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

We describe here the syntheses of optically pure (3a S ,4 S ,7a R )-hexahydro-4 H -furo[2,3- b ]pyran-4-ol and (3a R ,4 R ,7a S )-hexahydro-4 H -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 .