The Alkaloids, Volume 55: Chemistry and Biology (The Alkaloids)

CONTRIBUTORS

Numbers in parentheses indicate the pages on which the authors’ contributions begin.

PIRJO HANHIHEN (l), Laboratory for Organic and Bioorganic Chemistry, Technical University of Helsinki, FIN-02015, HUT Espoo, Finland LOUNASMAA (l), Laboratory for Organic and Bioorganic Chemistry, Technical University of Helsinki, FIN-02015, HUT Espoo, Finland

MAURI

JOSEPH l? MICHAEL (91), Centre for Molecular Design, Department of Chemistry, University of the Witwatersrand, Wits 2050, South Africa

vii

PREFACE

In this volume of The Alkaloids: Chemistry and Biology the recent progress on several quite different alkaloid groups is presented in two excellent chapters. The first, by Lounasmaa and Hanhinen, updates an area of indole alkaloids which has been neglected in the series for over 30 years, namely, the ajmaline group of alkaloids, where numerous advances in chemistry and biosynthesis have been made recently. The second chapter by Michael reports on the progress made in a vast area of alkaloid chemistry, those alkaloids with either an indolizidine or a quinolizidine nucleus derived from plant, marine animal, and fungal sources. Geoffrey A. Cordell University of Illinois at Chicago

ix

-

CHAPTER l-

THE AJMALINE GROUP OF INDOLE ALKALOIDS MAURI LOUNASMAA

AND PIRIO HANHINEN

Labonztory for Organic cmd Bioorgrmic Chemistry Technical University of Helsinki Espoo, Finland I. Introduction II. Occurrence III. Syntheses A. Masamune Synthesis of Ajmaline (17) B. Mashimo and Sato Synthesis of Isoajmaline (19) C. Mashimo and Sato Formal Synthesis of Ajmaline (17) D. Cook Enantiospecific Total Synthesis of (+)-Ajmaline (17) E. van Tamelen Proposal for a Synthetic Route to Ajmaline (17) F. Biomimetic Semisynthesis of Alstomacroline (SO) and Alstonisidine (78) IV. Reactions V. Biosynthesis and Biogenesis VI. Spectroscopy A. ‘H NMR Spectroscopy B. 13C NMR Spectroscopy C. Mass Spectrometry VII. Pharmacology VIII. Perspectives References L Inhoduction The ajmaline alkaloids have been reviewed only twice in “The Alkaloids” series (Z,2). Both articles appeared in the sixties and are substantially out-of-date. The need for a new review in the series is apparent. A review article in the series “Pnqyws in the Chemistry of Natuml Products” (3) was published in 1983, but even that will soon be twenty years old. Yearly summaries have been compiled by Saxton (4) and short reviews have occasionally appeared in connection with other topics (5-9). The present chapter covers the literature to October, 1999. Because of their close biogenetic relationship, earlier reviews (1-3) treated the ajmaline alkaloids together with the sarpagine alkaloids. The number of known structures in the two series has grown markedly, however, and to do this now would require a long and time consuming editorial process, which would diminish the relevance of the information when published. For this reason, we prefer to treat the THE ALKALOUIS, VOL. 55 0099-9598/01 $35.00

1

Copyright 0 2001 by Academc Press. All rights of reproduction in any form reserved.

2

MAURI LOUNASMAAAND

PIRJO HANHINEN

series separately, as was done in our recent review of the sarpagine alkaloids (IO). To facilitate a comparative use of the reviews, we have adopted a similar approach to the ajmaline alkaloids as we used for the sarpagine series. The number of known ajmaline structures (sensu sfticto) has grown markedly in recent years to a present count of 77 (compounds 1 - 77). Some of these might be artefacts and a few structures have not been convincingly determined (vide in@). In addition, seven bisindole alkaloids (compounds 78 - 84) containing at least one monomeric ajmalan unit have been isolated, increasing the total number to 84 (77 + 7). Ajmaline alkaloids contain the polycyclic ajmalan ring system [(except the rearranged perakan ring system (vide injm)]. The “biogenetic numbering” of Le Men and Taylor (11) is used throughout this article (Figure 1). It is noteworthy that the priority sequence for the C-17 substituents in the Cahn-Ingold-Prelog system is different in the absence and presence of the COOCH, substituent at C-16. Thus, for example, the 17R configuration in the absence of the COOCH, substituent and the 17s configuration in the presence of the COOCH, substituent correspond to the “same” three-dimensional arrangement of the substituents at C-17 (Figure 2). The 3-hydroxyajmaline derivatives [e.g. herbamine (85) and herbadine (86) (4)], which exist, in part, in the 2-acylindolenine form, and thus behave in a different manner, are not included in this review (Scheme 1). The various alkaloids of the seco ajmahnoid type [e.g. rhazicine (87), isorhazicine (88) and sandwicoline (89) (4)] are also excluded from the present review (Figure 3). In addition, some doubtful compounds of unknown structures (e.g. sandwicensine and ajmalinine), which have persisted in earlier lists of ajmaline alkaloids (I), have been rejected.

FIG. 1. Ajmalan ring system numberedaccording to Le Men and Taylor (11).

*

o$g$

FIG. 2. Application of the Calm-Ingold-Prelogpriority sequencesystem to mark the C-17 stereochemistryin the absenceand presenceof the COOCH, substituent.

1. THE AJMALINE

GROUP OF INDOLE ALKALOIDS

SCHEME 1. Equilibrium between the 3-hydroxyajmaline derivatives herbamine (85) and herbadine (86) and their 2-acylindolenine forms.

FIG. 3. Structures of rhazicine (87), isorhazicine (88) and sandwicoline (89), representing alkaloids of the 2,3-seco and 4,21-seco ajmalinoid types.

II. Occurrence All of the ajmaline alkaloids found thus far occur in the plant family Apocynaceae. To date, they have been recognized in the following genera: Alstonia, Aspidospenna, Cabucala, Melodinus, Rauvoljiti, Tonduzia (Alstonia), and Vinca. Of these, by far the most important genus is Rawova. A detailed account of the distribution of ajmaline alkaloids among different plant species is presented in order of increasing molecular weight in Table I. The alkaloid structures, with their melting points and [a], values where given, are presented in Table II. The CAS Registry numbers of individual compounds are indicated in both tables. The superscripts beside several of the compounds indicate plausible artefacts or structures which, in the writers’ opinion, are questionable or in need of supplementary confirmation.

l Of the two orthographiesused in the literature, Rauvolfia versusRauwolfia, the former is preferred in the present article.

