, and is summarized by expression 5a (264). 111.4

33.3

Me0

5a

370

BELKIS GOZLER

D. UV SPECTROSCOPY A pavine skeleton may be regarded as two N-methyl- 1,2,3,4-tetrahydroisoquinoline nuclei fused together. In accordance with this observation, the UV spectrum of a pavine alkaloid demonstrates close similarity to that of an analogous tetrahydroisoquinoline (153). 2,3,8,9-Tetrasubstituted N-methylpavines generally display a broad absorption band between 287 and 295 nm in polar solvents (6,8,25,153). However, a triplet absorption has also been reported in ethanolic solutions between 280 and 295 nm, where the lowest and highest wavelength absorptions may appear as shoulders (1,102,153).The UV absorption band of argemonine-type pavine bases split into a well-defined multiplet in cyclohexane (25,33).Munitagine-type bases behave in a similar manner, but the splitting is not as distinct and the molar absorptivities are lower (25). Some generalizations have been made about the effect of various substituents on the absorption maxima and molar absorptivities (165). As expected, the absorption band around 280 nm is displaced to lower wavelengths when two methoxyls are replaced by a methylenedioxy group. The UV spectra of pavines are slightly affected by protonation on nitrogen (153). Similarly, quaternary species furnish UV spectra which closely resemble those of their tertiary counterparts (153). In some pavine bases such as norargemonine (13), the expected bathochromic shift on addition of alkali has not been observed (102). The absorption maximum of isopavine alkaloids appear at 290-294 nm. The shoulder at 250 nm, which is missing in the spectra ofpavines, provides complementary information in distinguishing between pavine and isopavine alkaloids (7,67,69). Additionally, the Hofmann degradation products of the two nuclei have been shown to differ greatly in their UV spectral behavior (67,69,75). UV spectroscopy has been of little value in discriminating between positional isomers of the phenolic species. However, the UV spectra of the corresponding methine bases have been shown to behave differently on addition of alkali (110).

E. ORD, CD,

AND

ABSOLUTF CONFIGURATION

The determination of the absolute configuration of (-)-argemonine (5) has been of considerable importance with regard to its possible biosynthesis from the H

H

..

-OeM

NMe

.\ ’

Me0 I

A

5b

OMe

OMe


37 1

benzyltetrahydroisoquinoline, (+)-reticuline (158), of (S) configuration. The earliest assignment of an absolute configuration to (-)-argemonine, as illustrated in expression 5b, by Barton and co-workers (166) originated from exactly such a biogenetic hypothesis. The first experimental attempt to establish the absolute configuration of (-)argemonine involved an empirical method where ORD curves of this alkaloid and (+)-Troger’s base (159) of known absolute configuration (167) were correlated, as a result of which the (S)absolute configuration was reported for both asymmetric centers of (-)-argemonine (155). However, the method, not the conclusion, was challenged by Mason and co-workers, whose nonempirical analyses of CD spectra of the aforementioned two compounds, (-)-5 and (+)-159, at 80°K revealed that empirical comparisons of ORD curves may be of limited reliability in evaluating configurations (156,157). Their analyses of CD curves by means of an exciton model substantiated the previously assigned absolute configuration of (-)-argemonine (156,157).

159

A contemporaneous study on the same subject utilized a chemical correlation method where (-)-N-benzylargemonine chloride, obtained by sequential optical resolution and quaternization of (2)-N-methylpavine (5), underwent a multistep degradative process to furnish (-)-N,N-dimethyl-di-n-propyl aspartate. Comparison of this final product with L-aspartic acid of known chirality led to the absolute configuration of (-)-5 (115,158). (-)-Eschscholtzine (9) was assigned the same absolute configuration by correlation of its ORD curve and optical rotation with those of (-)-argemonine (115). Since other pavine alkaloids, such as (-)-norargemonine (13), (-)-bisnorargemonine (6), and (- )-caryachine (7),were already chemicaHy correlated with (-)-argemonine, they could be assigned the identical absolute configuration (115). The absolute configuration of (-)-caryachine was further confirmed by analogy of its CD spectrum to that of (-)-argemonine (112). Since (-)-eschscholtzidine (8) has been prepared by 0-methylation of (-)-caryachine, its absolute configuration was also firmly established (115). The close similarity of the ORD curves of these pavine alkaloids, all displaying positive Cotton effects centered at approximately 280, 235, and 206 nm, corroborated the previously attained conclusions (153). Further authentication was provided by a stereoselective synthesis of (-)-thalidine (21) and (-)-bisnorargemonine (6) from ( + ) - N -

312

BELKIS GOZLER

norreticuline (61) of established configuration (117) and also by an X-ray crystallographic study of (-)-argemonine methiodide, which furnished comprehensive information about structural details and the conformation of the molecule (159). A successful application of the aromatic chirality method (6) has led to the determination of the absolute configuration of (-)-amurensine (24), thus establishing the absolute configuration of the isopavine bases as shown in expression 24a (161). This result was later verified by the correlation of optical rotations and ORD curves of (-)-argemonine (5) and (-) -amurensinine (25) (67,70,160) as well as of their first-step Hofmann degradation products (160).

