Visible Light-Triggered Regiodivergent and Enantioselective Alkylation of Glycine Derivatives

Abstract

Regiodivergent asymmetric synthesis provides a powerful strategy for generating structurally diverse chiral molecules from common starting materials. However, achieving precise control over both regio- and stereoselectivity in radical-mediated processes remains a formidable challenge, largely due to the transient nature and flexibility of radical intermediates. To tackle this longstanding issue, we have developed a cooperative catalytic platform that integrates photoinduced hydrogen atom transfer (HAT) with chiral copper catalysis. This dual-catalyst system enables regiodivergent and enantioselective C(sp³)–H functionalization of N-aryl glycine derivatives using simple hydrocarbons as alkylating agents. Through systematic modulation of chiral ligands, additives, and other reaction parameters, we have achieved switchable formation of either C(sp³)–C(sp³) or C(sp³)–N bonds, leading to the selective synthesis of C- or N-alkylated products. The reactions proceed with high efficiency (up to 92% yield), excellent regiocontrol (>20:1 rr), and outstanding enantioselectivity (up to 96% ee). Importantly, this methodology facilitates site-selective alkylation of biologically relevant scaffolds and demonstrates tunable regioselectivity under mild photochemical conditions. Thus, it establishes a new paradigm for stereocontrolled bond construction in complex molecular architectures.

Keywords

Regiodivergent synthesis - Asymmetric synthesis - Hydrogen atom transfer - Chiral copper catalysis - C(sp³)–H functionalization

Publication History

Received: 28 May 2025

Accepted after revision: 14 July 2025

Accepted Manuscript online:
14 July 2025

Article published online:
05 August 2025

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