Stereoselective synthesis of constrained oxacyclic hydroxyethylene isosteres of aspartic protease inhibitors: aldol and Mukaiyama aldol methodologies for branched tetrahydrofuran 2-carboxylic acids

Abstract

The synthesis of diastereomeric 3-substituted-tetrahydrofuran 2-carboxylic acids in enantiopure form was achieved relying on aldol condensations of N-substituted alpha-amino aldehydes with enolates and enol silyl ethers of gamma-butyrolactone. Catalytic YbFOD leads to a high yield of a syn/syn-alpha-amino alcohol isomer. This was used as a constrained THF subunit in the synthesis of a peptidomimetic intended as an inhibitor of the enzyme BACE1, which is implicated in the cascade of events leading to plaque formation in Alzheimer's disease.