NMR and theoretical conformational studies of the anticholinergic physostigmine

The NMR parameters of (-)-physostigmine free base (1) in CD2Cl2, CDCl3 and DMSO-d(6) were used to determine stereospecific assignments. The vicinal ho monuclear coupling constants exhibited by the internally diastereotopic pyr rolidinyl protons of the C-ring can be interpreted as arising from an inter converting profile of conformations at the fast exchange limit. Physostigmi ne undergoes epimerization in solution via inversion of the labile chirotop ic and stereogenic N1 nitrogen atom, which results in the formation of (N - R,S)-N1-Me diastereoisomers. Protonation at the NI nitrogen leads to the ( N - S)NI-Me diastereoisomer of the corresponding salt of 1. Four conformati onal archetypes were calculated by molecular mechanics based on X-ray cryst allographically determined physostigmine. Copyright (C) 2001 John Wiley & S ons, Ltd.