Bisindole alkaloids

COLLECTIVE TOTAL SYNTHESIS OF TRYPTOPHAN-DERIVED ALKALOIDS 513 

SCHEME 14.4 New /ROC sequence and syntheses of 1,2-dehydroaspidospennidine, aspidospennidine, and vincadifformine. 

Tambar s group [57] and Prof. Mohanunad Movassaghi s group [58] reported the first total syntheses almost at the same time. After that. Prof. Jieping Zhu [59] and Prof. Xiao-Jiang Hao [60] finished their syntheses based on different synthetic strategies. 

In their isolation paper, Hao and cowoikers proposed a biosynthesis that conunenced with the coupling of tryptamine and kynuramine (Fig. 14.15). On the other hand. Prof. Uttam K. Tambar, coworker Xiangbing Qi, and Hongli Bao proposed an alternative biogenetic pathway, which involves an oxidative aryl-aryl coupling of two tryptamine derivatives to 

SCHEME 14.5 Tambar s total synthesis toward (+)-trigonoliimine C. 

The dimeric mould metabolite ditryptophenaline (186) has been very simply synthesised, albeit in only 3% yield, by the oxidative dimerization of cyclo-L-N-methylphenylalanyl-L-tryptophan 

Serpentinine has been found to occur in the root bark of 

Rauwolfia nitida. The stem bark of Strychnos decussata and S. 

Since the proton n.m.r. spectrum contains only four aromatic 

Four of the twenty-two alkaloids of the bark of Peschiera echinata are bisindole alkaloids these are voacamine, N-demethyl-voacamine, demethoxycarbonylvoacamine, and voacamidine. 

The application of infrared circular dichroism (IRCD) in the determination of absolute configurations has been discussed, with particular reference to caly-canthine.109 

Roxburghine D and a hitherto unknown stereoisomer, roxburghine X, have been isolated from Uncaria elliptica as yet, nothing is known about its stereochemistry. 

Details of the X-ray determination of the structure of geissospermine have now been published,111 and the relative stereochemistry of the secamines, the presecamines, and their synthetic analogues has been discussed.1116 

Tchibangensine (181) has been synthesized simply by condensation of tryp-tamine with geissoschizoic acid (182), followed by cyclization (by POCl3).lllc Reduction with sodium borohydride gives two C-17 epimers, which on hydrogenation afford the alio-isomers ochrolifuanine C and ochrolifuanine D. 

Among the alkaloids of the leaves and stem bark of Alstonia odontophora are pleiocorine (183), pleiocraline, and a new alkaloid which proves to be Na-desmethylpleiocorine (184), since on methylation (with CH20, NaBH3CN, and AcOH) it yields pleiocorine (183).59 

Calycanthine has been isolated44 from Pausinystalia macroceras this is the first report of the occurrence of this alkaloid in this genus. 

Details of the X-ray crystal-structure analysis of the bis-strychninoid alkaloid sungucine have been published,132 as well as details on the chemical and crystallographic determination of the structure of bonafousine.133 Isobonafousine (304), another constituent of the leaves of Bonafousia tetrastachya (Humboldt, 

Bonpland, et Kunth) Mgf., is composed of the same monomeric units, but the junction here is between C-12 of the hydroxycoronaridine component and a position adjacent to Nb in the hydrocanthine component. The structure of bonafousine being known, that of isobonafousine was determined by comparison of the mass and n.m.r. spectra of the two alkaloids, and the absolute configuration was deduced from its c.d. spectrum.133 

Alkaloid T, isolated earlier1340 from the stems and roots of Hazunta costata, proves134 to be tabernaelegantine A (305), and Alkaloid X, a new alkaloid from the 

Dupont, O. Dideberg, J. Lamotte, K. Kambu, and L. Angenot, Acta Crystallogr., Sect. B, 1980, 36, 1669. 

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Bisindole Alkaloids from Tryptophan. There are two widely different types of alkaloids derived from two tryptophan (26) units. The first is a rather small group of compounds based simply on the dimers of tryptophan which includes compounds such as calycanthine (113) (Table 10),... 

