Vincadifformine derivatives

Trichophylline, a novel alkaloid isolated from the roots of Catharanthus trichophyllus, has the structure 131, according to X-ray crystal structure analysis (145). Reduction of trichophylline with sodium borohydride gives an unsaturated lactone, formulated as 132. Oxidative fission of the C/D ring system in vincadifformine derivatives has been observed previously hence, trichophylline may arise by oxidation at C-21 of an appropriate precursor, such as a 19-hydroxytabersonine (88) or 108, to the hydroperoxide 133, followed by fission of the 20,21-bond and simultaneous migration of C-18. 

Reaction of vindoline (3) with the chloroindolenines derived from vin-cadifformine (127a), iJ -vincadifformine (133), -tabersonine (133a), or synthetic pandoline (34) (7/5, 116), followed by reduction of the resulting imines 145 and 145a (Scheme 40) with potassium borohydride, had given... 

Terpenoid Indole Alkaloids.—Important recent work has defined strictosidine (97) as a key intermediate in the biosynthesis of terpenoid indole alkaloids with both 3a- and 3/3-configurations. Some of this work, published earlier in preliminary form (cf. Vol. 9, p. 18), is now available in a full paper.26 In addition to those alkaloids examined earlier, strychnine, gelsemine, vincadifformine, isoreserpiline, aricine, isoreserpinine, and ajmaline have been shown to derive from strictosidine (data are also included for ajmalicine, for catharanthine, and for vindoline which had been reported earlier). 

Vincadifformine and tabersonine derivatives are selectively brominated at (C-ll) by Br2/HF/SbF51047. Significant amounts of 2-bromopyridine derivatives are obtained by bromination of lutidines in 20% oleum at 155-175 °C1048. 

The influence of aromatic substituents (chlorine, bromine, or nitro-groups) on the ease of oxidative rearrangement of derivatives of vincadifformine into derivatives of... 

A dihydroxy derivative of vincadifformine, formulated as 14,15-dihydroxyvincadifformine (101), has been isolated from Hazunta modesta var. modesta subvar. montana (103). Unfortunately, the paucity of alkaloid obtained precluded determination of its stereochemistry. 

Goniomitine (135), an alkaloid of a new structural type from the root bark of Gonioma malagasy E. May, is apparently the result of a much more far-reaching transformation of a vincadifformine precursor (146). Its structure was deduced on the basis of an analysis of its NMR spectra, including a comparison of its C chemical shift data with those of tryptophol and guettardine (136). It is included in this group on the basis of its presumed derivation from vincadifformine (77) by a series of plausible, unexceptional... 

In recent years some alternative, more refined, and higher yielding processes have been developed. One method that employs milder conditions than the earlier ones and avoids the formation of the N, -oxide involves ozonization of vincadifformine (76) in 0.43 M sulfuric acid in methanol at 60°C, which gives a 74% yield of a 7 3 mixture of vincamine (286) and 16-epivincamine in a one-pot reaction (276). Here again the 16-hydroxyindoienine derivative 285 is an intermediate, since it can be isolated if the ozonization reaction is conducted at 20°C. The stereochemistry of 285 follows from its reaction with potassium cyanate in dii clohexyl-lS-crown-6 and methylene chloride, which affords the hexai cUc urethane 294. Similarly, the ozonization of tabersonine (78) at 65°C affords a 71% yield of a mixture of 14,15-didehydrovincamine (287) and its 16-epimer (276). 

The same group of workers have also investigated the dye-sensitized photo-oxygenation of vincadifformine. After reduction of the reaction mixture with sodium thiosulfate, the related 16-hydroxyindolenine derivative 285 was obtained, which (without isolation) was rearranged in acetic acid to vincamine in 46% yield. Tabersonine behaved similarly (277). These results are broadly in agreement with those obtained by L6vy and his collaborators in an independent study of the photochemical oxidative rearrangement of vincadifformine (218). 

In all the preceding reactions the rearrangement of the vincadifformine skeleton to the eburnane skeleton was achieved via a 16-hydroxyindolenine derivative, such as 285 the analogous rearrangement of the 16-chloro deriv-... 

The photo-oxidation of vincadifformine (76) in the presence of Rose Bengal and potassium cyanide affords the nitriles 317 and 318, presumably by nucleophilic attack by cyanide ion on the appropriate C-3 or C-5,iVb-iminium ion iV-acetyl-2,16-dihydrovincadifformine gives mainly the 3a-cyano derivative (227). Tabersonine (78) and N-acetyl-... 

The alkaloids of the vincadifformine group are extremely difficult to quaternize at N, . In fact, attempts to form the b-methiodide from 2,16-dihydrotabersonine 323 result in the formation of the Ng-methyl derivative, and the A a-trifluoroacetyl derivative of 323 fails to react with methyl iodide in methanol. Interestingly, when 2,16-dihydrotabersonine is acylated with... 

The Kuehne biomimetic synthesis of alkaloids of the vincadifformine group (vide infra) proceeds via a transient secodine derivative, which is not usually isolated. However, in one of two syntheses of minovincine (265)... 

Kuehne s prodigious output on the synthesis of the anilinoacrylate alkaloids began with a sjmthesis of vincadifformine (76) and its 11-methoxy derivative, ervinceine (87) (328,329). The basic strategy involved the construction of a spirocyclic ammonium salt 552 from either the tetrahydro-iS-carboline derivative 553 (328) or the isomeric y-carboline derivative 554 (329), presumably via the common intermediates 555 and 556. When treated with base, ring C in the spirocyclic ammonium salt 552 was opened by... 

Later, a modified version of the synthesis was reported, in which the important secodine precursor is a tetrahydro-jS-carboline derivative, such as 557-559, rather than an indoloazepine ester, as in 560. This led to a simpler synthesis, the tetrahydro-/3-carboline derivatives required for the preparation of 557-559 being obtained directly from the appropriate trypt-amine derivative and pyruvic acid ester. By this route, ( )-vincadifformine (76), ( )-minovine (A g-methylvincadifformine) and ( ) ervinceine (87) were synthesized in comparatively high yield, and in essentially two stages from the starting tryptamine (330). 

The synthesis by Das et al. (338) started from the previously prepared protected indoleacrylic ester derivative 579, which was activated by mesyla-tion and oxidation and condensed with an appropriate aminoacetal to give the indoloazepine derivative 580. Release of the aldehyde function, followed by cyclization to the quaternary anunonium ion, fragmentation to the secodine 418b, and spontaneous cyclization, then gave vincadifformine (76) in 50% overall yield from 579 (Scheme 72) (338). 

Following their recent synthesis of ( )-vincadifformine (Scheme 75) (343,344), Szantay and his collaborators have contributed another s3mthesis of pseudovincadifformine and its epimers (392). Condensation of the trypt-amine derivative 587 with the aldehydoester 698 gave, via an unstable secodine derivative, the epimeric tetracyclic esters 715, which, without separation, were subjected to debenzylation, with partial epimerization and cyclization. The product, a mixture of the two cis C/D-fused pentacyclic... 

Ervinceine (40j), ervamycine (40k), and ervindnine (401) have been given5lc overall structures, without stereochemistry, which show that they correspond to the 11-methoxy-derivatives of vincadifformine, tabersonine, and lochnericine respectively. 

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