Indole alkaloids aspidosperma

David Wilkins obtained his Ph.D. in 1986 working with Professor A. H. Jackson and Dr. P. V. R. Shannon at University College Cardiff, Wales, working on the synthesis of the Aspidosperma indole alkaloids. He then did two years of postdoctoral studies with Professor P. M. Cullis at the University of Leicester, UK, working on the mechanism of thiophosphoryl-transfer reactions. In 1989, he joined the medicinal chemistry department at what was then Boots Pharmaceuticals in Nottingham (UK) and which became part of BASF Pharma in 1995. In 2001, he joined Key Organics Ltd., where he is currently employed as a principal chemist in the Contract Synthesis Department. 

Other groups of alkaloids that coincidentally have this ring structure will be discussed under better known groupings [e.g., the alkaloids of Aspidosperma (indole alkaloids. Chapter 34), Erythrina (benzylisoquinoline alkaloids. Chap-... 

The sequence could even be prolonged by including a Pummerer reaction. Thus, treatment of 4-103 with trifluoroacetic acid (TFA) gave the furan 4-104, which underwent a cycloaddition to furnish 4-105 the erythryna skeleton 4-109 was obtained after subsequent addition of a Lewis acid such as BF3- Et20 (Scheme 4.23) [33]. It can be assumed that 4-106, 4-107 and 4-108 act as intermediates. In a more recent example, these authors also used the procedure for the synthesis of indole alkaloids of the Aspidosperma type [34]. 

L-tyrosine Tyrosine-derived alkaloids Indole alkaloids Quinoline alkaloids /3-carboline alkaloids Pyrroloindole alkaloids Ergot alkaloids Iboga alkaloids Corynanthe alkaloids Aspidosperma alkaloids Protoalkaloids Terpenoid indole alkaloids True alkaloids... 

Mitaine, A.-C., Weniger, B., Sauvain, M., Lucumi, E., Aragon, R. and Zeches-Hanrot, M. 1998. Indole alkaloids from the tmnkbark of Aspidosperma megalocar-pon. Planta Medica, 64 487. 

The Aspidosperma alkaloid vincadifformine 1 is reasonably available, and can be readily transformed into the carbinolamine ether 2. Oxidation of 2 with MCPBA followed by methanolysis gives the hemiketal 3, and brief treatment of 3 with a 99 1 v/v mixture of CH2CI2/TFA at room temperature gives a mixture of 4 (42%) and 5 (11%). The yield of 4 is increased to 52%, while almost none of 5 is formed, if the treatment of 3 with acid is allowed to proceed at room temperature for 15 hours. Products 4 and 5 contain the gross skeleton of goniomitine 6, an indole alkaloid of an unusual structural type. 

The Aspidosperma family of indole alkaloids has inspired many synthetic strategies for the construction of their pentacyclic framework of the parent compound aspidospermidine (366), since the initial clinical success of two derivatives, vinblastine (10) and vincristine, as anticancer agents. The alkaloids such as (-)-rhazinal (369) and (-)-rhazinilam (6) have been identified as novel leads for the development of new generation anticancer agents [10,11]. Bis-lactams (-)-leucunolam (370) and (-t-)-epi-leucunolam (371) have bio-genetic and structural relationships with these compounds [236]. Recently, enantioselective or racemic total syntheses of some of the these natural product were achieved. One successful synthesis was the preparation of the tricyclic ketone 365, an advanced intermediate in the synthesis of aspidospermidine (366), from pyrrole (1) (Scheme 76) [14]. The key step is the construction of the indolizidine 360, which represents the first example of the equivalent intramolecular Michael addition process [14,237,238]. The DIBAL-H mediated reduction product was subject to mesylation under the Crossland-... 

Terpenoid Indole Alkaloids.—Current knowledge on the biosynthesis of terpenoid indole alkaloids, with particular emphasis on the very important results obtained with enzyme preparations from tissue cultures of Catharanthus roseus, has been authoritatively reviewed.53 Further work on cell lines of C. roseus that are able to produce Aspidosperma-type alkaloids has been published54 (cf. Vol. 11, p. 19). 

Another all-carbon Diels-Alder reaction is proposed for the biosynthesis of the indole alkaloids tabersonine 1-6 and catharanthine 1-7 of the Aspidosperma and Iboga family [28-31]. The compounds are formed via strictosidine 1-3, the first nitrogen-containing precursor of the monoterpenoid indole alkaloids, and stemmadenine 1-4, which is cleaved to give the proposed intermediate dehy-drosecodine 1-5 with an acrylate and a 1,3-butadiene moiety (Scheme 1-1). 

Aspidospermine one indole alkaloid was isolated from bark of Aspidosperma quebracho-bianco, displaying antimalaiial activity on Plasmodium falciparum (29). 

Eburnamine-Vincamine Alkaloids.—So far most of the effort on indole alkaloid biosynthesis has been concentrated on the Corynanthe, Aspidosperma, and Iboga systems. It is welcome, therefore, to see the preliminary results of an investigation of the biosynthesis of vincamine (10).6 Comparable incorporations were observed for [ar-3H]tryptophan, [ar-3H]stemmadenine (5), and [ar-3H]taber-sonine (9). These results support the proposal7 that vincamine is a transformation... 