An international team of experts review the whole field of alkaloid chemistry This volume contains three special non recurrent reviews on bisindole alkaloids, the biosynthesis of terpertoid indole alkaloids, and on pharma -cologicalty interesting ar>d chemically useful alkaloids it covers the period January 1969 to Jur>e 1970. 50Spp til 00... 

In addition to monomeric compounds, Tabemaemontana plants contain many bisindole alkaloids that are classified on the basis of constituent monomeric units, as in the extensive review by Cordell and Saxton in Volume XX of this series (14). This classification is more rational and comprehensive than others (I, 13, 15) and will be used as a guide for the representation of structural formulas and for the discussion of the chemistry of single alkaloids. 

The great number of different alkaloids found in Tabemaemontana precludes a discussion of the structure elucidation and chemistry of all of them. To keep the treatment concise, a major compromise was necessary. The alkaloids that have been reported in previous volumes of this treatise (as indicated in Table I) and their trivial modification will not be mentioned here. This compromise eliminates from the discussion well-established and long-known alkaloids that were isolated not only from Tabemaemontana but also from other genera. Moreover, the plumeran alkaloids isolated up to 1976 and ebuman-type and bisindole alkaloids isolated up to 1979 are covered in Volumes XVII and XX. The main efforts of this chapter will be focused on more recently isolated compounds, some of which are structurally and biogenetically relevant and have been found only in plants of the genus Tabemaemontana. 

Achenbach and Schaller have reported the isolation from the root bark of T. accedens of three monomeric alkaloids in addition to several bisindole alkaloids... 

E. Bisindole Alkaloids 1. Corynanthean-Aspidospermatan-Type Alkaloids... 

From 250 g of root bark of T. chippii, a small tree growing in the high forest or bush and occurring in the Ivory Coast and Ghana, nearly 4 mg of the new bisindole alkaloid vobparicine (200, C39H43N402) were isolated (62). The dimeric nature of this compound suggested by the molecular formula was con-... 

Ervafoline did not fragment under the acidic conditons used for the cleavage of other bisindole alkaloids. The complete structure and relative stereochemistry of ervafoline, as shown in formula 246, were determined by a single-crystal X-ray study. 

Another cultured cell line of Catharanthus roseus (EU4A), which does not produce detectable amounts of vinblastine and other bisindole alkaloids, was also examined for its ability to transform 78 (183). Cell-free extracts of the culture line were prepared, and the 35,000 X g supernatant solution was used. Incubations with 2r-tritioanhydiovinblastine yielded a mixture from which radioactive vinblastine (52) was isolated. The labeled vinblastine was reisolated after unlabeled carrier was added and rigorously purified by successive thin-layer chromatography, reversed-phase HPLC, and crystallization to constant specific activity. Boiled extracts could not produce labeled 52, thus supporting the involvement of enzymes in the conversion process. 

ISOLATION, STRUCTURE ELUCIDATION, AND BIOSYNTHESIS OF THE BISINDOLE ALKALOIDS OF CATHARANTHUS... 

Because of the previous inaccurate botanical determination of the Madagascan periwinkle, the alkaloids of this plant were formerly considered as Vinca alkaloids, an erroneous subclassification for alkaloids isolated from a plant belonging to the genus Catharanthus. It also should be noted that the alkaloids of C. roseus containing two different (most commonly indole and dihydroindole) alkaloid building blocks were, and sometimes still are, referred to as dimeric indole alkaloids. It is more accurate to use the term binary or bisindole alkaloids, since chemically these alkaloids are not dimers of two equal subunits, but rather comprised of two (bis) different alkaloid building blocks. 

The occurrence of structurally established bisindole alkaloids in Cath-aranthus roseus (L.) G. Don and in the minor species of Catharanthus, namely, C. lanceus (Boj. ex DC.) Pich., C. longifolius Pich., C. ovalis Mgf., C. pusillus (Murr.) G. Don, and C. trichophyllus (Bak.) Pich, is... 

Bisindole Alkaloids with Established Structures Isolated from Catharanthus Species... 

