Indolines are ubiquitous structural motifs occurring in pharmaceuticals and natural products. Here, we report a strategy for regio- and stereoselective C(sp³)–H functionalization of N-substituted indolines via carbene transfer chemistry mediated by engineered CYP119-based catalysts. These systems offer high enantioselectivity and high catalytic efficiency, as well as regiodivergent selectivity, furnishing an efficient and convenient route for diversification of these important scaffolds via direct C(sp³)–H functionalization. Selective functionalization of exocyclic C(sp³)–H bond in N-methyl indolines was also achieved, and a biocatalytic cascade combining enzyme-mediated α- and β-C(sp³)–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(sp³)–H carbene insertion.

中文翻译：

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自由基介导的 N 取代吲哚啉的区域发散 C（sp3）-H 官能化，通过酶促卡宾转移


吲哚啉是药物和天然产物中普遍存在的结构基序。在这里，我们报道了一种通过基于工程 CYP119 的催化剂介导的卡宾转移化学对 N 取代的吲哚啉进行区域选择性和立体选择性 C（sp³）-H 官能化的策略。这些系统具有高对映体选择性和高催化效率，以及区域差异选择性，为通过直接 C（sp³）-H 官能化实现这些重要支架的多样化提供了一条高效便捷的途径。还实现了 N-甲基吲哚啉中外环 C（sp³）-H 键的选择性功能化，并且结合酶介导的 α-和 β-C（sp³）-H 功能化的生物催化级联反应产生了在药物中发现的含多环吲哚啉的基序。机制和计算研究支持自由基介导的 C-H 功能化途径，并提供了对蛋白质介导的区域差异选择性的见解。总而言之，这项工作提供了一种直接且可调的策略，以访问功能化吲哚啉作为药物化学和天然产物合成的关键组成部分，并提供了对 P450 催化的 C（sp³）-H 卡宾插入机制的初步见解。