Since the last review on Picralima alkaloids was written (for Volume X) activity in this field has considerably abated and in consequence there is comparatively little new work to be reported. The main features of indole alkaloid biosynthesis have now been elucidated and the reader is referred to Battersby (1) for an authoritative summary of this fascinating topic. Preakuammicine (1) appears to be involved in the direct pathway to the Strychnos, Aspidosperma, and Iboga alkaloids, and although it has not been isolated from Picralima it is appropriate to include it here, and to note that its presence in very young seedlings of Vinca rosea has been established (2). Preakuammicine is almost certainly the precursor of akuammicine (2), a transformation which can also be achieved by treatment with base (2). 

The Ziegler group has described a creative approach to mitomycin derivatives and the related alkaloid FR-900482 that involves use of indoles as radical acceptors (Eq. 28) [62]. The key step involves cyclization of aziridinyl bromide 98 to 99 which was carried on to (+)-desmethoxymitomycin A. This reaction surely illustrates the unusual bond constructions that can be accomplished using free-radical chemistry. Interesting approaches to other indole alkaloid substructures have been reported as illustrated in Eqs. (29) [63] and (30) [64]. The former was developed in an approach to lysergic acid while the later is a model study for the synthesis of aspidosperma alkaloids. Neither of these interesting approaches has been brought to fruition. A synthesis of carbazomycin that involves an aryl radical cyclization for construction of the C3-C3a bond of an indole has also been described [65]. 

Gabetta (3) has summarized the indole alkaloids isolated between 1968 and mid-1972, and Aliev and Babaev (4) have discussed the physical properties of the many Aspidosperma-type alkaloids isolated from Vinca species. 

The ultimate goal of the syntheses of compounds with the Aspidosperma nucleus is vindoline (101). One component of many of the dimeric indole alkaloids of Catharanthus roseus, vindoline (101) is a structural component of vincaleukoblastine, the powerful oncolytic agent, and N-demethyl-N-... 

Without doubt, however, the most important technique to come to the fore in the last ten years is that of 13C NMR aided by Fourier transform instrumentation. The l3C resonances for many carbons in indole alkaloids have characteristic values, and consequently considerable structural information can be gained from the spectrum. In Table III the 13C NMR shifts of the carbon atoms of a number of alkaloids in the Aspidosperma series are given (20, 50, 51, 59, 100, 102, 109, 287-290). 

Table II tabulates the plant species which contain the complex indole alkaloids. The letters in this table correspond to the various structural types as coded in Figs. 2 and 3. Types I, II, and III are the major variations of the Cfl-Ci 0 unit which, in combination with tryptamine, formally elaborate the three significantly different groups of complex indole alkaloids Corynanthe, Iboga, and Aspidosperma. Such initial classification follows the outline set by Battersby [3, 3a) and others (2, 4, 5). The...

That the complex indole alkaloids contain a tryptamine unit is a requirement which is not always met at first sight. For example, some alkaloids from the Cinchona and Bemijia species (Rubiaeeae) (Volume VIII, Chapter 10 type Ij, Fig. 2) contain quinoline rings in their overall structures. Nevertheless, it has been shown that tryptophan is readily incorporated into these alkaloids and on this basis they are justly included in Table II. Furthermore, there are a number of complex alkaloids belonging to some Aspidosperma species (Apocynaceae) which seem to have lost the ethylamine side chain of a tryptamine unit (type li. Fig. 2). 

The Aspidosperma alkaloids are a group of more than 100 monomeric and dimeric monoterpene indole alkaloids with aspidospermidine (228) representing a key member of the class and sometimes considered to be the parent [68]. Numerous total syntheses of this pentacyclic compound have been reported. Our own contributions in the area were prompted by the discovery of a new method for preparing indoles via a palladium-catalysed Ullmann cross-coupling reaction that proceeds especially efficiently at close to room temperature [69] and which we felt could serve as the centrepiece in developing a new synthesis of compound 228 and, in the longer term, syntheses of dimeric members of the indole alkaloid class such as the clinically significant alkaloids vinblastine and vincristine. 

C19H26N2, Mr 282.43, mp. 147-149 °C soluble in acetone, chloroform, dilute acids. A monoterpenoid indole alkaloid of the Aspidosperma type, Q. occurs in both enantiomeric forms the (+)-form, (aJu +98° (CHCI3), in leaves and root bark of Pleiocarpa species as well as the bark of Stemmadenia species the (-)-form, [aJi, -100° (CHCI3), in Aspidosperma quebra-cho-blanco and other Aspidosperma species as well as Gonioma, Hunteria, and Rhazya species. 

Quebracho (cortex). The bark of the quebracho tree, Aspidosperma quebracho-bianco (Apocynaceae), a large tree (up to 20 m high), indigenous to the west of South America. The bark contains ca. 1% monoter-penoid indole alkaloids such as yohimbine, aspido-spermine, quebrachamine. The Aspidosperma alkaloids are structurally related to the Catharanthus alkaloid vindoline. Quebracho bark contains over 25 different alkaloids of widely differing types. ... 

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