Regio- and Enantioselective Catalytic δ-C-H Amidation of Dioxazolones Enabled by Open-Shell Copper-Nitrenoid Transfer

Controlling regio- and enantioselectivity in C-Hfunctionalizationreactions is of paramount importance due to their versatile syntheticutilities. Herein, we describe a new approach for the asymmetric & delta;-C(sp(3))-H amidation catalysis of dioxazolones using a Cu(I)precursor with a chiral bisoxazoline ligand to access six-memberedlactams with high to excellent regio- and enantioselectivity (up to>19:1 rr and >99:1 er). Combined experimental and computationalmechanisticstudies unveiled that the open-shell character of the postulated Cu-nitrenoidsenables the regioselective hydrogen atom abstraction and subsequentenantio-determining radical rebound of the resulting carbon radicalintermediates. The synthetic utility of this asymmetric cyclizationwas demonstrated in the diastereoselective introduction of additionalfunctional groups into the chiral & delta;-lactam skeleton as wellas in the rapid access to biorelevant azacyclic compounds.

Automated summary

A new method for the asymmetric C-H amidation of dioxazolones using a Cu(I) precursor with a chiral bisoxazoline ligand has been developed, allowing the synthesis of six-membered lactams with high selectivity (up to >19:1 rr and >99:1 er). Mechanistic studies suggest that the regioselective hydrogen atom abstraction and subsequent enantio-determining radical rebound of the resulting carbon radical intermediates are enabled by the open-shell character of the postulated Cu-nitrenoids. This asymmetric cyclization has demonstrated its synthetic utility in the diastereoselective introduction of additional functional groups into the chiral lactam skeleton and the rapid access to biorelevant azacyclic compounds.