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

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 (2R,3S)-N-(3-benzoyloxy-5-hexen-2-oxy)-4-methylthiazole-2(3H)thione in the presence of BrCCl3 provided (2R,3S,5S)-3-benzoyloxy-5-broniomethyl-2-methyltetrahydrofuran as the major product and the corresponding (2R,3S,5R)-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 (2R.3R)-ev-(3-benzoyloxy-5-hexen-2-oxy)-4-metliylthiazole-2(3H)thione. (C) 2003 Published by Elsevier Ltd.