Novel HIV-1 protease inhibitors encompassing a tertiary alcohol as part of the transition-state mimicking unit have been synthesized. Variation of the P1'-P3' residues and alteration of the tertiary alcohol absolute stereochemistry afforded 10 inhibitors. High potencies for the compounds with (S)-configuration at the carbon carrying the tertiary hydroxyl group were achieved with Ki values down to 2.4 nM. X-ray crystallographic data for a representative compound in complex with HIV-1 protease are presented.

Two series of P1'-extended HIV-1 protease inhibitors comprising a tertiary alcohol in the transition-state mimic exhibiting Ki values ranging from 2.1 to 93 nM have been synthesized. Microwave-accelerated palladium-catalyzed cross-couplings were utilized to rapidly optimize the P1' side chain. High cellular antiviral potencies were encountered when the P1' benzyl group was elongated with a 3- or 4-pyridyl substituent (EC50 = 0.18-0.22 microM). X-ray crystallographic data were obtained for three inhibitors cocrystallized with the enzyme.

Fast and direct methods have been developed for the small-scale carbonylative preparation of benzamides from aryl iodides, bromides, and chlorides in pure water. The reactions proceed by palladium catalysis using noninert conditions, solid Mo(CO)6 as the CO source, and controlled microwave superheating. Within 15 min of microwave processing, more than 90 aminocarbonylations were successfully performed in useful to excellent yields employing both primary and secondary amines. Using appropriate ratios of starting amines and aryl halides, the competing hydroxycarbonylation reaction was suppressed and only trace amounts of the corresponding carboxylic acids were detected. Based on this aqueous carbonylation, a facile preparation of a novel HIV-1 protease inhibitor was achieved.