424a

Other isopavines were also shown to possess the same (5S, 12s) configuration by virtue of the similarity of their CD spectra with that of (-)-amurensine (24) (112). The simultaneous synthesis of (-)-caryachine (7)and (-)-reframoline (29) from the same optically active precursor of known absolute configuration furnished further support for the established absolute configuration of the isopavine alkaloids (112). Noteworthy is the fact that the sign of optical rotation at the sodium D line can be used safely for assigning the absolute configuration of pavine and isopavine bases. Molecules that have a high negative rotation will have the same absolute configuration as (-)-argemonine and (-)-amurensine, whereas their dextrorotatory counterparts will correspond to their mirror images (26,115,161).

VI. Biosynthesis The work of Stermitz and co-workers (19) on the structure elucidation and establishment of (-)-argemonine (5) as the first representative of a novel framework also encompassed the earliest hypothesis about the biogenesis of this compound as being derived from a benzyltetrahydroisoquinoline.A probable biosynthetic sequence initiating from laudanosine (N-methyltetrahydropapaverine) was postulated, where argemonine was the primary product, converting to norargemonine (13) and bisnorargemonine (6) on successive demethylations (19). The possibility of a biogenetic connection between (+)-reticuline (158) and

Y

I

I

l-

l-

-

/

m

374

BELKIS GOZLER

(-)-argemonine (5) was investigated by feeding experiments on mixed plants of Argemone mexicana and A . hispida (166). Attempted incorporation of 14Clabeled (+)-reticdine into (-)-argemonine resulted in an insignificant uptake of the labeled precursor, a result attributable to the paucity of (-)-5 in the plant material investigated (25,166). The occurrence of four closely related pavine bases as well as (+)-reticdine (158) in Argemone munita and A . hispida encouraged Stermitz and Seiber (25) to postulate a possible biosynthetic route based on the intermediacy of (+)-158 (Scheme 33). The iminium salt 160 formed by in vivo oxidation of this benzyltetrahydroisoquinoline could undergo intramolecular p - and o-phenolic couplings to produce (-)-bisnorargemonine (6) and (-)-munitagine (12), respectively (Route A). It was emphasized that 0-methylations to yield (-)-norargemonine (13) and (-)-argemonine (5), which were also shown to be present, should have taken place after the cyclization, since such a process operating prior to pavine formation would have resulted in (-)-isonorargemonine (11) via (+)-laudanidhe (161) as an intermediate (Route B), neither of which were detected in the plants under investigation. In a later study by the same group (35), (+)-laudanidhe (161), (-)platycerine (14), and (-)-isonorargemonine (11) were isolated from Argemone grucilentu, whereas no (-)-bisnorargemonine (6) or (-)-argemonine (5) could be detected. This finding seemed to support Route B for the biosynthesis of the three first-named alkaloids. However, attention has also been drawn to the fact that the co-occurrence of (-)-munitagine (12) in A . gracilenta could not be efficiently accounted for in terms of Route B (35).It should be remarked at this point that natural 0-methylation and 0-demethylation processes are usually very facile and could have readily occurred with Argemone alkaloids. Additionally, a phenolic function is always a better supplier of electrons than a methoxyl group so that Route A above, starting with (+)-reticdine (158) and proceeding through the intermediacy of the iminium cation 160, is a rational possibility as a biosynthetic approach to the pavinoids. The biosynthesis of pavines from (+)-reticuline (158) through Route A has also been agreed upon by Barker and Battersby (115). They additionally suggested an equilibrium between the iminium ion 160 and the carbinolamine 162 (Scheme 34).

