CHIROSPECIFIC SYNTHESIS OF (+)-PILOCARPINE

An efficient chirospecific synthesis for (+)-pilocarpine (1a) using D-methionine or D-2-aminobutanol as chiral educt is described. Formation of the C3.sbd.C4 carbon bond at an early stage gave the key intermediate diethyl [cyano((1-tert-butoxycarbonyl)propyl)methyl]phosphonate. Wittig coupling of this phosphonate with 1-methyl-5-imidazolecarboxaldehyde introduced the imidazole moiety of the pilocarpine skeleton. Selective reduction of an .alpha.,.beta.-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.