Mechanism-based ligand design for copper-catalysed enantioconvergent C(sp3)-C(sp) cross-coupling of tertiary electrophiles with alkynes

• Published in: Nature chemistry Vol. 14; no. 8; pp. 949 - 957
• Main Authors: Wang, Fu-Li, Yang, Chang-Jiang, Liu, Ji-Ren, Yang, Ning-Yuan, Dong, Xiao-Yang, Jiang, Ruo-Qi, Chang, Xiao-Yong, Li, Zhong-Liang, Xu, Guo-Xiong, Yuan, Dai-Lei, Zhang, Yu-Shuai, Gu, Qiang-Shuai, Hong, Xin, Liu, Xin-Yuan
• Format: Journal Article
• Language: English
• Published: BERLIN NATURE PORTFOLIO 01.08.2022; Nature Publishing Group
• Subjects: Alkynes; Carbon; Chemistry; Chemistry, Multidisciplinary; Construction; Copper; Cross coupling; Design; Forging; Halides; Ligands; Physical Sciences; Radical groups; Science & Technology; Steric hindrance; S(N)1; QUATERNARY CARBON CENTERS; ENANTIOSELECTIVE CONSTRUCTION; STEREOCENTERS
• ISSN: 1755-4330; 1755-4349
• DOI: 10.1038/s41557-022-00954-9

In contrast with the well-established enantioconvergent radical C(sp(3))-C cross-coupling of racemic secondary alkyl electrophiles, the corresponding coupling of tertiary electrophiles to forge all-carbon quaternary stereocentres remains underexplored. The major challenge arises from the steric hindrance and the difficult enantio-differentiation of three distinct carbon substituents of prochiral tertiary radicals. Here we demonstrate a general copper-catalysed enantioconvergent C(sp(3))-C(sp) cross-coupling of diverse racemic tertiary alkyl halides with terminal alkynes (87 examples). Key to the success is the rational design of chiral anionic N,N,N-ligands tailor-made for the computationally predicted outer-sphere radical group transfer pathway. This protocol provides a practical platform for the construction of chiral C(sp(3))-C(sp/sp(2)/sp(3)) bonds, allowing for expedient access to an array of synthetically challenging quaternary carbon building blocks of interest in organic synthesis and related areas.