Synthesis and stereoselective reduction of (±)-, (+)- and (–)-6-substituted-6-azabicyclo[3.2.1]octan-3-one

Abstract

Starting with 6-oxabicyclo[3.2.1]oct-3-en-7-one 6, a three step, general synthetic route to both racemic and optically active 6-substituted 6-azabicyclo[3.2.1]octan-3-ones has been developed. Opening of the lactone ring of 6 with amines gave amides which were reduced with lithium aluminium hydride to amino alcohols. Allylic oxidation of amino alcohols 8a, 8b, 12 and 13 with manganese dioxide provided the bicyclic ketones 1b, 1c, 14 and 15, respectively, without isolation of the intermediate monocyclic ketones. Methods for stereoselective reduction of the bicyclic ketones to the corresponding 6-substituted 6-azabicyclo[3.2.1]octan-3α-ols and -3β-ols have been developed. Displacement of the R-α-methylbenzyl chiral auxiliary from the diastereomeric alcohols 16, 17, and 20, 21 by catalytic debenzylation followed by reductive amination provided the optically active 6-methyl-6-azabicyclo [3.2.1]octan-3-ols 1d–1e, respectively. The absolute stereochemistry of all reported optically active compounds has been established by comparison of diastereoisomers 10 and 11 with the R-(+)-methylbenzylamine amides derived from optically enriched lactone 6.