Solid phase assisted synthesis of HIV-1 protease inhibitors. Expedient entry to unsymmetrical substitution of aC2symmetric template

Abstract

A solid phase synthesis has been developed leading up to unsymmetrical HIV-1 protease inhibitors that are not readily available by conventional solution phase chemistry (18a–g). To prepare these compounds the hydroxyl group of (1S,2R)-(–)-cis-1-phthalimido-2-indanol (3) was coupled to a Merrifield resin via a dihydropyrane linker. Cleavage of the phthalimido protecting group and reaction of the liberated amine with the bis-activated symmetrical diacid 15 resulted in the resin bound amide 16. Coupling of 16 with amino acids and amines followed by hydrolysis produced the desired unsymmetrical products 18a–g from which potent HIV-1 protease inhibitors were identified, e.g., 18e (ki= 0.1 nM), 18a (ki= 0.2 nM) and 18c (ki= 2 nM).Key words: HIV, inhibitor, protease, solid phase.