Synthesis of enantiomerically pure stereogenically labile 4-aryl-2-hydroxytetronic acids from enantiomerically pure silyl-protected mandelaldehydes: Aci-reductone analogues of propionic acid nonsteroidal anti-inflammatory agents

Article abstract of DOI:10.1021/jo00116a015

Enantiomerically pure 4-aryl-2-hydroxytetronic acids (3) are expected to be useful tools for determining the mechanism by which corresponding racemic aci-reductones produce their multiple biological effects. Our published synthetic methods for the construction of the title compounds were only useful for the preparation of 4-alkyl analogues owing to facile racemization of the chiral benzylic proton with 4-aryl systems. The synthesis of these enantiomerically pure 4-aryl aci-reductones has now been accomplished in four steps by condensing enantiomerically pure tert-butyldimethylsilyl protected mandelaldehydes 16a-c with the anion of ethyl 1,3-dithiane-2-carboxylate in the presence of pivaloyl chloride to yield protected β,γ-dihydroxy-α-ketobutanoates 22a-c after dithiane hydrolysis. Reaction of 22a-c with tetrabutylammonium fluoride resulted in silyl deprotection, cyclization, and pivaloyl migration to afford 2-(pivaloyloxy)tetronic acids 25a-c. Pivaloate deprotection by either acid hydrolysis or selective hydride reduction produced enantiopure targets 3a-c.