Radical-Mediated Regiodivergent C(sp 3 )-H Functionalization of N-Substituted Indolines via Enzymatic Carbene
Bo M Couture1, Ru Cui1, Jia-Min Chu2
1Department of Chemistry and Biochemistry, University of Texas at Dallas, Richardson, TX, 75080, United States.
Abstract:
Indolines are ubiquitous structural motifs occurring in pharmaceuticals and natural products. Here, we report a strategy for regio- and stereoselective C(sp 3 )-H functionalization of N-substituted indolines via carbene transfer chemistry mediated by engineered CYP119-based catalysts. These systems offer high enantioselectivity, high catalytic efficiency, as well as regiodivergent selectivity, furnishing an efficient and convenient route for diversification of these important scaffolds via direct C(sp 3 )-H functionalization. Selective functionalization of exocyclic C(sp 3 )-H bond in N-methyl indolines was also achieved and a biocatalytic cascade combining enzyme-mediated α- and β-C(sp 3 )-H functionalization yielded a polycyclic indoline-containing motif found in drugs. Mechanistic and computational studies support a radical-mediated C-H functionalization pathway and provide insights into protein-mediated regiodivergent selectivity. Altogether, this work offers a direct and tunable strategy to access functionalized indolines as key building blocks for medicinal chemistry and natural product synthesis and provides first insights into the mechanism of P450-catalyzed C(sp 3 )-H carbene insertion.
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