3

P

308.4

294.4

292.4

MW

C20H24N20

CIdI22N20

Cl612ON2O

Formula

509-38-6

68160-76-9

36063-54-4

(+I-3

2

(+)-1

CAS Registry Number

(+)-Tetraphyllicine [Serpinine] [Semperflorine]

Nortetraphyllicine

(+)-Rauflorine

Compound

Rauvolfia Rauvolfia Rauvolfia Rauvolfia Rauvolfla Rauvoljio Rauvolfia Rauvolfia Rauvolfia Rauvolfia Rauvolfio Rauvolfio Rauvoljia

RauvoJfia Rauvolfia RauvolJia Rauvoljio Rauvolfia Rauvolfia Rauvolfia var. Rauvolfia Rauvolfia caffm cumminsii degencrt mauiensis m o m basiana nitida obscum oreogiton sandwicensis sellowii seventina suaveolens tetmphylla

caffm cumminsii macrophylla m o m basiana nitida oreogiton sempcrjlorenr sempetjlomns volkensii vomitoria

Rauvolfia confertiflom

Plant source(s)

AJMUINE ALKALOIDSO F PLANTORIGIN

TABLE1

23 24 25 25 16 17 26 27 2.5 28 29 30 31

20,21 22

13 14 15 16 17 18 19

12

Refs.

m

C2oH22N2O2

C20H24N202

C20H24N20Z

322.4

324.4

324.4

4360-12-7

326.4

C,oH2&J2O2

65 136-98-3

(+)-I7

16

(-)-15

(+)-14

30171-06-3

639-30-5

(+)-13

12

(+)-I 1

104748-99-4

70509-S 1-8

3911-19-l

CAS Registry Number

324.4

C20H24N202

C2oH22N2O2

322.4

324.4

Formula

MW

(+)-Ajmaline [Raugalline] [Rauwolfine]

Dihydronorpurpeline [Na-Demethyldihydropurpeline]

(-)-Ajmalidine

(+)-Norseredamine [N,-Demethylseredamine]

(+)-12-Hydroxymauiensine

Aspidosperma spegaszinii Melodinus bakmsae var. paucivenosus Rauvolfio balansae

mauiensis nitida salicgolia sellowii tettuphylla vomfton’a cumminsii

19

45 46

35 17 43 28 316 330 14,40,44

14 42 22

Rauvolfia cumminsii Rauvolfia sumatrano Rauvolfia vomiton’a Rauvolfia Rauvolfia Rauvolfia Rouvolfia RauvoJfia Rauvolfia Rauvolfia

36

22a

40 226,336,41

Refs.

Rauvoljia media

Rauvol$ia vomitoria

Rauvolfia cumminsii Rouvolfia vomitoria

Plant source(s)

I (Continued)

17-O-Deacetyl-12-methoxyvinorine [ 17-GDeacetyl-21-deoxy12-methoxyvomilenine]

(+)-Mitoridine

Compound

TABLE

ssp. balansae Rauvolfia balansae ssp. schumanniana var. basicola Rauvolfia boliviana Rauvoljio biauriculaia Rauvolfia caffm Rauvolfia cam bodiana Rauvolfia canescens Rauvolfia chinensis Rauvolfia confetiiflom Rauvoljia cubana Rauvolfia cummittrii Rauvolfla degeneri RauvolJia densiflom Rauvolfia fmticosa Rauvolfla hotemphylla Rauvolfia indecom Rauvolfa ligustrina Rauvolfia littomlis Rouvoljia macmphylla Rauvoljio mom basiana Rauvolfio nitida Rauvolfia obscum Rauvolfia oreogiton Rauvolfia pemkensis Rauvolfia schueli Rauvolfia sellowii Rauvolfia setpentina Rauvolfo sevenetii Rauvolfia spathulata

(continues)

47 48 49JO 51 52 53 54 55 24 25 56 57 58 59 60 61 37 16 17 26 27 62 63 28.64 65 19 19

19

MW

326.4

326.4

Formula

(+)-19

(+)-18

CAS Registry Number

509-37-5

6989-79-3

TABLE

Refs.

I (Continued)

Plant source(s)

336.75

32

cubana mauiensis sandwicensis sempeflorens sempeflorens sempeflorens viridis vomitoria

656 76

Compound

69 20 70 34,71 72

30 66 67 68

Rauvolfia suaveolens Rauvolfa tetmphylla Rauvolfia vcrticillata Rauvolfia verticillata var. hainanensis Rauvolfia verticillata var. rubriocmpa Rauvolfia viridis Rauvolfia volkentii Rauvolfia vomitoria Rauvolfia yunnanensis Tonduzia long$olia (+)-Sandwicine

Rauvolfa Rauvolfia Rauvolfia Rauvolfia var. Rauvolfia var. Rauvolfia

confertiflora sempeflorens vin’dis serpentina vomitotia

54 19

19,74

73 25 25 19

(+)-Isoajmaline

Rauvolfia Rauvolfia var. Rauvolfia Rauvolfia

(+)-23 (+)-24

(+)-25

26

2246-33-5

391 l-20-4

3382-93-2

336.4

338.5

338.5

(+)-22

70522-05-3

81525-52-2

336.4

(-)-21

(+)-20

336.4

34020-07-o

334.4

W-WV’,

6835-90-l

326.4

Vincamajoreine

(+)-Seredamine

(+)-Purpeline

(+)-Rauflexine

(+)-17-O-Acetylnortetraphyllicine

(-)-Vinorine [2 I-Deoxyvomilenine] [2-Deshydronortetraphyllicine]

(+)-Isosandwicine

24,44 226.41 226

Rauvol/ia cumminsii Rauvolfia vomitoria Rauvolfia vomitoria

(continues)

44 39 22,41

82

17

78 78 81

79 80 19,74

19.78

77 19378

33b, 75

I9

Rauvolfia cumminsii Rauvolfia mom basiana Rauvolfia vomiton’a

Rauvolfia reflera

Rauvolfia nitida

A lstonia yunnanensts Rauvolfia balansae spp. balansae Rauvoljin balansae spp. schumanniana var. basicola RauvoJfia caffm Rauvolfia perahensis Rauvolfia sempetjlorens var. vin’dis Rauvolfia sevenetii Rauvolfia spathulata Vinca minor

