The alkaloids chemistry and biology vol 55

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 numerou

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

MAURI LOUNASMAA (l), Laboratory for Organic and Bioorganic Chemis- try, Technical University of Helsinki, FIN-02015, HUT Espoo, Finland

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

vii

PREFACE

gress 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

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)

“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

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 numbered according to Le Men and Taylor (11)

FIG 2 Application of the Calm-Ingold-Prelog priority sequence system to mark the C-17 stereochemistry in the absence and presence of the COOCH, substituent

1 THE AJMALINE GROUP OF INDOLE ALKALOIDS 3

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,

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

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 orthographies used in the literature, Rauvolfia versus Rauwolfia, the former is preferred

in the present article

z

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

pentacyclic compound 102 which was hydrogenated to 103 Reduction of 103 with lithium triethoxyaluminium hydride led to the corresponding benzyl derivative 104,

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

dimethyloxosulfonium methylide (MezS’OCHz-) to the corresponding oxirane 110

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)

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

%-lEME 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

LiAIH,; xiv H,O

The first enantiospecific total synthesis of (+)-ajmaline [(+)-171 was developed

by Cook et al (Zbl) D-(+)-Tryptophan methyl ester (126) was converted

benzyltetracyclic ketone (-)-107, which was then transformed into the a$- unsaturated aldehyde (-)-128 When compound (-)-128 was stirred with 3-bromo-4-

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,,

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)

ii ClCH,CN; iii Me,S+OCH;, DMSO; iv AIH,; v H,/Pd/C; vi PhCOCI

Thirty years ago van Tamelen and Oliver (162) presented a synthetic route,

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

(Scheme 6)

1 THE AJMALINE GROUP OF INDOLE ALKALOIDS 23

“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)

S C H E M E 6 van Tamelen synthesis of ajmaline (17) via the “deoxyajmalal system” Reagents: i DCWTsOH; ii spontaneously

133

SCHEME 7 Attempts by Lounasmaa and Hanhinen to effect the spontaneous “biogenetic- type 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

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

(143) (Scheme 9)

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

8

35

37

42 MAURlLOUNASMAAANDPIRJOHANHlNEN

A TRANSFORMATION OF VOMILENINES INTO PERAKINES

Compounds such as perakine (31) and raucaffrinoline (35), with their rearranged ajmaline structures, are now considered to be artefacts, formed from E- vomilenine (32) during the isolation process (166)

A striking general feature of compounds 31 and 35 is that the C-19 methyl group is p (when the quinuclidine ring system is considered) Another interesting point is that, in their formation, the attack during the recyclization procedure can take place only from the P-side In the case of E-vomilenine (32), this would lead,

which has never been detected (Scheme 10) In view of this, Lounasmaa and Hanhinen have recently suggested that “alkaloids” 31 and 35 are formed from Z- vomilenine (raucaffriline? vide sups) (33) rather than from E-vomilenine (32)

to perakine (31)

Partial reduction of the formed perakine (31) (Cannizzaro reaction) then easily affords raucaffrinoline (35)

1, THE AJMALINE GROUP OF INDOLE ALKALOIDS 43 Takayama et al (1676) have shown that both synthetic E-vomilenine (32) and synthetic Z-vomilenine (33) are transformed to perakine (31), but the latter is transformed much faster and under less drastic conditions This supports the assumption that perakine (31) is “directly” formed from Z-vomilenine (33) (vide supm), which is more or less totally “consumed” during the isolation procedure and which is thus difficult to detect as a naturally occurring alkaloid

A similar procedure starting from majorinine (lo-methoxy&vomilenine) (46) can be expected to lead, also via its Z-isomer, to IO-methoxyperakine (45) and then, after reduction and acetylation [lo% acetic acid was used in the applied extraction procedure (Il8)], to vincawajine (57) (167~)

B TRANSFORMATION OF AJMALINE INTO RAUMACLINE

An efficient transformation of ajmaline (17) into raumacline (144), which

is a biotransformation product of ajmaline in cell cultures of Rauvolfia serpentina, was developed by Endress and Stockigt (168) Ajmaline (17) was reduced with NaBH4 in citrate/phosphate buffered solution (pH 6.0) to 4,21-secoajmaline (145) which, by riboflavin-sensitized photo-oxidation, afforded raumacline (144) in 86% total yield (Scheme 13)

a-l

*@ iJ&

SCHEME 13 Transformation of ajmaline (17) into raumacline (144) Reagents: i NaBH,,

C USE OF AWINE IN THE PARTIAL SYNTHESIS OF (-)-2O-