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

F. Xu, R. A. Reamer, R. Tillyer, J. M. Cummins, E. J.J. Grabowski, P. J. Reider, D. B. Collum, J. C. Huffman

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)11212-11218
Number of pages7
JournalJournal of the American Chemical Society
Volume122
Issue number45
DOIs
StatePublished - Nov 15 2000
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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