Rauvolfia sempetj7otenr var. viridis Rauvolfia vomitoria

C21H24N203

352.4

(-)-30

135649-95-5

(-)-32

(+)-31

(+)-29

73012-74-5

688-50-g

C20H26N203

342.4

(+)-28

99612-65-4

350.4

C,lH,P2O2

340.5

(+)-27

6109-18-7

4382-56-3

C21H26N202

338.5

CAS Registry Number

350.4

Formula

MW

Rhazyn stricta A lstonia yunnanensis Rauvolfia balansae ssp. balansae Rauvolfia biaun.culata RauvolJia caffm Rauvolfia pemkensis Rauvolfia sellowii Rauvolfia sprucei Rauvolfia sumatmna Rauvolfia volkensii Rauvolfia vomitoria Voacanga afn’cana Rauvolfia balansae spp. balansae

(+)-Perakine [Raucaffrine]

(-)-Vomilenine

Rauvolfia vomitoria

Rauvolfia serpentha

(-)-Leepacine

(+)-Ajmalinol

(+)-Sandwicolidine

Rauvolfia reflexa

Vinca elegantissima var. Vinca major Vinca major

[ IO-Methoxytetraphyllicine]

(+)-Reflexine

Plant source(s)

I (Continued)

Compound

TABLE

78

62 89 90 91 92 93 94

496,88

48

77 19

87

86

85

82

83,84

83

Refs.

33

34 (+)-35

107585-43-3

25926-60-7 36285-l 1-7

350.4

350.5

?]

(+)-Raucaffrinoline

17-O-Acetyltetraphyllicine

Raucaffriline [Z-Vomilenine

basic& biauriculata caffi sellowii revenetii spathulata vomitoria

.4 lstonia venenata Rauvolfia balansae spp. balansae Rauvolfia balansae spp. schumanniana var. basicola Rauvolfia coffra Rauvol/a nitida Rauvolfia sellowii Rauvolfia sempeflorens var. vin’dis Rauvolfia sevenetii Rauvol/io spathulata RauvolJia volkensii Rauvolfia vomitoria

Rauvolfia volkensii

Rauvol/ia caffra

VW. Rauvolfia Rauvo&x Rauvolfia Rauvolfia Rauvolfia Rauvolfia

(continues)

78 78 92 98

496,97 17 89 74

78

96 78

92

88a

48 79 89 78 78 95

78

352.4

352.4

352.4

MW

C21H24N203

C21H24N203

C21H24N203

Formula

38

(+)-37

21641-60-I

110044-96-7

(+)-Quebrachidine

(+)-36

4835-69-2

19,20-Dihydrovomilenine [ 1-Demethyl-2-dehydro17XLacetylajmaline]

(+)-Vincarine

Compound

CAS Registry Number

TABLE

I (Continued)

112 113 114 78

78

Rauvolfia balansae ssp. balansae Rauvolfia balansae ssp. schumanniano var. basicola

I07 108 I09 696 I10 110 Ill

99 100 101 102 103 104 105 106

Refs.

Vinca erecta Vinca herbacea Vinca major

A lstonia consm’cta A lstonia macmphylla Alstonfa muellenana A lstonia odontophom A lstonia spectabilis A lstonia sphaervcapitata Aspidospcrma quebmcho-blanco Cabucala eythrocarpa var. etythrocatpa Cabucala srriohsta Cabucala tondosa Rauvolfia discolor Rouvol/a viridis Rauvolfia vomiton’a Tabemaemontana undulata Vinca libanotico

Plant source(s)

K

(-)-45

163461-45-8

64986-27-2

380.4

380.4

48

49

(*)-SO (*)-St

65 19-30-S

108195-74-o

98301-75-g

not given

57800-02-9

380.5

382.5

394.5

394.5

396.5

(-)-47

46

44

19918-92-4

43

368.5

CAS Registry Number

1784-05-6

Formula

366.5

MW

138

A lstonia boulindaensis = A lstonia lanceolifera A lstonia sphaerocapitata

104

122

79

124~

135 84b,84c,136 137

84c,I306.134

118

496 92 33a.133

132

Refs.

Alstonia deplanchei

Rauvoljia caffra

A lstonia macrophylla

l’inca erecta Vinca major Vinca pubescens

Vinca major

Vinca major

Rauvolfia caffm Rauvoljia volkensii Rauvolfia vomiton’a

Vinca major

Plant source(s)

I (Continued)

(&))-IO-Methoxyvincamajine

(A))-Norvincamedine

21-Acetyl-19,20-dihydrovomilenineb

19-Hydroxy-19,20-dihydrovincamajine*

(-)-Majoridine [Majdinine]

Majorinine [ IO-Methoxyvomilenine]

(-)-IO-Methoxyperakine

17-GAcetylajmaline

17-Epivincamajine [Vinoamajinine]

Compound

TABLE

(-)-59

(-)-a0

(-)-61

142750-28-5

94444-3 1-2

24190-04-3

454.5

470.6

c2&30N204

%H3oW’s

438.5

(-)-58

94444-30-I

C&oWs

(-)-57

164176-14-I

424.5

438.5

56

19775-56-5

410.5

C24H2SN20S

55

107603-58-7

(-)-54

(-)-53

(-)-52

410.5

132268-03-2

132242-26-3

912-27-6

(%+-WV’4

C23H2SN204

408.5

396.5

396.5

(-)-17-U-Benzoylvincamajine

(-)-lo-Methoxyvincamedine N-oxide

(-)-I I-Methoxyvincamedine

(-)-lo-Methoxyvincamedine

(-)-Vincawajine

17,21-O,CJ-Diacetylajmaline

Ajmalinimine

(-)-Vincamedine [Vincamajine acetate]

(-)-I I-Methoxy-17-epivincamajine

(-)-1 I-Methoxyvincamajine

143 496 24 118 104 144

104

145 122

Rouvolfia serpentino Rouvo&o coffro Rouvolfo cumminsii Vinco mo~‘or A lstonio sphoerocopitoto A lstonio pittien’ = Tonduzio pittieri

A lstonio sphoerocapitoto

Alstonia mocrophylla Alstonio vieilloniii

(continues)

99 122 104 140 141 142

I39

139

A Istonio constricta A lstonto deplonchei Alstonio sphoerocapitato A lstonio undulota Vinco dij/onnis Vinca major

Alstonia pittieri = Tondusio pittten’

A lstonio pittieri = Tonduzia pittieri

;;;

