Pilocarpine isopilocarpine syntheses

Roylance showed that pilocarpidine on -methylation yielded two products, pilocarpine and neopilocarpine (see below), thus confirming Hamack s suggestion that pilocarpidine is the imino-base corresponding to pilocarpine, Spath and Kunz showed that pilocarpidine, on treatment with alcoholic sodium ethoxide, is converted into isopilocarpidine (nitrate, m.p. 109-111°), which, on quaternary methylation, yields isopilocarpine metho-salts (methopicrate, m.p. 119-120°). The confirmation of these observations by the synthesis of pilocarpidine and isopilocarpidine and their conversion into pilocarpine and isopilocarpine has been described already. 

A stereoselective synthesis of (+)-pilocarpine (7) starting from L-histidine (2) has been worked out by Noordam et al. (88 - 90). Use was made of the S configuration of the amino acid, which is the same as that of C-3 of the lactone ring in both (+)-pilocarpine and (+)-isopilocarpine. Furthermore, regioselective N-alkylation reactions of the imidazole nucleus of histidine had been developed by Beyerman et al. (29,91). Schemes 3 and 4 depict the different ways of the regioselective alkylations. For the synthesis of pilocarpine, the N7I-methylation has been performed via Nb-protection with the 4-nitrobenzenesulfonyl group, instead of the benzoyl group (29). 

---