Synthesis of Efavirenz via Asymmetric Alkynylation
Practical Asymmetric Synthesis of Efavirenz (DMP 266), an HIV-1 Reverse Transcriptase Inhibitor.
J. Org. Chem. 1998;
14 December 2018 (online)
Efavirenz (Sustiva®) is an HIV-1 reverse transcriptase inhibitor that was approved by the FDA in 1998 for the treatment of HIV/AIDS. The classic DuPont–Merck synthesis depicted incorporates a highly enantioselective addition of lithium acetylide K (as the tetrameric complex F) to ketone E mediated by chiral chaperone J. The synthesis proceeds in 62% overall yield in just seven steps. Since all intermediates were crystalline, no chromatography was required.
For the mechanism of the acetylide addition, see: A. Thompson et al. J. Am. Chem. Soc. 1998, 120, 2028. For further practical refinements in the nucleophilic addition, see: A. Choudhury et al. Org. Process Res. Dev. 2003, 7, 324. A large scale enantioselective alkynylation of ketone D mediated by chiral chaperone J gave adduct I directly in 95% yield (er > 99:1) on a 4.5 mol scale: WO 1998 51676.