Aspidosperma—iboga-type alkaloids

The ability of 1,2 (or l,6)-dihydropyridines to undergo a Diels-Alder reaction with dienophiles such as methyl vinyl ketone, methyl acrylate, and acrylonitrile has been utilized in the synthesis of polyfunctional isoquinuclidine as a key intermediate in the synthesis of aspidosperma- and iboga-type alkaloids (66JA3099). 

It is interesting to note that while vindoline and catharanthine are abundant in Catharan-thus roseus (L.) G. Don, a carbomethoxycleavamine (the initially presumed biogenetic precursor of the binary alkaloids), could not be detected or isolated. This suggested to Atta-ur-Rahman (45) that the VLB-type alkaloids are formed by union of Iboga and Aspidosperma alkaloids, an idea reinforced by biochemical studies (46-49). 

Researches carried out to the early part of 1966 have been comprehensively reviewed and the present account will set out from that point. In brief, the situation reached at that time was as follows. Despite their bewildering variety, three main groups of alkaloids had been recognised (a) the Corynanthe-Strychnos type, e.g. ajmalicine (1) and akuammicine (2) which possess the non-tryptamine unit (3), (b) the Aspidosperma type, e.g. vindoline (4), in which the non-tryptamine unit appears as (5), and (c) the Iboga type, e.g. catharanthine (6), having still a different arrangement of the non-tryptamine unit (7). 

Biogenetic Pathways of the Corynanthe-Aspidosperma and Iboga-type Partial Structures of Monoterpenoid Indole Alkaloids (Carbons indicated by a dotted line may be omitted)... 

Most L-tryptophan-derived secondary products still possess the indole ring system of this amino acid. Some compounds, however, are quinoline, pyrrole or benzene derivatives. Additional rings may be present yielding complicated structures, like that of ergoline and / -carboline alkaloids (cf. the formulas of ergotamine, Corynanthe, Strychnos, Iboga and Aspidosperma-type alkaloids). 

B, Iridoid Indole Alkaloids. Most jS-carbolines are derived from tryptamine and the iridoid secologanin (D 6.1.2). In dependence on the structure of the iridoid part alkaloids of the Corynanthe-Strychnos type as well as of the Aspidosperma and Iboga types may be distinguished. The latter are formed by rearrangement of the iridoid part which is shown schematically in Fig. 259 and in detail in Fig. 261. 

Fig. 261. Transformation of ajmalicine to alkaloids with Corynanthe-type, Iboga-type, and Aspidosperma-type skeletons...

Intrigued by the hypothesis of a dehydrosecodine (120) as a key bioge-netic intermediate in the natural generation of alkaloid structures of both the Aspidosperma (tabersonine, 121) and the Iboga (catharanthine, 21) types (Scheme 33) 108, 109) we developed efficient biomimetic synthe-... 

For (essentially) the first time recently, strains of C. roseus cultures have been obtained which will synthesize Strychnos, Iboga, and Aspidosperma alkaloids.34 This opens up the exciting possibility of studying the biosynthesis of those alkaloids lying beyond the Corynanthe type, such as (102), by using enzyme preparations from tissue cultures, which have proved so powerful for the early stages of biosynthesis (see above). 

If the C-15, C-16 bond is oxidatively cleaved, the secodine skeleton results (the proposed progenitor of the Aspidosperma and the iboga systems) through alternative Diels-Alder type cyclizations to afford tabersonine and catharanthine. The bisindole alkaloids of Catharanthus roseus reflect the union of vindoline and catharanthine to afford anhydrovinblastine modification affords the clinically significant alkaloids, vinblastine (VLB) and vincristine (VCR Fig. 39). The alkaloids, particularly VCR, are important as anticancer agents and have led to the development of the semisynthetic derivatives vindesine and vinorelbine (Fig. 40). Synthetic approaches are available to join the monomeric precursors. The enzymatically controlled sequence of reactions from tabersonine to vindoline has been elucidated. 

Secodine Group. In the biogenetic interrelationship of the three major mono-terpene-tryptamine alkaloid types, i.e. strychnos, aspidosperma, and iboga, the necessary changes in the aliphatic skeleton can be schematically represented... 

Rearrangements of Iboga and Aspidosperma Types. It is possible to envisage the biological rearrangements of the monoterpene-tryptamine alkaloid skeleta as proceeding via a common intermediate (132), reversibly derivable, at least on paper (see below) from each of the skeletal types, providing that a structure at the correct oxidation level is chosen. Thus tabersonine (133) (aspidosperma). 

Tabersonine (28), another /J-anilinoacrylate derivative, has been postulated to be a key biosynthetic precursor of all the Aspidosperma alkaloids and possibly also the iboga alkaloids. It is therefore a key compound for synthetic endeavors, but any potential synthesis of tabersonine poses an interesting problem because of the 14,15-double bond. Thus a biogenetic-type synthesis would involve the acrylic ester 478, the very ester postulated as the biosynthetic precursor of the Aspidosperma and iboga alkaloids. To date, efforts to produce this highly reactive ester have failed. 

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...

For reasons of brevity, some skeletal variations are not clearly defined in Figs. 2 and 3 and some have been omitted. In particular, the picraline (Volume VIII, p. 147), the echitamine (Volume VIII, p. 174) 78), and the aspidodasycarpine 53) skeletons have been merged into type If. The new alstophylline type 39, 40) is somewhat hidden in the Id reprepresentation. Gelsemine (Volume VIII, p. 95) has been included in the oxindole type Ic. Type Ila Iboga) includes several closely related rearranged alkaloids (Volume VIII, Chapter 9) which are not shown in Fig. 3. An unusually modified Aspidosperma structure 83) is related to type III6 and is listed as such. 

Terpenoid indole alkaloids This group of alkaloids is very large and contains more than 3000 compounds. Three types of nucleus occur here the corynanthe, iboga, and aspidosperma ... 

In contrast to the many Aspidosperma-Aspidosperma type bisindoles found in the leaf extract of the Malaysian T. divaricata vide infra), the stem extract provided only one bisindole, conodusarine (509), which was of the iboga-vobasine type 309). The spectral data indicated that conodusarine (509) is constituted from the union of 3-vobasinyl and 3-oxovoacangine moieties via a 3-11 bond. The presence of the latter alkaloid in the same plant provided additional support for the assignment. 

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