Copper-catalyzed enantioselective Sonogashira-type oxidative cross-coupling of unactivated C(sp3)−H bonds with alkynes

• Published in: Nature communications Vol. 10; no. 1; pp. 5689 - 10
• Main Authors: Zhang, Zhen-Hua, Dong, Xiao-Yang, Du, Xuan-Yi, Gu, Qiang-Shuai, Li, Zhong-Liang, Liu, Xin-Yuan
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12.12.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 140/131; 639/638/549/933; 639/638/549/972; 639/638/77/883; Alkynes; Bonding; Catalysts; Chemistry; Copper; Cross coupling; Enantiomers; Humanities and Social Sciences; Intermediates; Laboratories; Ligands; multidisciplinary; Nitrogen; Oxidation; Science; Science (multidisciplinary); Solvents
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-13705-1

Transition metal-catalyzed enantioselective Sonogashira-type oxidative C( sp 3 )—C( sp ) coupling of unactivated C( sp 3 )−H bonds with terminal alkynes has remained a prominent challenge. The difficulties mainly stem from the regiocontrol in unactivated C( sp 3 )—H bond functionalization and the inhibition of readily occurring Glaser homocoupling of terminal alkynes. Here, we report a copper/chiral cinchona alkaloid-based N,N,P -ligand catalyst for asymmetric oxidative cross-coupling of unactivated C( sp 3 )—H bonds with terminal alkynes in a highly regio-, chemo-, and enantioselective manner. The use of N -fluoroamide as a mild oxidant is essential to site-selectively generate alkyl radical species while efficiently avoiding Glaser homocoupling. This reaction accommodates a range of (hetero)aryl and alkyl alkynes; (hetero)benzylic and propargylic C( sp 3 )−H bonds are all applicable. This process allows expedient access to chiral alkynyl amides/aldehydes. More importantly, it also provides a versatile tool for the construction of chiral C( sp 3 )—C( sp ), C( sp 3 )—C( sp 2 ), and C( sp 3 )—C( sp 3 ) bonds when allied with follow-up transformations. Enantioselective oxidative cross-coupling of unactivated C( sp 3 )−H bonds and terminal alkynes is challenging. Here, the authors developed a copper/cinchona alkaloid catalyst for the asymmetric Sonogashira-type alkynylation of C( sp 3 )-H bonds via radical intermediates.