Enantioselective synthesis of tacrine–huperzine A hybrids. Preparative chiral MPLC separation of their racemic mixtures and absolute configuration assignments by X-ray diffraction analysis

Abstract

A new synthesis of racemic 7-substituted bicyclo[3.3.1]non-6-en-3-ones, rac- 4, whose key-step involves the reaction of a vinyl triflate, rac- 7, with an organometallic reagent, has been developed. This procedure has been applied to the enantioselective synthesis of (+)- and (−)-7-ethylbicyclo[3.3.1]non-6-en-3-one, (+)- and (−)- 4b, from which both enantiomers of the cholinesterase inhibitor, tacrine–huperzine A hybrid, 9b, have been obtained. Rac- 9b and its related compounds rac- 9a and rac- 10a were separated into their enantiomers on a preparative scale by medium pressure liquid chromatography (MPLC) using microcrystalline cellulose triacetate as the chiral stationary phase. X-ray diffraction analysis of (−)- 10a as the o-iodobenzoic acid salt, allowed us to establish its absolute configuration and deduce those of other enantiopure tacrine–huperzine A hybrids.