Stereoselective Hydroazidation of Amino Enones:  Synthesis of the Ritonavir/Lopinavir Core

The base-catalyzed hydroazidation of α‘-amino α,β-unsaturated ketones with in situ generated hydrazoic acid was found to proceed with high stereoselectivity in favor of the syn product. The stereoselectivity is controlled by the configuration of the enone and syn/anti ratios up to 7:1 were obtained with secondary and tertiary amines at low temperature. By this route the diamino alcohol core of HIV-PR inhibitors ritonavir and lopinavir was synthesized in 37% yield from phenylalanine.