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). 

Further variants on the terpenoid indole alkaloid skeleton (Figure 6.82) are found in ibogaine from Tabemanthe iboga, vincamine from Vinca minor, and ajmaline from Rauwolfia serpentina. Ibogaine is simply a C9 Iboga type alkaloid, but is of interest as an experimental drug to treat heroin addiction. In a number of European countries, vincamine is used clinically as a vasodilator to increase cerebral blood flow in cases of senility, and ajmaline for cardiac arrhythmias. Ajmaline... 

A study describing the stereochemical synthesis of an isoquinuclidine building block for the synthesis of iboga-type alkaloids has been recently described [105]... 

The indole alkaloids of this type are called iboga-type alkaloids and are found only in Apocynaceae plants. 

Thus the critical synthetic 1,6-dihydropyridine precursor for the unique isoquinuclidine system of the iboga alkaloids, was generated by reduction of a pyridinium salt with sodium borohydride in base (137-140). Lithium aluminum hydride reduction of phenylisoquinolinium and indole-3-ethylisoquinolinium salts gave enamines, which could be cyclized to the skeletons found in norcoralydine (141) and the yohimbane-type alkaloids (142,143). 

The synthesis of tacamonine, an indole alkaloid of the Iboga type, was accomplished in both racemic and homochiral forms, by incorporating a classical 6-exo-trig radical cyclization in the key step of the synthesis (Reaction 7.57) [52], The cyclization produced piperidinone in a 72% yield as a diaster-eomeric mixture. 

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). 

Tacamonine, an indole alkaloid of the Iboga type, isolated from Tabermemontana eglandulosa, the root of which is used to treat snake bites in Zaire, bears structural similarity to the Hunteria alkaloids, eburnamonines, which possess vasodilator and hypotensive activities. Its synthesis in racemic and homochiral form was accomplished by incorporating a classic 6-exo-trig radical cyclization in the key step of the synthesis (Scheme 6)71. The radical precursor 6 was constructed in a 7-step synthesis by starting from racemic or chiral propane-1,3-diol. The radical cyclization of 6 produced the piperidinone in 72% yield as a diastereomeric mixture, which was then transformed into tacamonine. 

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). 

Vinblastine (117) and vincristine, well-known antitumor bisindole alkaloids, are biogeneticaUy derived from the coupling of vindoHne (123, Aspi-dospema type) and catharanthine (124, Iboga type). Recent progress (since a comprehensive review by Kam and Choo ) on the chemistry of these alkaloids is described in this section. 

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...

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