(+)-64

3 1282-07-2

110941-51-O (+)-65

104998-32-5

512.6

520.6

520.6

61

68

69

(-)-70

154849-47-5

68160-77-o

144379-35-I

3 1148-63-7

530.6

532.6

546.6

546.6

66

(-)-a3

466-57-9

62

502.6

CAS Registry Number

64675-2 1-4

Formula

488.6

MW

(-)-l7-O-(3’,4’,5’-Trimethoxybemoyl)quebrachidine

4’-Hydroxy-3’,5’-dimethoxybenzoylvincamajine

17-O-(3’,4’,5’-Trimethoxybenzoyl)seredamine

A lstonia constricta

A lstonia angustifolia

Rauvolfia cumminsii

Alstonia macmphylla A lstonia vieillardii

Rauvolfia obscum Rauvolfia vomitoria

17-O-(3’,4’,5’-Trimethoxybenzoyl)ajmaline [Willicourtine] 17-O-(3’,4’-Dimethoxybenzoyl)vincamajine [Vincamajine 17-O-veratrate]

Rauvolfia serpentine

(+)-Ajmalimine

Rauvolfia co/m

Rauvolfia obscum Rauvolfia vomitotia

(-)-Rauvomitine

(+)-Raucaffricine

Rauvolfia vomitoria

Plant source(s)

Norrauvomitine

Compound

TABLE I cconrinued~

99,120

149

14

124b 122

38 148

147

88a,886

38 I46

22b.336

Refs.

5

(-)-71

(-)-72

(-)-73

(-)-74

75

(-)-76

77

(-)-78 (-)-79

(+)-80

not given’

71385-80-3

57800-05-2

57800-03-O

71385-81-4

57808-41-o

57800-04-I

36474-13-2 80765-85-I

199800-14-l

546.6

560.7

576.7

586.7

590.7

602.7

616.7

672.9

674.8

690.9

A lsronia boulindaensis = A lstonia lanceolifera A lslonia boulindaensis = Alstonia lanceoli/em Alstonia muellen’ana Rauvolfia reflexa Rauvol/ia sumatmna .4 lstonia macrophylla

(-)-lo-Hydroxy-17-O-(3’,4’,5’trimethoxycinnamoyl)vincamajine lo-Methoxy-17-O-(3’,4’,5’trimethoxycinnamoyl)vincamajine (-)-Alstonisidine (-)-Flexicorine

(+)-Alstomacroline

A lstonia boulindaensis = Alstonia lanceolifera A lstonia constricta

(-)-17-O-(3’,4’,5’-Trimethoxycinnamoyl)vincamajine

A lslonia boulindaensis = Alstonia lanceolifem

A lstonia boulindaensis = A lslonia lanceolijera

(-)-10.Hydroxy-17-O-(3’,4’,5’trimethoxybenzoyl)vincamajine

lo-Methoxy-17-O-(3’,4’,5’trimethoxybenzoyl)vincamajine

A lskwtia boulindaensis = A lstonia lanceolifem A lstonia vieillatdii

Alsfonia macrophylla

(-)-17-O-(3’,4’,5’-Trimethoxybenzoyl)vincamajine

(-)-1 -N-(3’,4’,5’-Trimethoxybenzoyl)quebrachidine [Norvincamajine N(l)-t&Omethylgallate]d

(continues)

152

91

I51

150

138

138

138

120

138

138

122

1380

l24b

z

f

c c

18

1. THEAJMALINEGROUPOFINDOLEALKALOIDS

19

lIL Syntheses A. hffwuma

SYNTHESIS OF AJMALm

(17)

Masamune el al. (158) were the first to present a total synthesis of ajmaline (17). Condensation between N-methyl-3-indolacetyyl chloride (90) and ethyl hydrogen A3-cyclopentenylmalonate (91) (in the form of Mg chelate) led to ketoester 92. Reaction of 92, first with methoxyamine (MeONH,) and then with LiAIH,, afforded epimeric a,y-amino alcohols 93, which were converted into the dibenzoyl derivative 94. Treatment of 94 with 0~0, yielded diol 95, which was cleaved with NaIO,+. Spontaneous ring formation followed, leading to the tricyclic aldehyde 96. Warming 96 with acetic acid at 5O’C for 1 h led to the tetracyclic aldehyde 97. Conversion of 97 into the cyan0 compound 98 was achieved by treatment first with hydroxylamine (NHzOH) and then with benzoyl chloride (PhCOCl). Ethylation with EtI, using triphenylmethylsodium in THF as a base, led to monoethyl derivatives 99. Removal of the benzoyl group from the ester with sodium methoxide afforded the hydroxy compound 100 which was oxidized with dimethyl sulfoxide (DMSO) and acetic anhydride to aldehyde 101. Acid-catalyzed cyclization of aldehyde 101 (equilibrium between the C-16 isomers) yielded the pentacyclic compound 102 which was hydrogenated to 103. Reduction of 103 with lithium triethoxyaluminium hydride led to the corresponding benzyl derivative 104, which, by hydrogenolysis, was converted to compound 105. Compound 105 was treated with LiAlH4 to afford the non-isolated imine 106 (apparently in the form of a chelate). Addition of water led first to aldehyde 17’(chano form), which mainly exists in the cyclized form 17 (Scheme 2). B. MASHIMOAND

SATO SYNTHESISOF ISOAJMALINE(~~)

The Mashimo and Sato synthesis of isoajmaline (159) starts from the ketone 107, which is a general synthetic intermediate in the ajmaline (and sarpagine) series. Ketone 107 was condensed with n-propanal to yield the propylidene derivative 108. Hydrocyanation of 10s led to compound 109, which was converted with dimethyloxosulfonium methylide (MezS’OCHz-) to the corresponding oxirane 110. Reductive oxirane cleavage by means of AlH, afforded the alcohol 111. Debenzylation, dibenzoylation, and selective 0-debenzoylation yielded, via compound 112, alcohol 113, which proved to be isomeric with the Masamune intermediate 100. Oxidation of 113 with DMSO-Ac,O gave aldehyde 114 which was equilibrated (114 * 115) and cyclized to 116. Compound 116 was hydrogenated to 117, which was first treated with the Meerwein reagent (Et,OBF,) and then reduced with NaBH, to afford compound 118. Reductive debenzylation of 118 led to compound 119, which Robinson (154) had earlier transformed to isoajmaline (19) via 120 (Scheme 3). C.MASHIMOAND

SATOFORMAL

SYNTHESISOF AJMALME(17)

Masamune and Sato (160) also presented a formal total synthesis of ajmaline

20

MAURI LOUNASMAAAND

PIRJO HANHINEN

(17). The general intermediate 107 (vidc supm) was transformed into the corresponding pyrrolidine-enamine 121, which, when reacted with chloroacetonitrile, afforded the nitrile 122. Epoxide formation led to compound 123, which was reductively cleaved to the alcohol 124. Hydrogenolysis of 124 yielded the debenzylated compound 125 which was dibenzoylated to the Masamune intermediate 98 (Scheme 4).

