Thalidomide metabolites and analogs. Part 2: Cyclic derivatives of 2-N-phthalimido-2S,3S (3-hydroxy) ornithine

E-(5-N-phthaloyl)-2-pentenoic acid benzyl ester was dihydroxylated by a Sharpless AD-mix protocol followed by mononosylation of the resultant 2R,3S diol. Azide displacement of the mononosylate followed by protection with the TBDMS group gave the ε-N-phthaloyl-substituted-β-tert-butyldimethylsilyloxy-α-azidocarboxylic acid benzylester. Hydrazinolysis resulted in removal of the phthalimide group with concomitant lactamization to the 4-silyloxy-3-azidopiperidinones. Staudinger reduction of the azidopiperidinones followed by N-phthaloylation and hydrolysis of the silyl group afforded the 4′-hydroxylated-6′-deoxythalidomide derivatives.