Chem Catal. 2024 Nov 21;4(11):101133. doi: 10.1016/j.checat.2024.101133.
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.
PMID:42524225 | PMC:PMC13409402 | DOI:10.1016/j.checat.2024.101133