SCHEME 2. Masamunesynthesisof ajmaline (17). Reagents:i. A; ii. MeONH,; iii. LiAIH,; iv. PhCOCI; v. 0~0,; vi. NaIO,; vii. spontaneously;viii. AcOH, 50°C; ix. NH,OH; x. PhCOCl; xi. Na”Ph,C, THF, EtI; xii. MeONa; xiii. Ac,O, DMSO; xiv. HCl, AcOH, Ac,O; xv. H,/PtO,; xvi. LiAl(OEt),H; xvii. H,/PtO,; xviii. LiAIH,; xix. H,O.

1. THE AJMALINE

%-lEME

GROUP OF INDOLE ALKALOIDS

3. Mashimo and Sate synthesis of isoajmaline (19). Reagents: i. EtCHO, triton B;

ii. KCN; iii. Me,S+OCH;; iv. AIH,; v. H,/Pd/C; vi. PhCOCI; vii. MeOH (1% NaOH); viii. Ac,O, DMSO; ix. Ac,O, AcOH, HCI; x. H,/PtO,; xi. Et,O+BF6, NaBH,; xii. Hz/PI/C; xiii. LiAIH,; xiv. H,O. D. COOK ENANTIOSPECIFIC TOTAL SYNTHESIS OF (+)-AJMALINE

(17)

The first enantiospecific total synthesis of (+)-ajmaline [(+)-171 was developed by Cook et al. (Zbl). D-(+)-Tryptophan methyl ester (126) was converted enantiospecificaliy, via intermediate 127, to the optically active (-)-Nbbenzyltetracyclic ketone (-)-107, which was then transformed into the a$unsaturated aldehyde (-)-128. When compound (-)-128 was stirred with 3-bromo-4heptene in the Barbier-Grignard process conditions the 1,4-addition products 129qb

22

MAURILOLJNASMAAANDPIRJOHANHINEN

(together with 1,2-addition products) were obtained. The aldehyde function of 129a,b was protected as the ethylene acetal 130a,b. Oxidative cleavage (OsO,, NaIO,) of the olefinic bond in 130a,b yielded the epimeric aldehydes 131a,b. Epimerization of the undesired isomer 131b permitted access to the desired isomer 131a in X30% total yield. Catalytic debenzylation, followed by addition of acetic anhydride (Ac,O), led to the sarpagine ring system 132. When 132 was treated with acetic acid and cont. aqueous HCI for 3 h, and the mixture reacted with Ac20/HCI,, the 2-hydroxyajmaline derivative 133 was obtained in 85% yield. The alcohol 133 was hydrogenated (H,/PtO,) in the presence of BF,/Et,O to afford diacetylajmaline (56) and its 2-epi-analog 134. Hydrolysis of diacetylajmaline (56) (K(,CO,/HsO/MeOH) yielded (+)-ajmahne [(+)-171 (Scheme 5).

122

124

125

SCHEME 4. Mashimo and Sato formal synthesisof ajmaline (17). Reagents:i. pyrrolidine; ii. ClCH,CN; iii. Me,S+OCH;, DMSO; iv. AIH,; v. H,/Pd/C; vi. PhCOCI.

E. VAN TAMELEN PROPOSALFOR A SYNTHETIC ROUTE TO AJMALINE (17) Thirty years ago van Tamelen and Oliver (162) presented a synthetic route, which they claimed to lead, via the sarpagan ring system (“deoxyajmalal system”), to the six-ring indole alkaloid ajmahne (17). The “crucial steps” in their scheme were the regioselective formation of the A4@-iminium ion 136 (realized by decarbonylation; 135 + 136) and subsequent spontaneous bond formation between C-S and C-16 (spontaneous “biogenetic-type cyclization”; 136 + 137a * 137b) (Scheme 6).

1. THE AJMALINE

13Ob Ga)-HR

129b ~20~6

\

13lr c2o-k 131b GZO+@ OAC

66 c2-k~ 134b c-2Ha

k

132

23

GROUP OF INDOLE ALKALOIDS

133

R

P

”

SCHEME 5. Cook enantiospecifictotal synthesisof (+)-ajmaline (17). Reagents:i. PhCHO, MeOH, rt, 2h; ii. NaBH,, -3O’C to -lO”C, 3 h; iii. (MeO)sCHCH&HzCOOMe, TFA, CHCI,, A, 12 h; iv. NaH, MeOH, toluene, A, 4 h; v. HOAc, HCI, A, 12 h; vi. LDA, CICH,SOPh, KOH; vii. LiCIO,, dioxaae,A; viii. CHsCHsCH=CHCHBrCH,CH,, Mg/THF, 0°C; ix. HO-CH,-CH,-OH, pTSA; x. OsO.,fIHF/pyridine,NaHSO,; xi. NaIO&ieOH, 0°C; xii. NaOMe/MeOH, flash chromatographicseparation; xiii. H,/PdIC, DME, 2 d; xiv. Ac,O/DMAP; xv. HOAc/HCI, 3 h; xvi. Ac,O/HCIs, 18 h; xvii. H,/PtO,, CH,CI,, BF,/Et,O; xviii. K,CO,/H,O (5%) MeOH.

For a long time, the van Tamelen synthesis of ajmaline (17) via the “deoxyajmalal system” was authoritative in the field. However, in contrast to van Tamelen and Oliver, Lounasmaa and Hanhinen (163) were unable to detect a spontaneous “biogenetic-type cyclization”, and were unable to cyclize compound 138 (or similar ones) to the “deoxyajmalal ring system”(138 + 139 + 140) (Scheme 7).

The failure to realize a spontaneous “biogenetic-type cyclization” casts doubt on the results of van Tamelen and Oliver (162). It also places into question the proposed biogenetic formation of the sarpagine/ajmaline skeleton (vide in&z). In rationalizing their failure to repeat the van Tamelen cyclization, Lounasmaa and Hanhinen argued (164) that the shortest possible distance between the reactive sites

24

MAURI LOUNASMAAAND

PIRJO HANHINEN

C-5 and C-16 in intermediate 139 is about 2.70 A. This is far too large to permit bond formation between C-5 and C-16 (Fig. 4).

SCHEME 6. van Tamelen synthesis of ajmaline (17) via the “deoxyajmalal Reagents: i. DCWTsOH; ii. spontaneously.

system”.

