Highly Enantioselective 1,2-Addition of Lithium Acetylide-Ephedrate Complexes:  Spectroscopic Evidence for Reaction Proceeding via a 2:2 Tetramer, and X-ray Characterization of Related Complexes

The key step in the manufacturing process for the HIV reverse transcriptase inhibitor efavirenz (Sustiva) involves addition of the 2:2 tetrameric complex 6 [formed from lithium cyclopropylacetylide (5) and lithium (1R,2S)-N-pyrrolidinylnorephedrate (4)] to ketone 2, to give 3 in 95% yield and 98% en...

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Bibliographic Details
Published in:Journal of the American Chemical Society 2000-11, Vol.122 (45), p.11212-11218
Main Authors: Xu, Feng, Reamer, Robert A, Tillyer, Richard, Cummins, Jordan M, Grabowski, Edward J. J, Reider, Paul J, Collum, David B, Huffman, John C
Format: Article
Language:English
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Summary:The key step in the manufacturing process for the HIV reverse transcriptase inhibitor efavirenz (Sustiva) involves addition of the 2:2 tetrameric complex 6 [formed from lithium cyclopropylacetylide (5) and lithium (1R,2S)-N-pyrrolidinylnorephedrate (4)] to ketone 2, to give 3 in 95% yield and 98% enantioselectivity. Studies of acetylide-alkoxide complexes in solution by NMR spectroscopy and in the solid state by X-ray crystallography are described. Studies of the asymmetric addition reaction involving 2:2 tetramer 6 using low-temperature NMR spectroscopy provide conclusive evidence for formation of 2:1:1 tetramer 9 containing the product alkoxide 3. Observation of this reaction intermediate strongly supports the proposed reaction mechanism involving the tetramer 6 in the stereo-determining step.
ISSN:0002-7863
1520-5126
DOI:10.1021/ja0022728