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Synfacts 2019; 15(01): 0005
DOI: 10.1055/s-0037-1611443
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart · New York

Synthesis of Efavirenz via Asymmetric Alkynylation

Contributor(s):
Philip Kocienski
Pierce ME. * Chen C.-y. * Tillyer RD. * et al. The DuPont Pharmaceuticals Company, Deepwater and Merck Research Laboratories, Rahway, USA
Practical Asymmetric Synthesis of Efavirenz (DMP 266), an HIV-1 Reverse Transcriptase Inhibitor.

J. Org. Chem. 1998;
63: 8536-8543
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Publication History

Publication Date:
14 December 2018 (online)

 
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Key words

efavirenz - reverse transcriptase inhibitor - asymmetric alkynylation - chiral chaperone

Significance

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.


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Comment

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.


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