A Photochemical Route to Optically Active Hexahydro-4H-furopyranol, a High-Affinity P2 Ligand for HIV-1 Protease Inhibitors.

Abstract

We describe here the syntheses of optically pure (3aS,4S,7aR)-hexahydro-4H-furo[2,3-b]pyran-4-ol and (3aR,4R,7aS)-hexahydro-4H-furo[2,3-b]pyran-4-ol. These stereochemically defined heterocycles are important high-affinity P2 ligands for a variety of highly potent HIV-1 protease inhibitors. The key steps involve an efficient Paternò-Büchi [2 + 2] photocycloaddition, catalytic hydrogenation, acid-catalyzed cyclization to form the racemic ligand alcohol, and an enzymatic resolution with immobilized Amano Lipase PS-30. Optically active ligands (-)-6 and (+)-6 were obtained with high enantiomeric purity. Enantiomer (-)-6 has been converted to potent HIV-1 protease inhibitor 3.