Radical-Mediated Regiodivergent C(sp3)–H Functionalization of N-Substituted Indolines via Enzymatic Carbene Transfer

Indolines are ubiquitous structural motifs found in pharmaceuticals and natural products but modification of these scaffolds via selective C(sp3)–H functionalization represents a major challenge. Herein, we report the regio- and stereoselective C(sp3)–H functionalization of N-substituted indolines to produce both -and-functionalized indolines via carbene transfer chemistry with engineered iron-based CYP119 catalysts. These transformations are shown to proceed with high regio- (up to >99%) and enantioselectivity (up to 98% e.e.) as well as excellent catalytic efficiency (up to 99% yield and 8,900 TON), furnishing an efficient and regiodivergent route for diversification of this class of medicinally relevant molecules via direct C(sp3)–H functionalization. We further show that these catalysts can enable selective functionalization of exocyclic C(sp3)–H bond in N-methyl indolines and that enzyme-mediated a-and b-C(sp3)–H functionalization can be combined in a biocatalytic cascade to yield polycyclic indoline-containing scaffolds, which can be found in many drugs. Finally, computational and experimental mechanistic studies provide evidence for the occurrence of a radical-mediated C–H functionalization pathway, providing first insights into the mechanism of P450-catalyzed C(sp3)–H carbene insertion. Altogether, this work provides a direct and tunable strategy for the synthesis of functionalized indolines as key building blocks for medicinal chemistry and natural product synthesis and it sheds light into the mechanism of P450-catalyzed C(sp3)–H functionalization via carbene transfer.