(+)-158-

no

kon OMe

(+) - 1 6 0

SCHEME34

(+) - 1 6 2

375


The fact that pavine and isopavine alkaloids have the same absolute configuration also suggests an alternative biosynthetic sequence where both nuclei are derived from a common 4-hydroxybenzyltetrahydroisoquinoline precursor (Scheme 35) (77,135).A dehydration reaction to afford a 1,2-dihydrobenzylisoquinoline, followed by cyclization, would yield a pavine. Alternatively, disH'

1

/ HO

:NMe

M e0-"" HO

NMe

' OH

'&OH

mew

I

HO HO

NMe

21 or

Me0

no 6 or

12

SCHEME35

376

BELKIS GOZLER

placement of the 4-hydroxy group by the benzylic moiety would lead to an isopavine. The recent isolation of the first naturally occurring 4-hydroxybenzyltetrahydroisoquinoline, (+)-roemecarine (163), along with the corresponding Noxide, (+)-roemecarhe 2a-N-oxide (164), from Roemeria carica, a member of a genus known to produce isopavines, has lent some support to the abovementioned hypothetical biogenetic sequence (168). HO

H

Meos Me M" e 0W

N

M %H e

Me0

Me0

Me0

[+I-1 6 3

(+)

-164

An interesting variation on the above theme for the biosynthesis of the pavines and isopavines has been proposed by Dyke (169). This proceeds via a quinone methine intermediate. The precursor, a 1-benzyltetrahydroisoquinoline-3-carboxylic acid 165 oxidizes to a quinone methide 166, which then decarboxylates to afford a reactive enamine 167. Cyclization then readily furnishes a pavine. Alternatively, hydration of the enamine 167 at C-4 would ultimately result in formation of an isopavine (Scheme 36). An alternate precursor for achieving the same result may be ( +)-reticuline (1581, which would oxidize to quinone methide 168. Direct cyclization would result in an isopavine skeleton, whereas conversion to the enamine 167 would lead to a pavine. Similarly, a hydroxylation of the methide 168 at C-4 to furnish species 169 would either yield an isopavine by cyclization, or a pavine via the intermediacy of the 1,2-dihydro compound 167 (Scheme 37) (169). Undoubtedly, work with labeled precursors is in order at this point to establish with certainty the exact biosynthesis of the pavine and isopavine bases.

VII. Chemotaxonomic Considerations The presence of pavines and isopavines has been used to provide assistance for taxonomic classifications, and to determine intergeneric and phylogenic relationships in the genera Papaver and Argemone. The results of extensive chemical research on Papaver species demonstrated that morphologically distinct sections are also chemically distinguishable by virtue of their alkaloidal profile (170). Out of nine well-defined sections of Papaver, the Section Scapiflora, which displays

M

e

O

q

M

y

H

HO

166 165 d e c a r b o x y l a t ton

MHO e

o

q

M

I

e

hydration

'

HO&

q

h

I l

e

167

I

cyciization

isopavine

cycl iza t ion

pavine

SCHEME 36

isopa wine

[Ol

(+]-158

hydration OH

169

168

Me0

cyclization

OH

'

OMe

167

SCHEME 37

____)

eavlne

378

BELKlS GOZLER

remarkable homogeneity with regard to qualitative and quantitative alkaloidal content (68,85),is the only section where isopavine bases, e.g., (-)-amurensine (24) and (-)-amurensinine (25), are constant components. The occurrence of (-)-0-methylthalisopavine (26) in Papaver rudicatum (Section Scapiflora) further substantiates the presence of isopavines as a chemotaxonomical characteristic of this section (78). More recent work, however, reports the occurrence of (-)-amurensinine as a minor constituent in Papaver tauricola (Section Miltantha); this instance represents the first occurrence of an isopavine alkaloid in a Papaver species outside the Section Scapiflora (89). It has been suggested that the presence of (-)-amurensinine (25) as the main alkaloid in various Meconopsis species indicates the relationship of this genus with Papaver species of the Section Scapiflora (80).By way of parallel thinking, the genus Roemeria, which is known to produce isopavine bases, can be interrelated with the Pupaver species of the Section Scapiflora as well as with Meconopsis species. Since morphological characters were found to be insufficient in establishing subdivisions of the genus Argemone, the alkaloidal contents were taken into consideration. The suggestion has been made by Slavik and Slavikovh (37)that this genus could be divided into two groups depending on the presence or absence of pavine alkaloids. At a later time, Stermitz (170)combined the results of extensive chemical work on Argernone species with the hitherto accumulated knowledge based on morphological grounds to divide the genus into four alliances. He demonstrated the correlation of this classification with that suggested according to morphological characteristics. Although not totally decisive in assisting taxonomic placement or identity of species (36,38), this classification proved to be of considerable aid in predicting new sources of pavine alkaloids (38,63) and in establishing phylogenetic relationships (38,170). A tentative phylogenetic hypothesis for the evolution of the genus Argemone has been proposed within this context (170).Thus, since the Section Scapiflora is claimed to include the most primitive Papaver species, the production of pavineisopavine alkaloids may well be considered a primitive characteristic. If the relationship of Papaver species of the Section Scapiflora and the pavine-producing genera, Argemone and Eschscholtzia, is valid, it follows that Argemone species which produce pavine alkaloids would have to be considered the most primitive in the genus. On the other hand, Argemone species which lack the capacity to elaborate pavines would have to be considered the most recently evolved.

