NMR and theoretical conformational studies of the anticholinergic physostigmine

The NMR parameters of (−)‐physostigmine free base (1) in CD2Cl2, CDCl3 and DMSO‐d6 were used to determine stereospecific assignments. The vicinal homonuclear coupling constants exhibited by the internally diastereotopic pyrrolidinyl protons of the C‐ring can be interpreted as arising from an interconverting profile of conformations at the fast exchange limit. Physostigmine undergoes epimerization in solution via inversion of the labile chirotopic and stereogenic N1 nitrogen atom, which results in the formation of (N − R,S)‐N1Me diastereoisomers. Protonation at the N1 nitrogen leads to the (N − S)‐N1 Me diastereoisomer of the corresponding salt of 1. Four conformational archetypes were calculated by molecular mechanics based on X‐ray crystallographically determined physostigmine.