文献类型：期刊文献

英文题名：Modular α-tertiary amino ester synthesis through cobalt-catalysed asymmetric aza-Barbier reaction

作者：Wu, Xianqing[1,2];Xia, Hanyu[1,2];Gao, Chenyang[1,2];Luan, Baixue[1,2];Wu, Licheng[1,2];Zhang, Chengxi[1,2];Yang, Dawei[3];Hou, Liting[1,2];Liu, Ning[1,2];Xia, Tingting[1,2];Li, Haiyan[1,2];Qu, Jingping[1,2,3];Chen, Yifeng[1,2]

机构：[1]East China Univ Sci & Technol, Frontiers Sci Ctr Materiobiol & Dynam Chem, Sch Chem & Mol Engn, Key Lab Adv Mat, Shanghai 200237, Peoples R China;[2]East China Univ Sci & Technol, Feringa Nobel Prize Scientist Joint Res Ctr, Frontiers Sci Ctr Materiobiol & Dynam Chem, Sch Chem & Mol Engn,Joint Int Res Lab Precis Chem, Shanghai, Peoples R China;[3]Dalian Univ Technol, State Key Lab Fine Chem, Dalian, Peoples R China

年份：2024

卷号：16

期号：3

外文期刊名：NATURE CHEMISTRY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:001121319000001)，CCR-EXPANDED(收录号:WOS:001121319000001)】；

基金：This work was supported by NSFC/China (22171079, 22371071), the Natural Science Foundation of Shanghai (21ZR1480400), the Shanghai Rising-Star Program (20QA1402300), the Shanghai Municipal Science and Technology Major Project (grant no. 2018SHZDZX03), the Program of Introducing Talents of Discipline to Universities (B16017), the China Postdoctoral Science Foundation (2021M701197, 2023T160215), the Shanghai Sailing Program (23YF1408800) and the Fundamental Research Funds for the Central Universities. We thank the Analysis and Testing Center of East China University of Science and Technology for help with NMR and high-resolution mass spectrometry analysis. Y.C. thanks B. Feringa (University of Groningen) and A. Schuppe (Vanderbilt University) for insightful discussions.

语种：英文

摘要：Unnatural chiral alpha-tertiary amino acids containing two different carbon-based substituents at the alpha-carbon centre are widespread in biologically active molecules. This sterically rigid scaffold is becoming a growing research interest in drug discovery. However, a robust protocol for chiral alpha-tertiary amino acid synthesis remains scarce due to the challenge of stereoselectively constructing sterically encumbered tetrasubstituted stereogenic carbon centres. Herein we report a cobalt-catalysed enantioselective aza-Barbier reaction of ketimines with various unactivated alkyl halides, including alkyl iodides, alkyl bromides and alkyl chlorides, enabling the formation of chiral alpha-tertiary amino esters with a high level of enantioselectivity and excellent functional group tolerance. Primary, secondary and tertiary organoelectrophiles are all tolerated in this asymmetric reductive addition protocol, which provides a complementary method for the well-exploited enantioselective nucleophilic addition with moisture- and air-sensitive organometallic reagents. Moreover, the three-component transformation of alpha-ketoester, amine and alkyl halide represents a formal asymmetric deoxygenative alkylamination of the carbonyl group. Robust protocols for the synthesis of chiral alpha-tertiary amino acids remain scarce due to the challenge of constructing congested tetrasubstituted stereocentres. Now a cobalt-catalysed enantioselective aza-Barbier reaction of ketimines with various unactivated alkyl halides has been developed, forming diverse chiral alpha-tertiary amino esters with high enantioselectivity and excellent functional group tolerance.