VIII. Homopavines and Homoisopavines The homopavines and homoisopavines constitute a very small group of unnatural bases which have been synthesized by some of the routes designed for the

379


synthesis of pavine and isopavine alkaloids (132a,I38,139,I71,172). The intermediates in the synthetic processes are the properly substituted l-phenethylisoquinolines. The first homopavine, (*)-homoargemonine (174), was synthesized in 1973 in an attempt to construct pavine analogs with improved analgesic activity (Scheme 38) ( I 71). The corresponding 1-phenethylisoquinoline 173 was obtained by a Bischler-Napieralski condensation of 2-(3,4-dimethoxyphenyl)ethylamine (170) and 3-(3,4-dimethoxyphenyl)propionic acid (171) via the hydroxyamide intermediate 172. Compound 173 was then successively quaternized, reduced by lithium aluminum hydride, and treated with acid to afford the tetracyclic compound (5)-174. The acid-catalyzed cyclization of properly substituted aminoacetaldehyde dialkyl acetals was shown to be a suitable method in the construction of a homoisopavine (Scheme 39) (132a,172). Treatment of N-[ 1,3-bis(3,4-dimethoxyphenyl)propyl]aminoacetaldehyde dimethyl acetal (175) with concentrated hydrochloric acid afforded the N-norhomoisopavine 176 in 39% yield. This cyclization was also accompanied by some 0-demethylation. Product 176 could be readily N-methylated using formaldehyde and sodium borohydride to afford the homoisopavine (t)-177 (172). The 'H-NMR and mass spectral data of homopavines and homoisopavines are in conformity with those of the pavine and isopavine bases, respectively. A brief note should be made, however, on a divergent mode of fragmentation in the mass

170

o on

a

+

~

I

OMe OMe

b:

1. P 2 0 5

h

b OMe O M

e

172

173

J

171

Y

174 OMe bhle

SCHEME38

e

380

BELKIS GOZLER OMe

1.

Hp NCHzCH(OMe)2

2.

reduction

*

1 7 5 &OMe OMe

@OM.

176

177

SCHEME 39

M Me0

e

o

w

r e a r r a n g e d M+

I Me0

Me0 (

(81%)

bI(44%)

SCHEME 40

38 1


spectra of the homoisopavines, where ions (a) formed by the expected retroDiels-Alder reaction undergo further fragmentation to furnish the stable anthracene derivative (b) (Scheme 40) (172).

IX. Aporphine-Pavine Dimers An investigation of the alkaloidal contents of Thalictrum polygamum yielded a number of alkaloids (83) among which were the two novel type aporphinepavine dimers, (-)-pennsylpavine (178) and (-)-pennsylpavoline (179) (163). Compound 178, readily determined to have a dimeric structure due to the mlz 680 parent peak in the mass spectrum, was ascribed a 1,2,9,10-tetrasubstituted aporphine-pavine skeleton based on the observation that the UV spectrum 230,280sh, 288,308sh, 320 sh nm) was essentially a combination of the UV spectrum of a 1,2,9,10-tetrasubstituted aporphine and a pavine. In the mass spectrum, prominent peaks clearly accounted for the mode of fragmentation expected of the proposed structure (Scheme 41). In particular, the presence of the mlz 649 (M - CH,NH,)+ and the mlz 648 (M - CH3NH3)+ together with a relatively small mlz 637 (M - CH2=NCH3)+ ion pointed to an aporphine-pavine rather than an aporphine-isopavine structure.

4.01 d d f J 6 H Z )

ome 4.43 d d

(-1-1 7 8

[-)-1

79

4 O M e at

6 3.76(6H), 3.78(3H), 3.88(3H)

4 OMe at

6 3.75(3H), 3.76(6H), 3.91(3H)

4 ArH

6 6 . 4 8 ( 2 H ) , 6 . 5 2 ( 1 H ) , 6.6011H)

4 A r H at

6 6 . 4 5 ( 1 H ) , 6 . 4 9 ( 1 H ) , 6.55(2H)

at

The key information on the pavinoid portion of the molecule was provided by the 60-MHz ‘H-NMR spectrum, where two one-proton doublets at 6 4.06 and 4.50 represented the bridgehead protons of a 2,3,7,%tetrasubstituted pavinane

382

BELKIS G6ZLER

Me

Me0

’

Me

?

