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 compl ex 6 [formed from lithium cyclopropylacetylide (5) and lithium (1R,2S)-N-py rrolidinylnorephedrate (4)] to ketone 2, to give 3 in 95% yield and 98% ena ntioselectivity. 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 usin g low-temperature NMR spectroscopy provide conclusive evidence for formatio n of 2: 1:1 tetramer 9 containing the product alkoxide 3. Observation of th is reaction intermediate strongly supports the proposed reaction mechanism involving the tetramer 6 in the stereo-determining step.