133

SCHEME7. Attempts by Lounasmaa and Hanhinen to effect the spontaneous “biogenetictype cyclization” of van Tamelen. Reagents: i. m-CPBA; ii. TFAA [or i. m-CPBA; ii. TFAA; iii. KCN; iv. AgBF,].

FIG. 4. The shortest possible distance between the reactive sites C-5 and C-16 in intermediate 139. F. BIOMIMETIC

SEMISYNTHESIS OF ALSTOMACROLTNE (80) AND ALSTONISIDINE (78)

Le Quesne and ~011. (156, 157, 165) found that when macroline (141) and quebrachidine (36) were allowed to stand for 72 h in a dilute aqueous HCI solution at room temperature, they were converted into alstomacroline (SO), which is claimed

1. THE AJMALINE

GROUP OF INDOLE ALKALOIDS

25

to be naturally occurring in A Isfonia macmphylla (152). In the writers’ opinion the mild conditions needed for the reaction strongly suggest that alstomacroline (80) is an artefact. Treatment of 80 with BF&O at O ’C for 6 h led to alstonisidine (78) (Scheme 8).

80

78

SCHEME 8. Biomimetic semisynthesis of alstomacroline (81) and alstonisidine (79). Reagents:i. 0.2 N HCI, 2O“C, 72 h; ii. BF,/EtaO.

IV. Reactions At the outset we would like to emphasize the generally easy interconversion between ajmaline and sarpagine derivatives, schematically presented here for the not yet naturally found 1,2-didehydroquebrachidine (142) and polyneuridine aldehyde (143) (Scheme 9).

SCHEME 9. Schematic view of the interconversion between ajmaline and sarpagine derivatives.

%

Mp. 240-242’C (acetone) [c& +184’ (MeOH)(25)

[70509-79-41 Amorphous (22~) [a], n.r.

[61

[68160-76-91 Mp. 28O’C dec. (22~) [ulD n.r.

PI

\

IO-Hydmxynortetmphyliicine

N

OH

[(+)-4l [6883-73-41

N ’ Ho w3

(PY)OW

(+)-Mauiensine (17s)

:I T

blDZ7+21O

[68160-75-S] Amorphous (14) [a], n.r.

151

Nomitoridine

0

Nottetmphyllicine

OH

Mp. 221’C (MeOH) kdDZO+312’ (c 1.54, CHC1&(12)

Mp. 320-322T (acetone)(flu)

[(+I-31 [509-38-61

[36063-54-41

(+)-Tetmphyllicine

\

[(+)-ll

N

OH

(+)-Rauflorine

9

N H

0

AJMALINE ALKALOID STRUCTURES

TABLE II

2

N H

H

N

[aID +36' (c 0.67, CHCQ(30)

[65061-33-81 Mp. n.d. MD a0 (40)

[(*)-lo1

m’-b

I

(It)-Norpmpeline

-

’

0

[(+)-8l

[23944-24-31 Amorphous (30)

0

N

Endolobine 191 [67627-71-81 Mp. 26O’C dec. (39) [aID n.r.

9

I

(+)-Nomjmaline

OH

(+)-Nomjmalidine [71 [93552-59-l] Amorphous (13) blD24 +183.8’ (c 0.3, CHCl&(f3)

Ho N \

[70509-S l-8] Amorphous (22~) [aID n.r.

PI

17-O-Dercetyl-12-methoxyvinorine

OH

(continues)

(+)-Mitotidine K+)-w [3911-19-l] Mp. 322’C (MeOH + subl.)(ll) talD’8 +175O * 4O (c 1.04, py)(41)

0

[(+)-I41 [30171-06-31 Mp. 242-24% (CHC1&42) +32.6” f 0.5” (c 3.65, MeOH)(42) [aID22

(+)-Norseredamine

[(+)-I31 [ 104748-99-41 Mp. 260°C (36) [a], +lOO’ (c 1, MeOH)(36)

(+)-12-Hydmxymauiensine (17s)

[509-37-q Amorphous (75) [aID +180° (CHCQ(25)

(40)

Amorphous [aID n.r.

(+)-Sandwicine (17s)

K+)-w

(17s)

(anh.) (MeOH)(154)

Dihydnwoqmtpeline WI [65 136-98-31

Mp. 241-242°C (MeOH)(28) [alD25 -80’ (c 1, AcOH)(153)

OH

[a], +144' (c 0.8, CHC1&(154)

[(+)-171 [4360-12-71 Mp. 200-202’C

[639-30-51

(i-)-Ajmaline

[(-I-151

II (Confinued)

(-)-Ajmalidine

0

TABLE

(Jcc+b

N

ococy

[81525-52-21 Amorphous (17) blD22+41° (c 0.01, MeOH)(I7)

[(+Pl

[6835-90-l] Mp. 25O’C (MeOH aq.)(75) MDzo+I30 (c 1.18, CHCQ(75)

(+)-17-O-Acetylnortetmphyllicine

N

[(+wl

N H

(+)-lsosandwicine (17s)

‘I 9

[34020-07-O] Mp. 117-l 19’C (Et20)(77) [aI2 -33’ (c 0.05, CHCIJ(77)

t(-Pll

[6989-79-31 Mp. 265°C dec. (MeOH aq.)(lSI) [a]D'8 +72' (c, 0.7, CHCl&(fS4)

[(+)-w

N’

(-)-Vinotine

I T

(+)-koajmaiine

OH

T

I Y w3

N \

@=3

h

N

0

N

(+)-Putpeline [(+)-241 [2246-33-51 Mp. 155’C (ether/hexane)(QI) blDz5+333’ (CHCI,)(II)

q

/

Rauflexine [231 [70522-05-31 Mp. 154-l 55’C (EtOAc/petr. ether) (82~) [a], n. r.

WO

0

%

[(-)-3w [135649-95-S] Mp. n.d. [aID -91’ (MeOH)(87)

[(*PIa [99612-65-41 Mp. 213-214’C (EtOH:AcOEt 9:1)(85) [4D2o227’ (CHClJ(85)

Mp. 246-247’C (MeOH)(83) [a], n.r.

