Practical Asymmetric Synthesis of Efavirenz (DMP 266), an HIV-1 Reverse Transcriptase Inhibitor

Abstract

A highly enantioselective and practical synthesis of the HIV-1 reverse transcriptase inhibitor efavirenz ( 1 ) is described. The synthesis proceeds in 62% overall yield in seven steps from 4-chloroaniline ( 6 ) to give efavirenz ( 1 ) in excellent chemical and optical purity. A novel, enantioselective addition of Li-cyclopropyl acetylide ( 4a ) to p -methoxybenzyl-protected ketoaniline 3a mediated by (1 R,2 S )- N -pyrrolidinylnorephedrine lithium alkoxide ( 5a ) establishes the stereogenic center in the target with a remarkable level of stereocontrol.