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

Site- and enantioselective cross-coupling of saturated N-heterocycles and carboxylic acids-two of the most abundant and versatile functionalities-to form pharmaceutically relevant alpha-acylated amine derivatives remains a major challenge in organic synthesis. Here, we report a general strategy for the highly site- and enantioselective alpha-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 alpha-amino C-H bonds in the presence of benzylic, allylic, acyclic alpha-amino, and alpha-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.

Automated summary

Site- and enantioselective alpha-acylation of saturated N-heterocycles with in situ-activated carboxylic acids is achieved using a modular approach that combines hydrogen-atom-transfer reactivity of photocatalytically generated chlorine radicals with asymmetric nickel catalysis. This strategy selectively functionalizes cyclic alpha-amino C-H bonds without affecting benzylic, allylic, acyclic alpha-amino, and alpha-oxy methylene groups. The protocol displays excellent chemo-, site-, and enantioselectivity and can be used for late-stage diversification, including the synthesis of previously inaccessible Taxol derivatives.