Copper-catalyzed enantioselective Sonogashira-type oxidative cross-coupling of unactivated C(sp3)\u2212H bonds with alkynes

Zhen-Hua Zhang,Xiao-Yang Dong,Qiang-Shuai Gu,Xin-Yuan Liu,Zhong-Liang Li,Xuan-Yi Du

doi:10.1038/s41467-019-13705-1

Zhen-Hua Zhang, Xiao-Yang Dong + Show 4 more

Open Access

https://doi.org/10.1038/s41467-019-13705-1

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Abstract

Transition metal-catalyzed enantioselective Sonogashira-type oxidative C(sp3)—C(sp) coupling of unactivated C(sp3)−H bonds with terminal alkynes has remained a prominent challenge. The difficulties mainly stem from the regiocontrol in unactivated C(sp3)—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(sp3)—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(sp3)−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(sp3)—C(sp), C(sp3)—C(sp2), and C(sp3)—C(sp3) bonds when allied with follow-up transformations.

Highlights

Transition metal-catalyzed enantioselective Sonogashira-type oxidative C(sp3)—C(sp) coupling of unactivated C(sp3)−H bonds with terminal alkynes has remained a prominent challenge
We have recently developed a copper/cinchona alkaloid-based N,N-ligand catalyst, which could intimately associate with alkyl radical species for realization of asymmetric alkene difunctionalization[43,44,45,46]
We describe our efforts toward the development of radical asymmetric oxidative cross-coupling of unactivated C(sp3) −H bonds with terminal alkynes enabled by copper(I)/cinchona alkaloid-based N,N,P-ligand catalysis

Summary

Introduction

Transition metal-catalyzed enantioselective Sonogashira-type oxidative C(sp3)—C(sp) coupling of unactivated C(sp3)−H bonds with terminal alkynes has remained a prominent challenge. We have recently developed a copper/cinchona alkaloid-based N,N-ligand catalyst, which could intimately associate with alkyl radical species for realization of asymmetric alkene difunctionalization[43,44,45,46] Inspired by these works, we wondered if this catalyst system would be suitable for tandem site-selective HAA on unactivated C (sp3)−H bonds and enantioselective coupling with terminal alkynes (Fig. 1b). We describe our efforts toward the development of radical asymmetric oxidative cross-coupling of unactivated C(sp3) −H bonds with terminal alkynes enabled by copper(I)/cinchona alkaloid-based N,N,P-ligand catalysis This protocol provides a range of chiral alkynyl amides and alkynyl aldehydes (Fig. 1c) and, together with further transformations, offers a general way for chiral C(sp3)–C(sp), C(sp3)–C(sp2), and C(sp3)–C(sp3) bond construction

Methods

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Conclusion