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
详细信息 查看全文
- 作者：Feng Xu ; Robert A. Reamer ; Richard Tillyer ; Jordan M. Cummins ; Edward J. J. Grabowski ; Paul J. Reider ; David B. Collum ; and John C. Huffman
- 刊名：Journal of the American Chemical Society
- 出版年：2000
- 出版时间：November 15, 2000
- 年：2000
- 卷：122
- 期：45
- 页码：11212 - 11218
- 全文大小：107K
- 年卷期：v.122,no.45(November 15, 2000)
- ISSN：1520-5126
文摘
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) andlithium (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-raycrystallography 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 theproduct alkoxide 3. Observation of this reaction intermediate strongly supports the proposed reaction mechanisminvolving the tetramer 6 in the stereo-determining step.