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

Publikationsverlauf

Eingereicht: 28. Mai 2025

Angenommen nach Revision: 14. Juli 2025

Accepted Manuscript online:
14. Juli 2025

Artikel online veröffentlicht:
05. August 2025

• References

• 1a Mahatthananchai J, Dumas AM, Bode JW. Angew Chem Int Ed 2012; 51: 10954
• 1b Ping L, Chung DS, Bouffard J, Lee S-G. Chem Soc Rev 2017; 46: 4299
• 1c Nájera C, Beletskaya IP, Yus M. Chem Soc Rev 2019; 48: 4515
• 2a Zhan G, Du W, Chen Y-C. Chem Soc Rev 2017; 46: 1675
• 2b Collins S, Sieber JD. Chem Commun 2023; 59: 10087
• 3a Romero NA, Nicewicz DA. Chem Rev 2016; 116: 10075
• 3b Xiong T, Zhang Q. Chem Soc Rev 2021; 50: 8857
• 3c Nagib DA. Chem Rev 2022; 122: 15989
• 4a Sibi MP, Manyem S, Zimmerman J. Chem Rev 2003; 103: 3263
• 4b Mondal S, Dumur F, Gigmes D, Sibi MP, Bertrand MP, Nechab M. Chem Rev 2022; 122: 5842
• 5a Gu Q-S, Li Z-L, Liu X-Y. Acc Chem Res 2019; 53: 170
• 5b Schwinger DP, Bach T. Acc Chem Res 1933; 2020: 53
• 6a Gansäuer A, Shi L, Otte M. J Am Chem Soc 2010; 132: 11858
• 6b Zhang Z, Slak D, Krebs T. et al. J Am Chem Soc 2023; 145: 26667
• 7 Li L, Yang S, Xu Z, Li S, Jiang J, Zhang Y-Q. J Am Chem Soc 2024; 146: 13546
• 8 Wang X, Xue J, Rong Z-Q. J Am Chem Soc 2023; 145: 15456
• 9 Fan C, Dhawa U, Qian D, Sakic D, Morel J, Hu X. Angew Chem Int Ed 2024; 63: e202406767
• 10 Yang F, Chi L, Ye Z, Gong L. J Am Chem Soc 2025; 147: 1467
• 11 Cheung PSK, Fang J, Mukherjee K, Mihranyan A, Gevorgyan V. Science 2022; 378: 1207
• 12 Qi R, Wang C, Huo Y. et al. J Am Chem Soc 2021; 143: 12777
• 13 Li Y, Lei M, Gong L. Nat Catal 2019; 2: 1016
• 14a Chen C, Peters JC, Fu GC. Nature 2021; 596: 250
• 14b Chen J-J, Fang J-H, Du X-Y. et al. Nature 2023; 618: 294
• 15a Zhang W, Wang F, McCann SD. et al. Science 2016; 353: 1014
• 15b Xu P, Fan W, Chen P, Liu G. J Am Chem Soc 2022; 144: 13468