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 NN 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.