Department of Chemistry, Tianjin University, Tianjin 300072, China; Department of Applied Chemistry, China Agricultural University, Beijing 100193, China; UMR 6014 CNRS, Laboratoire COBRA de l’IRCOF, Université et INSA de Rouen, Rue Tesniere, F-76130 Mont Saint Aignan, France; and Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Science, Shanghai 200032, China

Asymmetric construction of stereogenic carbon centers featuring a trifluoromethyl group from prochiral trifluoromethylated substrates.

Trifluoromethyltrimethylsilane: nucleophilic trifluoromethylation and beyond.

http://pubs.acs.org/doi/pdf/10.1021/acs.oprd.5b00325

Flow Chemistry: Recent Developments in the Synthesis of Pharmaceutical Products

Enantioselective Catalytic Formation of Quaternary Stereogenic Centers

Chiral tertiary alcohols and R-tertiary amines are important building blocks of naturally occurring and artificial biologically active molecules. Although there are catalytic asymmetric oxidation and amination reactions to access these chiral building blocks, the catalytic asymmetric addition of carbon nucleophiles to ketones and ketimines, which can simultaneously construct a carbon skeleton and tetrasubstituted stereogenic center, is synthetically more efficient (Scheme 1). Realizing the catalytic asymmetric addition to ketones and ketimines (tetrasubstituted carbon synthesis), however, is generally more challenging than addition to aldehydes or aldimines (trisubstituted carbon synthesis) for two main reasons: (1) ketones and ketimines are significantly less reactive than aldehydes and aldimines; (2) enantio-face differentiation of ketones and ketimines is more difficult due to the smaller steric and electronic differences between the two substituents on prochiral carbons. Therefore, asymmetric catalysts that promote C-C bond-formation to ketones and ketimines should have high catalyst activity and enantioselectivity.

Asymmetric Synthesis of Tertiary Alcohols and α-Tertiary Amines via Cu-Catalyzed C−C Bond Formation to Ketones and Ketimines

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.

Susan J. Morgan

Papers

Practical asymmetric synthesis of Efavirenz (DMP 266), an HIV-1 reverse transcriptase inhibitor