An Efficient and Practical Synthesis of the HIV Protease Inhibitor Atazanavir via a Highly Diastereoselective Reduction Approach

Abstract

An efficient and practical synthesis of the HIV-1 protease inhibitor Atazanavir was developed by employing the diastereoselective reduction of ketomethylene aza-dipeptide isostere 10 as the key and final step. The high diastereoselectivity of the amino ketone reduction by lithium tri- tert -butoxyaluminum hydride in diethyl ether to afford the desired syn -1,2-amino alcohol structure was achieved by Felkin−Anh control as a result of the bulky and chiral N -(methoxycarbonyl)- l - tert -leucinyl moiety as the nitrogen protecting group. The coupling of the two key intermediates, N -(methoxycarbonyl)- l - tert -leucine acylated benzyl hydrazine 7 and chloromethyl ketone 9, via an S N 2 reaction furnished the amino ketone 10 in high yield under our optimized conditions. Our new methodology features the late introduction of the S -hydroxyl group and the early acylation of benzyl hydrazine and chloromethyl ketone with N -(methoxycarbonyl)- l - tert -leucine, respectively, which confers high efficiency and easy purification.