[3382-93-21

(-)-Leepacine

(+)-Sandwicolidine

PI

H

I(+)-291* [73012-74-S] Mp. 209-21O“C (benzeneiMeOH)(86) [4D3o +132” (CHC13)(86)

(+)-Ajmalinol

Vincamajoleine

OH

OH

[(+)-271 [6109-l&7] Mp. 26O’C dec. (acetone)(82u) [a],, +126” (CHC1&(82u)

1391l-20-41 Mp. 297’C (acetone + subI.) [aID’* +60” f 2” (c 0.74, CHClJ(41)

[(+wl

(17s)

(+)-Reflexine

(+)-Seredamine

TABLE II (Continued)

w L

(-)-Vomilenine w-321 [6880-SO-81 Mp. 207’C (MeOH)(95) [aID -720 (C 0.5, ~~)(95)

qcocy

OH

(+)-Quebmchidine

[(+I-361 [4835-69-21 Mp. 276-278’C (benzene)(fOSb) blDz6 +54’ (CHCl,)(IOSb)

17-O-Acetyltetmphyllicine [25926-60-71 Mp. n.d. [a], n.r.

(+)-Raucafftinoline I(+)-351b [36285-l l-71 Mp. 249-251’C (78) [aID +l I“ (CHCQ(78)


cZr

‘(p)s

‘HI)

LO'E

‘(sI-H

‘2~

1 -jl‘Oplr

‘2~

p dI'jI[

S‘d*Iy

(61) ‘801 ‘WI ‘LSI ‘L91 ‘891 ‘OLI ‘281 ‘(%OOI) ES1 ‘LLZ ‘162 ‘(+ti 80E :Sk’l (61) ‘@d 0~18 aas ‘(681) XI I-H ‘HI) 9I.L ‘(6-H ‘HI) 01.L YOI-H ‘HI) 18’9 ‘(ZI-H ‘HI) 99’9 ‘(61-H ‘ZH L =ar‘srr ‘b ‘9 ‘HI) zz’s ‘(LI-H ‘ZH 6 =‘I”I f ‘P ‘HI) ZL’P ‘(E-H ‘ZH SO >“‘r ‘ZH 1 --dPt‘Er ‘ZH 01 ==+“? ‘(PP)P ‘HI) ZYE ‘(d[z-H

'ZH 91 =d***op*r ‘(p)pp‘~~)

~L'I

‘(*I-H‘ZH

L ,6*‘s*r

‘p Jq ‘~1)

Et’1 tE13a3 ‘ZHH OOP) W4N H, :b-(+)I =‘!=W”W-(+I

:I~-(+)I awwWw?r.-(+I

‘ICI ‘WI ‘LSI ‘281 ‘ES1 ‘LLZ ‘162 ‘(%OOI ‘+J”I) 80E :SF’I ‘aIq81!8AP BlEp ON :HI

s ,dg‘Sr ‘zH ZI =d@g r ‘PP ‘HI)

(It) ‘=V aas ‘(0)

zg.1 ‘(~~-H'zH

‘(P)PP ‘HI) L6’Z ‘(S-H ‘ZH I w”g’s r ‘ZH S =dg’sr ‘ZH L =g1‘5r ‘(P)PP ‘HI) 68’2 ?H~-N ‘s ‘HI) SL’Z ‘(91-H ‘ZH P ~l’slr ‘ZH L zgl‘jf ‘ZH 6 =L1‘glr ‘(p&p ‘HI) pp’z ‘(d*I-H ‘w 1 QPI’Er ‘zH p ,ZI’dPI r ‘ZH PI =dp’%lr ‘(P)PP ‘HI) SO’Z ‘(‘39-H ‘ZH I -ug'sr ‘2~ ~1 =dg“'gr '(p)p ‘HI) ~O'Z‘(IJPI-H ‘ZH 1 -sl"D+"f‘~~ 01 =orl'Ef

=dg"gf ‘(p)p ‘HI) L S‘81r‘p '~‘HI)

LP'Z py1

‘@PI-H ‘ZH ‘(~PI-H‘zH

1 -sl‘Dpl[ I JPI'Q‘zH

‘ZH 01 =wl‘E[ 5 =jt‘d~I

r ‘ZH

‘ZH

'(p)pp‘HI)

88'1

‘(dg-H

PI =dP1’DP1r‘(P)PP ‘HI) ZP’I :ka3

~1 =d*@rIr

s 3‘5y

‘q

:h-(+)I wowW+)

‘ZHyv OOP)ll.lw

‘ZH

H,

51

(ZZ) ‘OEI ‘VP1 ‘891 ‘691 ‘t81 ‘P81 ‘E9Z ‘(+t’@ 767 :Sk’J (061) OW aas ‘(681) X~-H ‘HI) zz’L ‘(II-H ‘HI) 0I.L YOI-H ‘HI) 58.9 W-H ‘HI) LL’g ‘(6I-H ‘ZH L >Etf ‘ZH 1 -dPI'E P ‘ZH 01 =q“E1 ‘(PP)P ‘HI) 6S’E ‘ (dr z-H‘DIZ-H ‘JaP ‘HZ) OS’E ‘(Z-H ‘ZH SO >“r ‘(p)s ‘HI) LE’E ‘(S-H ‘(P)PP ‘HI) ZT’[ ‘(SI-H ‘ZH I w5+pIf ‘ZH 5 ,gI‘jIy ,jI’d*Ir 'pp ‘HI) ~1.c ‘(91-H 'ZH 5 =91'5lr ‘ZH L ,91'5r ‘(~)~p ‘HI)

‘(Ur ‘HE) $Z’I :((Khl

@ZZ) ‘LII ‘OtI ‘Et’1 ‘WI ‘891 ‘691 ‘OLI ‘P81 ‘6PZ ‘E9Z ‘LLZ ‘E6Z ‘(%ooI ‘+l@ P6Z :SYI (ozz) XZI-HI I-H ‘OI-H ‘ZH~V 09) m H, :(Z) aup!I[kIdvnapoN

‘6-H I”I ‘HP) CL-9’9 ‘@P ‘HI) E’S ‘(s ‘HI) 8’s ‘(w ‘HZ) SS’E ‘(P ‘HZ) I’c ‘(S ‘HI) O’Z ‘(S ‘I-II) ~8.1 ‘(P ‘HE) WI

-=“’ f ‘ZH ‘(81~H‘ZH

69'1

S’s*r ‘b Jq ‘HI) 1~'s ‘(E-H ‘ZH ~'0 ‘ZH I w”9’sr ‘w 5 =dg’rf ‘ZH L =‘*“[ 85’2 ‘@9-H ‘=H 1 ZI =dg"ogf'pp'~l)

P 00

III (Continued)

[(+)-71:

0.95 (3H, L H-18),

3.8 (IH, d, H-2), 4.3 (IH, 9, H-3), 6.5-7.4 (4H,

(+)-Mitoridine [(+)-111: ‘H NMR: No data available. 294, 293, 214, 199, 198, 173, 160. (41) MS: 322 0,

