Site- and enantioselective cross-coupling of saturated N-heterocycles with carboxylic acids by cooperative Ni/photoredox catalysis

Xiaomin Shu, Zhong De, Qian Huang, Leitao Huan and Haohua Huo ()
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Xiaomin Shu: College of Chemistry and Chemical Engineering, Xiamen University
Zhong De: College of Chemistry and Chemical Engineering, Xiamen University
Qian Huang: College of Chemistry and Chemical Engineering, Xiamen University
Leitao Huan: College of Chemistry and Chemical Engineering, Xiamen University
Haohua Huo: College of Chemistry and Chemical Engineering, Xiamen University

Nature Communications, 2023, vol. 14, issue 1, 1-10

Abstract: Abstract Site- and enantioselective cross-coupling of saturated N-heterocycles and carboxylic acids—two of the most abundant and versatile functionalities—to form pharmaceutically relevant α-acylated amine derivatives remains a major challenge in organic synthesis. Here, we report a general strategy for the highly site- and enantioselective α-acylation of saturated N-heterocycles with in situ-activated carboxylic acids. This modular approach exploits the hydrogen-atom-transfer reactivity of photocatalytically generated chlorine radicals in combination with asymmetric nickel catalysis to selectively functionalize cyclic α-amino C−H bonds in the presence of benzylic, allylic, acyclic α-amino, and α-oxy methylene groups. The mild and scalable protocol requires no organometallic reagents, displays excellent chemo-, site- and enantioselectivity, and is amenable to late-stage diversification, including a modular synthesis of previously inaccessible Taxol derivatives. Mechanistic studies highlight the exceptional versatility of the chiral nickel catalyst in orchestrating (i) catalytic chlorine elimination, (ii) alkyl radical capture, (iii) cross-coupling, and (iv) asymmetric induction.

Date: 2023
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DOI: 10.1038/s41467-023-35800-0

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