Additionally, there had, for many years, been a vast synthetic effort underway aimed at the synthesis of the two monomeric units, where it was anticipated that the two units could be joined to form the vinblastine-type bisindole alkaloids. Coincidentally, as it transpired, 20 years of effort in the areas of synthesis and biosynthesis converged, at almost the same time, on the compound 3, 4 -anhydrovinblastine (8). 

This review of the biosynthesis of the bisindole alkaloids of C. roseus is organized along a developing biosynthetic pathway, as far as possible, and relies on the notion that the most sophisticated studies are those utilizing the purified enzyme systems. Biosynthetic studies on the other monoterpene indole alkaloids are not reviewed here. 

Hutchinson and co-workers (775) in the course of studies aimed at the investigation of the formation of the bisindole alkaloids in whole plants of... 

Goodbody and co-workers (7/9) have examined the production of alkaloids in root and shoot cultures induced from seedlings of C. roseus. The pattern of alkaloids in the root cultures was similar to that of the roots from intact plants. Thus ajmalicine (39) and catharanthine (4) were produced, but no vindoline (3), a major leaf alkaloid, and no bisindole alkaloids. Similarly, the pattern of the alkaloid content of the shoot cultures was like that of the leaves of the intact plant, showing the presence of vindoline (3), catharanthine (4), and ajmalicine (39), with 3 predominating. A search for the bisindole alkaloids in the cultures indicated the presence of anhydrovinblastine (8) and leurosine (11) in the shoot cultures (2.6 and 0.3 xg/g fresh weight, respectively), but no vinblastine (1) or vincristine (2). 

Although ajmalicine (39) is not on the pathway to the bisindole alkaloids, it is a compound of substantial commercial interest, and several of the intermediates in its formation are probable intermediates in the extended biosynthetic pathway. This work is therefore reviewed for the purpose of completeness of studies on C. roseus. Considerable progress has been made on the biosynthesis of ajmalicine (39), and the studies on the formation of strictosidine (33) and cathenamine (76) have already been described. One of the preparations described by Scott and Lee was a supernatant from a suspension of young seedlings of C. roseus which af-... 

The only study of the biosynthesis of bisindole alkaloids in intact plants using advanced precursors was reported by Scott and co-workers in 1978... 

More recently, Kutney and co-workers (220) have investigated whether the same dihydropyridinium intermediate 109 is involved in the enzymatic conversion of catharanthine (4) and vindoline (3) to anhydrovinblastine (8) as is involved in the chemical conversion. Use of a cell-free preparation from a 5-day culture of the AC3 cell line gave 18% of the bisindole alkaloids leurosine (11), Catharine (10), vinamidine (25), and hydroxy-vinamidine (110), with 10 predominating. When the incubations were carried out for only 5-10 min, the dihydropyridinium intermediate was detected followed by conversion to the other bisindole alkaloids, with FAD and MnClj required as cofactors. Clearly a multienzyme complex is present in the supernatant, but further purification led to substantial loss of enzymatic activity. The chemical formation of anhydrovinblastine (3) is carried out with catharanthine A-oxide (107), but when this compound was used in the enzyme preparation described, no condensation with vindoline (3) occurred to give bisindole alkaloids. This has led Kutney and co-workers to suggest (220) that the A-oxide 108 is not an intermediate in the biosynthetic pathway, but rather that a 7-hydroperoxyindolenine... 

Higher plants are a very important source of medicinally useful compounds. Catharanthus roseus is one of the most important of these plants, and this chapter focuses on the further isolation work directed at the identification of new potentially more active and/or less toxic bisindole alkaloids. In addition, the biosynthesis of the indole alkaloids of C. roseus is reviewed. While the former area of research has been dominated by sophisticated high-field NMR and high-resolution mass spectral analyses. 

Scheme 8. Current biogenetic ideas for the bisindole alkaloids of Catharanthus roseus.

MEDICINAL CHEMISTRY OF BISINDOLE ALKALOIDS FROM CATHARANTHUS... 

Naturally Occurring Bisindole Alkaloids from Catharanihus. 153... 

Modifications of the Upper Half (Velbanamine Portion) of Bisindole Alkaloids 155... 

Modifications of the Lower Half (Vindoline Portion) of Bisindole Alkaloids. 166... 

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