(*)-Norpurpeline [(*)-IO]: ‘H NMR (60 MHz, (CD&SO): 1.6 (IH, m), 2.5 (2H, s), 3.70 (lH, d, H-2), 3.80 (3H, s, Ar-OCH3), 6.55-6.70 (3H , m, H-9, H-10, H-l I), 8.32 (lH, s, NH). (40) MS: 322 @I+, 100%). 293, 211, 199, 198, 174, 173, 160, 108, 98. (40)

Endolobine (9): ‘H Nh4R (CDCI,): 1.60 (3H, H-18), 3.75 (3H, s, -OCH,), 5.18 (lH, q, H-19), 6.64 (3H, m, H-9, H-11, H-12), 8.27 (IH, s, NH). (39) MS: 322 @f+, lOO%), 294, 293, 279, 265, 214, 213, 200, 199, 198, 186, 174, 173, 160, 108. (39)

(+)-Norajmaline [(+1-S]: ‘H NMRz No data available. MS: 312 (h4+), 297, 283, 183, 182, 169, 168, 144, 143, 131, 130. (30), see also (37)

‘H m:

1.5 W, m, 2 x H-19), 2.1 (I-4 s), 3.15 (IH, m, H-21), 3.55 [ (lH, m, H-9 (sic!)], m, H-9, H-10, H-l 1, H-12). (13) MS: 310 (X4+), 295, 293, 282, 281, 184, 183, 180 (lOO%), 169, 168, 144, 143, 130. (13)

(+)-Norajmalidine

IO-Hydroxynortetraphyllicine (6): ‘H NMR: No data available. MS: 310 @I+. lOO%), 309, 279, 256, 200, 199, 186, 185, 184, 164, 159, 146, 113. (Z2a)

Normitoridine (5): ‘H NMR: No date available. MS: 308 @I+, lOO%), 279, 265, 200, 199, 198, 173, 172, 160, 146, 108. (14)

TABLE

Dihydronorpurpeline (16): ‘H NMR: No data available. MS: 324 (A@). (40)

(-)-Ajmalidine [(-)-151: ‘H NMR: No data available. MS: 324 (A4+), 296,295, 198, 183, 182, 157, 144 (100%). (205) see also (201)

(+)-Norseredamine [(+)-141: ‘H NMR (100 MHz, (CD&SO): 1.61 (3H, d, J = 6 Hz, H-18), 3.74 (3H, s, Ar-OCH& 4.22 (lH, s, H-17), 4.9-5.4 (IH, m, -OH), 5.15 (lH, q, J = 6 Hz, H-19), 6.5-6.8 (2H, m, H-10, H-11), 7.05 (IH, g, J = 6.5 Hz, J = 2 Hz, H-9). 8.31 (lH, s, NH). (42) MS: 324 @I+, lOO%), 293, 200, 199, 198, 184, 173, 164, 160. (12)

(+)-12-Hydroxymauiensine [(+)-131: ‘H NMR (400 MHz, CDCI,:CD,OD 3:2): 1.25 (lH, dd, J,,cp= 12 Hz, J,,ep= 5 Hz, H-6P), 1.65 (lH, br d, Jt,,,,= 7 Hz, H-18), 1.85 (IH, dd(d), Jt&,,+= 14 Hz, J3,,&= 10 Hz, J,%,,,-- 1 Hz, H-14@, 2.00 (IH, d(d), J6c,at-,=12 Hz, J,,,,- 1 Hz, H-6a), 2.20 (IH, dd(d), J14cl,p= 14 Hz, J,,,,,s- 4.5 Hz, JJ,t49- 1 Hz, H-14P), 2.50 (IH, dd(d), Jt,,t,= 9 Hz, Js,,,= 7 Hz, Jls,,e- 4.5 Hz, H-16), 2.94 (IH, dd(d), Js,,s= 7 Hz, J,,c9= 5 Hz, Js,&-- 1 Hz, H-5), 3.06 (lH, s, N-CH,), 1 Hz, H-15), 3.07 (lH, s(d), JV’ 0.5 Hz, H-2), 3.32 (lH, d, Jzlc,zlp= 15 Hz, H-21@, 3.48 (lH, d, J21c52,p= 3.03 (M W4>J,,al,= J15,,g- 4.5 Hz, JI,,,,15 Hz, H-2lfQ 3.63 (lH, dd(d), J3,14a= 10 Hz, Js,+,9- 1 Hz, J2s< 0.5 Hz, H-3), 4.68 (IH, d, J16,,,= 9 Hz, H-17), 5.25 (lH, br ct. J,,,,c= 7 Hz, H-19), 6.63 (lH, H-IO), 6.68 (2H, H-9, H-l 1). (36) MS: 324 (l/l>, 307,293, 199, 198. (36)

17-O-Deacetyl-12-methoxyvinorine (12): ‘H NMR (60 MHZ, CDsOD): 1.2 (3H, br s), 1.66 (3H, d), 1.88 (lH, s), 3.08 (3H, d), 3.58 (IH, br s), 3.78 (3H, s), 5.35 (lH, m), 6.81-7.87 (JH, m, H-9, H-10, H-l 1). (220) MS: 322 @A+, lOO%), 321,294,279, 200, 199, 198, 173, 160, 134, 130, 109, 108. (22~)

s

(+)-Isosandwicine [(+)-20): ‘H w (“00 MHZ, CDCQ: 1.00 (IH, t, J,g,,g= Jlqy= 7 HZ, H-181, 1.32 (IH, dd, Jasep= 12 HZ, J,,,p= 5 HZ, J2,ap- 0.5 Hz, H-6P), 1.33 (lH, m, J20,21= 7 HZ, J,,p- 1 HZ, H-201, 1.41 W-L m, H-191, 1.68 W-L m, H-19), 1.73 (lH, def, H-14a, H-14P), 2.00 (IH, m, JtI,,- 5 HZ, J,4p,ls- 4 Hz, J,,,,,,- 1 Hz, J14a,15< 1 Hz, H-15), 2.04 (lH, d(d), Jcapp= 12 Hz, J1,,- 1 Hz, H-6a), 2.46 (lH, ddd, J,,,,,= 9 Hz, J5,16=6 Hz, Jls,16” 5 Hz, H-16), 2.82 (lH, s, N-CH,), 3.04 (IH, s(d), JZap- 0.5 Hz, JZ3< 0.5 Hz, H-2), 3.56 (lH, d(dd), J3,,4cI- 10 HZ. Js,,~P