Tryptophan physostigmine

Kawahara, M., Nishida, A., Nakagawa, M. (2000) An Efficient Synthesis of Optically Active Physostigmine from Tryptophan Via Alkylative CycUzation. Organic Letters, 2, 675-678. 

The proof of structure of dehydroesermetholemethine gave considerable further support to the 3a-methylpyrrolo[2,3-6]indole structure for physostigmine proposed by Robinson. The Robinson structure for the alkaloid also was derived easily from tryptophan, thus offering an obvious biogenetic route of synthesis by the plant (this will be discussed in more detail later). 

In the original paper which presented Robinson s structure for physostigmine Stedman and Barger (13) suggested a possible biosynthetic route to the physostigmine ring system (see accompanying scheme). Tryptamine, produced by decarboxylation of tryptophan, was... 

Julian and Pikl (38) have also proposed a route of biosynthesis of physostigmine. They considered that the essential steps involved first oxidation and then methylation of tryptophan to an oxindole LII which was reductively ring closed to the physostigmine ring system. It will be... 

The Indole Family. Tryptophan is also the precursor of another large alkaloid family based on the indole system. Usually, indole is found fused to other rings, as in physostigmine (3.22). Here, a pyrrolidine ting is fused to the b-face of indole. This alkaloid occurs in calabar beans. It is a potent inhibitor of cholinesterase, and like other such chemicals, it causes contraction of the pupil of the eye. In harmine (3.23), a pyridine ring is fused to the b-face. 

Physostigmine from the Calabar bean Physostigma venenosum (Fig. 130) is an indole alkaloid of simple structure. It is derived from tryptophan via its biogenic amine, tryptamine. 

Finally, two important classes of compounds have to be mentioned since they have inspired many synthetic chemists. The pyrroloindole alkaloids result from the cyclization of tryptamine, as found in physostigmine (formed by a cationic mechanism after methylation in position 3 of the indole not shown) or in chimonanthine (presumably formed by a radical coupling mechanism Scheme 1.8). The ergot alkaloids are derived from the 3,3-dimethylallylation on position 4 of the indole in tryptophan whose further cyclization and oxidation processes afford the natural products (e.g., lysergic acid, Scheme 1.8, and ergotamine), which have had important medical applications [34]. 

While phenyl pyrrole derivatives have not been isolated from higher plants, a number of plant alkaloids have been shown to be derived from tryptophan (Manske, 1965). Several of these plants, such as the calabar bean (Physostigma venenosum Balf.) and the family Calycanthaceae [Calycanthus L. and Chimonanthus Lindl.), yield compounds, e.g. physostigmine (VIII) and folicanthine (IX) whose biosynthesis may follow a pathway similar to that of pyrrolnitrin. 

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