_____)

‘

Me0

Me0

+

\

M

e

t

i

a

o

M

e

OMe

&OMe

HZ

’

Me0

OH

Me0

\

0Me

I 10 0 Y o 1

’ OH

(5%)

I

Mf (36%)

“‘pMe Me0

Me0 -0Me

0

0Me

+

’I

Me0

\

(

2 6 ‘10 I

0.

Me0 &!Me

I 2 0 010 I

OH j

2 2 010 1

SCHEME41

(Section V,B). The upfield shift of the H-6’ to 6 4.35 and the downfield shift of H-9’ to 6 6.43 on acetylation were in conformity with what has been observed on acetylation of the phenolic monomeric pavine base, (-)-platycerine (14). The second dimeric base, (-)-pennsylpavoline (179), was shown to correspond to C-1-demethylpennsylpavine.Specifically, its NMR spectrum was devoid of the 6 3.7 1 singlet which represents the C- 1 methoxyl absorption in (--)pennsylpavine (178). Evaluation of CD spectra of these novel dimers and comparison with those of the aporphine (+)-N-methyllaurotetanine and the pavine (-)-platycerine led to the assignment of the absolute configurations as depicted in expressions 178 and 179. These dimers are probably derived biosynthetically from the aporphine-benzylisoquinoline dimers, (-)-pennsylvanine and (-)pennsylvanamine, which were found in the same plant (7,173).


383

X. Pharmacology Synthetic (*)-argemonine (5) has been resolved, and the enantiomeric methiodides were shown to display neuromuscular junction blocking properties as determined in vivo on cat hypoglossal nerve-tongue muscle preparations (116). The observed curarimimetic potency results from the quaternized nitrogen in the tetrahydroisoquinoline skeleton, a structural feature resembling the nondepolarizing blocking agents represented by the well-known bisbenzylisoquinoline, (+)-tubocurarine. The effect of stereochemical and configurational variations on curarimimetic potencies have been thoroughly investigated on the two compounds in question. It has been shown that there is a modest preference of the (S) configuration over the ( R ) configuration (about 2 : 1). The ED,, curarimimetic potency ratio is 1.7 : I for the (S) levorotatory argemonine methiodide to the (R) dextrorotatory analog (116). Quaternization of synthetic (&)-argemonine (5) with 1,lO-diiododecane led to the bisquatemary compound, N,N'-decamethylenebis(N-methylpaviniumiodide) (180), which was comparable in curarimimetic potency to (+)-tubocurarine (174). The enantiomeric and meso forms of this compound were, therefore, considered suitable probes for further pharmacological experiments. There is a significant preponderance of blocking activity by the (R,R) configuration over the (S,S) arrangement in the bisquaternary series. This is exactly the reverse of what has been established for the monoquaternary enantiomeric probes. The cause of this trend is not, however, immediately apparent. It should also be pointed out that the potency of the meso form with respect to the enantiomers was found to be dependent on the animal used for the assay (174).

M ""'QO eM0e

'

OMe

Me Me0

180

Various pharmacological activities have been attributed to the pavine alkaloids, but no pavinoid species has been claimed as a therapeutic agent. A

384

BELKIS GOZLER

number of naturally occurring pavines and some of their simple analogs have shown weak analgesic activity in mice ( 1 71). Alterations in aromatic substitution did not result in increased potency (171). Pain relieving and antiarrhythmic properties have been reported (38). (-)-Bisnorargemonine (6) caused slight to moderate inhibition of motor activity in mice; the central nervous system depressant effect was not significant enough to consider the alkaloid as a potential drug (13). During the antimicrobial activity screening of Thalictrum revolutum alkaloids, (-)-argemonine (5) and (-)-eschscholtzidine (8) were shown to be only weakly active against Mycobacterium smegmatis (42). The isopavine analog 181 has been reported to display varying pharmacological activity (147). Likewise, Nomoto and Takayama have reported that appropriately substituted pavine and isopavine compounds exhibit specific pharmacological activity, but no details have appeared (123).

