Catalytic Enantioselective Conjugate Addition of Diethylzinc to A-Alkylidene Esters and Application to Scalable Synthesis of Hiv Protease Inhibitor Tipranavir*

摘要

Tipranavir is the only nonpeptidomimetic inhibitor of HIV-PR, which has been approved for use by the FDA in 2005. It retains useful activity against strains resistant to ritonavir and cross-resistant to other protease inhibitors, suggesting that Tipranavir could be very valuable when used in combination with a subset of these structurally unrelated drugs. This compound includes two widely separated chiral centers and instability of the dihydropyrone core. So far, there are two main approaches to obtaining optically active Tipranavir, namely resolution of a racemic mixture and asymmetric synthesis using chiral reagents or auxiliaries. The catalytic asymmetric synthesis of important challenge. Herein, we report an efficiently catalytic enantioselective conjugate addition of Et2Zn to α-alkylidene β-ketoesters and malonates, as well as application to scalable synthesis of Tipranavir (Scheme 1).