Synthesis of enantiopure (2 R)-configured muscarine alkaloids via selective alkoxyl radical ring-closure reactions

Abstract

A new synthesis of (−)-muscarine, (+)- allo-muscarine, (−)- epi-muscarine, and (−)- epiallo-muscarine has been devised which utilizes selective alkoxyl radical cyclizations for constructing tri-substituted tetrahydrofuran units. Photolysis of (2 R,3 S)- N-(3-benzoyloxy-5-hexen-2-oxy)-4-methylthiazole-2(3 H)thione in the presence of BrCCl 3 provided (2 R,3 S,5 S)-3-benzoyloxy-5-bromomethyl-2-methyltetrahydrofuran as the major product and the corresponding (2 R,3 S,5 R)-isomer as the minor. These building blocks were converted into enantiomerically pure (+)- allo-muscarine (from the major alkoxyl radical cyclization product) and (−)-muscarine (from the minor product). Temperature and substituent effects on the diastereoselectivity of the underlying alkoxyl radical cyclization have been investigated. (−)- epi-Muscarine and (−)- epiallo-muscarine have been prepared likewise, starting from (2 R,3 R)- N-(3-benzoyloxy-5-hexen-2-oxy)-4-methylthiazole-2(3 H)thione.