181 REFERENCES

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INDEX A

Argentamine, 127, 162 Argentine, 123, 152 Argentinine, 33, 59 Aristolactam BII, 35 Aristolactam-N-glucoside, 32, 46, 61 Aristolactams, 32, 59 Aristolochic acid I, 43, 54, 57 Aristolochic acid 11, 44, 57 Aristolochic acid 111, 31, 58 Aristolochic acid IV, 31, 58 Aristolochic acids, 31, 40, 47, 54, 57 in insects, 302 Aristolochic amides, 31, 41, 59 Aristoloside, 3 1, 59, 60 Asimilobine, 33, 61 Aurodrosopterin, 205, 23 1

13-Acetoxyanagyrine, 125 Actinidine, 197, 212, 249 I-Acylisoquinolines, 3 Adaline, 202, 232, 280 Adlumidine, 23 Adlumine, 23 Albertamine , 13 1, 177 Albertidine, 129, 172 Albertine, 130, 177 Alkaloid LC-2, 123, 149 Alkylamines, in ants and insects, 197, 288 1-Alkylisoquinolines, 3 Allomatrine, 129, 139, 140, 172 Allomatrine N-oxide, 139 11-Allylcytisine, 122, 149 Aloperine, 128, 167 5-Alpha,9-alpha-dihydroxymatrine,131, 182 9-Alpha-hydroxymatrine, 131, 178 3-Alpha-hydroxysophoridine, 130, 180 Alpha-isosparteine, 135 4-Alpha-hydroxysparteine, 124, 156 Alteramine, 152 Amides, in ants and insects, 197, 204, 205, 288 Ammodendrine, 147 Amurensine, 327, 329, 331, 372 Amurensinine, 327, 329, 331, 346 Amurensinine N-metho salt, 328, 329, 332 Anabaseine, 196, 212, 248 Anhydroschumannificine, 73, 91 Antheroline, 18 Ants, alkaloids in, 194, 211 Apomorphine, Reissert synthesis, 14 Aporphine-pavine dimers, 38 1 1-Aralkylisoquinolines, 3 Argemonine, 319, 322, 324, 340, 342, 370, 383 Argemonine N-metho salt, 323, 328 Argernonine N-oxide, 323

B Baptifoline, 163 1-Benzylisoquinolines, by Reissert synthesis, 5 Beta-hydrastine, 23 Beta-isosparteine, 135 Bicuculline, 22 Biopterin, 299 Bisnorargemonine, 319, 324, 334, 340 Buchenavianine, 69, 78 Bulbocapnine, N-alkyl analogs, 15

C Caaverine, 17 Cadiaine, 162 Cadiamine, 121, 143 Calgunnenine, 126 Calpunnenine, 161 Camoensidine, 128, 165 Camoensine, 127, 165 Canthin-6-one model, synthesis, 25 Capitavine, 70, 78 Caryachine, 320, 322, 325, 335, 339, 371 39 1

INDEX

Caryachine N-oxide, 320, 323 Catalaudesmine, 127, 162 Catalauverine, 127, 162 Catatine, 53 Cepharadion A, B, 35, 51, 52 Cepharanone A, B, 35, 59 Chamaetine, 125, 159 Chromanone alkaloids, 67 UV-Spectra, 79, 92 IR-Spectra, 80, 92 MS-Spectra, 81, 93 NMR-Spectra, 81, 95, 96, 97 biosynthesis, 83, 97 Chrysin, 76 Cinegalleine, 126, 162 Cinegalline, 126, 162 Cinevanine, 126, 162 Cineverine, 126, 162 Coccinelline, 202, 232, 272, 274 Convergine, 202, 232, 272, 274 Cordrastine, 23 Corlumine, 23 Corunnine, 17 Corydione, 52 Cryptaustyline, 103, 106, 114 Cryptowoline, 103, 106, 111 Cularine, Reissert synthesis, 11 Cuspidaline, 33 1-Cyanoisoquinolines, 3 Cyclanoline, 33

D Danaidal, 199, 221 Danaidone, 199, 221, 259 Darvasamine, 129, 172 Darvasine, 129, 172 Darvasoline, 131, 181 Debilic acid, 31, 37, 59 Dehydrocrebanine, 48 Dehydroisoalbine, 122, 137 5,6-Dehydroisolupanine, 125 Dehydrolaudanosoline, 104 5,6-Dehydrolupanine, 124, 159 5,17-Dehydromatrine, 173 Dehydronantenine, 52 7,8-Dehydrosophoramine, 130, 176 13,14-Dehydrosophoridine,130,139,175 11,12-Dehydrosparteine, 125

12,13-Dehydrosparteine, 125 Deoxodihydroleontalbimine,174 Deoxomatrine, 130, 173 Deoxysepiapterin, 299 Desoxocamoensidine, 166 2,5-Diaikylpyrrolines, in ants, 256 Dihydroalbertine, 177 9,lO-Dihydroaristolochicacids, 45 Dihydroisocarbostyril, 3 Dihydrolactyllumazine, 201, 23 1 10,13-Dihydrolupanine, 126 Dihydronitraramine, 168 Dihydroxanthommatin, 201, 225, 271 Dimethamine, 123, 153 Dimethylphenethylamine, 209 4,5-Dioxodehydrocrebanine,5 1 10,13-Dioxylupanine, 160 Ditermamine, 127, 163 10,17-Dixo-beta-isosparteine,124, 155 Domesticine, 17 Doryfiavine, 41 Drosopterin, 205, 231, 301

