173676-60-3Relevant articles and documents
In situ recycling of chiral ligand and surplus nucleophile for a noncatalytic reaction: Amplification of process throughput in the asymmetric addition step of efavirenz (DMP 266)
Choudhury, Anusuya,Moore, James R.,Pierce, Michael E.,Fortunak, Joseph M.,Valvis, Ioannis,Confalone, Pat N.
, p. 324 - 328 (2003)
The synthesis of efavirenz (DMP 266) involves a highly enantioselective asymmetric reaction of ketone 2a with lithium cyclopropylacetylide 3a in the presence of (1R,2S)-pyrrolidinylnorephedrine (PNE) 4b as the chiral mediator to produce 6b, a key advance
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
Xu, Feng,Reamer, Robert A.,Tillyer, Richard,Cummins, Jordan M.,Grabowski, Edward J. J.,Reider, Paul J.,Collum, David B.,Huffman, John C.
, p. 11212 - 11218 (2000)
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.
Enantioselective alkynylation of a prochiral ketone catalyzed by C2-symmetric diamino diols
Jiang, Biao,Feng, Yan
, p. 2975 - 2977 (2007/10/03)
C2-Symmetric diamino diols were used as chiral ligands to induce the asymmetric addition of lithium acetylides to carbonyl groups. The enantiomeric excesses (up to 99% ee) depended on the structure of the acetylene.
Practical asymmetric synthesis of Efavirenz (DMP 266), an HIV-1 reverse transcriptase inhibitor
Pierce, Michael E.,Parsons Jr., Rodney L.,Radesca, Lilian A.,Lo, Young S.,Silverman, Stuart,Moore, James R.,Islam, Qamrul,Choudhury, Anusuya,Fortunak, Joseph M. D.,Nguyen, Dieu,Luo, Chi,Morgan, Susan J.,Davis, Wayne P.,Confalone, Pat N.,Chen, Cheng-Yi,Tillyer, Richard D.,Frey, Lisa,Tan, Lushi,Xu, Feng,Zhao, Dalian,Thompson, Andrew S.,Corley, Edward G.,Grabowski, Edward J. J.,Reamer, Robert,Reider, Paul J.
, p. 8536 - 8543 (2007/10/03)
A highly enantioselective and practical synthesis of the HIV-1 reverse transcriptase inhibitor efavirenz (1) is described. The synthesis proceeds in 62% overall yield in seven steps from 4-chloroaniline (6) to give efavirenz (1) in excellent chemical and optical purity. A novel, enantioselective addition of Li-cyclopropyl acetylide (4a) to p-methoxybenzyl-protected ketoaniline 3a mediated by (1R,2S)-N-pyrrolidinylnorephedrine lithium alkoxide (5a) establishes the stereogenic center in the target with a remarkable level of stereocontrol.
Use of an Ephedrine Alkoxide to Mediate Enantioselective Addition of an Acetylide to a Prochiral Ketone: Asymmetric Synthesis of the Reverse Transcriptase Inhibitor L-743,726.
Thompson, Andrew S.,Corley, Edward G.,Huntington, Martha F.,Grabowski, E. J. J.
, p. 8937 - 8940 (2007/10/02)
The asymmetric synthesis of L-743,726 was achieved in six steps with an overall yield of 31 percent.The asymmetry was introduced using a lithiated ephedrine to mediate acetylide addition to a trifluoromethyl ketone with an enantiomeric excess of 96-98 percent.
