Chirospecific Synthesis of (+)-Pilocarpine

Article abstract of DOI:10.1021/jo00360a015

An efficient chirospecific synthesis for (+)-pilocarpine (1a) using D-methionine or D-2-aminobutanol as chiral educt is described.Formation of the C3-C4 carbon bond at an early stage gave the key intermediate diethyl phosphonate.Wittig coupling of this phosphonate with 1-methyl-5-imidazolecarboxaldehyde introduced the imidazole moiety of the pilocarpine skeleton.Selective reduction of an α,β-unsaturated nitrile to the corresponding allylic alcohol, stereocontrolled hydrogenation of the olefin, and epimerization of (+)-isopilocarpine to (+)-pilocarpine via kinetic protonation led to formation of the natural alkaloid.This methodology allows chirospecific syntheses of the four possible stereoisomers of pilocarpine.A short and convenient route to (+/-)-pilocarpine based on the key intermediate phosphonate is also described.