E Eillipticine, 26 Ekapterin, 202, 230 Emetine, Reissert synthesis, 24 Epiaphylline, 124, 156 Epilamprolobine, 121, 142 11-Epileontidine, 128, 167 Epilupinine, 120, 140 Epimyrtine, 121, 144 Epipederine, 293 Erythropterin, 206, 230, 301 Escholamine, 6 Escholtzidine, 322, 325 Escholtzidine N-Metho salt, 321, 323 Escholtzine, 319, 321, 322, 325 Escholtzine N-metho salt, 323 Escholtzine N-oxide, 321, 323 13-Ethoxylupanine, 126, 162 Euphococcinine, 202, 232, 280

F Ficine, 68, 75, 84 Formylcinegalleine, 162 Fusenine, 35

393

INDEX

G Glomerin, 208,225 Goebeline, 131, 183

Isosophoramine, 181 Isosophoridine, 139,170 Isotincotorine, 122 Isoxanthopterin, 199,201,205,230,301 Isoxazoles, in insects, 296

H

J Harmonine, 202,237,288 Heliotrine, 260 3-Heptyl-5-methylpylizidine, 261 Hexahydrotinctorine, 151 3-Hexyl-5-rnethylindolizidine,270 Hippocasine, 202,232,273,276 Hippodamine, 202,232,272,276 Hispidulin, 76 Homoglomerin, 208,225 Homoisopavines, 378 Homopavines, 378 d-Hydrastine, 23 Hydrastine, 33 8-Hydroxyapomorphine, 14 10-Hydrox yapomorphine , 14 11-Hydroxyapomorphine, 14 7-Hydroxy-beta-isosparteine,124,155 Hydroxydanaidal, 199,201,221,260 2-Hydroxy-3,8-dimethoxypavinan,319,322 9-Hydroxymatrine, 178 8-Hydroxyquinoline-2-carhoxylic acid, 204,

225 I Ichthyopterin, 208,230 Imenine, 19 Intcgenirnine, 222 Isocaryachine, 320,335,338 Isocinevanine, 162 Isodrosopterin, 205,231 Isoficine, 68,75,84 Isokuraramine, 122,146 Isoleontalbine, 129 Isomatrine, 129, 139,140,171 Isonorargemonine, 322,326,334,374 Isopavine, 327 Isopavine alkaloids spectra, 365,369 biosynthesis, 374 Isopavines, unnatural analogs, 356 Isoschumanniphytine, 73,88

Jacobine, 222 Jacoline, 222 K Khombifoline, 154 Kuraramine, 122,146

L Lamprolobine, 120,142 Laudanosoline, oxidation of, 110 Lemannine, 130,175 Lemannine N-oxide, 139 Leontalhamine, 131,177 Leontalbine, 129,173 Leontalbinine, 129,174 Leontane, 181 Leontidine, 127,164 Leontifonnine, 122,145 Leontisrnidine, 177,179 Leontismine, 131, 181 Leucopterin, 198,230,301 Lindenianine, 124,157 Lupinine, 118,135,140 Lycopsamine, 200,221 M Magnaflorine, 33 Mamanine, 121,136,143 Mamanine N-oxide, 121 Matridine, 181 &-Matrine, 139 Matrine, 138,140 Matrine N-oxide, 138 Mecambridine, 21 9-Methoxy-ellipticine, 26 2,3-Methylenedioxy-4,8,9-trimethoxypavinan,

320,322 4-Methylpyrrole-2-carboxyiate, 257

394

INDEX

Monocrotaline, 222, 260 Monomorine I, 263 Monomorine VI, 270 Monomorines, 196 Munitagine, 319, 322, 336 Myrrhine, 202, 232, 273 Myrtine, 121, 144

N N-Acetylcytisine, 123, 148 N-Allylaloperine, 128, 167 N-Demethylbuchenavianine, 69, 78 N-Demethylcapitavine, 69, 70, 79 N-Ethylcytisine, 123, 148 N-Formylcytisine, 122, 148 N-Hydroxynitraramine, 128, 168 N-Methylaloperine, 128, 167 N-Methylanhydroschumannificine, 73, 91 N-Methylisoschumanniophytine,74, 89 N-Methylschumagnine, 74, 91 N-Methylschumannificine, 72, 90 N-Methylschumanniophytine, 74, 89 N-Methyltaiiscamine, 47 N-Methyltetrahydrocytisine, 122 N-(3-Oxobutyl) cytisine, 123, 148 Nandazurine, 17, 52 Nantenine, 52 Naringenin, 77 Neodrosopterin, 205, 23 I Neosophoramine, 130, 176 Nitraramine, 128, 168 Nitropolyzonamine, 263 Norargemonine, 319, 322, 326, 334 Norpontevedrine, 54 Nuttalline, 125, 159

0 0-Demethylbuchenavianine, 69, 78 0-Methylcryptaustoline, 105, 108, 114 0-Methylcuspidaiine, 33 0-Methyldauricine, 9 0-Methylthalisopavine, 328, 332, 346, 355 0,N-Bisdemethylbuchenavianine, 69, 78 Octahydromatrine, 173 Ommatine, 270 Ommochromes, in insects, 200 Orientalidine, 21 Orientaline, 34

Oxocampostelline, synthesis, 11 Oxocularine, synthesis, 11

P Papilochrome 11, 200, 271 Pavine alkaloids spectra, 362, 367 biosynthesis, 372 Pavines, unnatural analogs, 356 Pederamide, 290 Pederine, 203, 289, 292 Pederone, 203 Pennsylpavine, 381 Pennsylpavoline, 381 Petrosine, 121, 145 Petrosine-A, 121, 145 Petrosine-B, 121, 145 Phyllospadine, 69, 75, 76, 86 Piperidines, in ants, 195, 211, 238 Platycerine, 322, 324, 336 Platycerine N-metho salt, 323 Platycerine, synthesis, 13 Pohakuline, 121, 136, 143 Polyamines, in insects, 206 Polyzonimine, 208, 215, 258 Pontevedrine, 35, 52, 53 Precoccinelline, 202, 232, 272, 274 hestephanine, 34 Propyleine, 202, 232, 272, 276 Pseudopederine, 203, 288 Pterorhodin, 202, 231 Pteridines, in insects, 197, 230, 298 Pyrazines, in ants, 197, 200, 204, 218, 283 Pyrrolidines, in ants, 195, 214, 251 Pyrrolizidines, in ants, 199, 221, 259

Q Quettamine, synthesis, 12 Quinazolinones, in insects, 297 Quinolines, in insects, 270

R Reframidine, 328, 329, 332, 346, 352, 254 Reframine, 328, 329, 332, 346, 349 Reframine N-metho salt, 329, 338 Reframoline, 328, 329, 332, 336, 339, 348, 349

395

INDEX

Reissert anion reaction, 4 Remrefine, 327 Reticuline, by Reissert synthesis, 6 Retronecine, 260 Roemecarine, 376 Robitukine, 71, 89, 99 Rosmarinine, 203 Rugosinone, 7

S Sardosemine, 127, 162 Schumagnine, 74, 92 Schurnannificine, 72, 90 Schumanniofoside, 75 Schummaniophytine, 71, 87 Senecionine, 222 Seneciphylline, 222 Sepiapterin, 201, 208, 231, 299 Skatole, 198, 207 Solenopsins, synthesis, 238, 245 Sophocarpine, 184 Sophoranol N-oxide, 131 Sophorbenzamine, 131, 182 Sophoridine, 129, 139, 140, 169 Sophoridine N-oxides, 130, 139, 171 Sophorine, 121, 144 Stenusine, 203, 212, 246 Stephanine, 34 Subsessiline, 18 Supinidine, 260 T Takatonine, 6 Taliscanine, 32, 47

Tetramethoxy aristolochic acid, 47 Thalicmidine, 17 Thalidicine, 328, 329, 330, 332 Thalidine, 328, 329, 330, 332 Thalipoline, 320 Thalisopavine, 328, 329, 332, 346 Thermopsamine, 124, 156 Tinctorine, 122, 149 Trigonelline, 74 Trimethoquinol analogs, 9 Tsukushinamine A , 124, 137, 154 Tsukushinamines B and C, 124, 154 Tubemlactam, 32, 61 Tuberosine, 33 Tuberosinone, 33, 61 Tuberosinone-N-glucoside,33, 61

U Urocanic acid, 199, 237 Usaramine, 222

V Violapterin, 201, 231 Virgiboidine, 123, 149 Virgidivarine, 123, 138, 149 Virgiline, 158 Vochysine, 69, 77, 86

X Xanthommatin, 200, 205, 225, 270 Xanthopterin, 198, 230, 301


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