Stereoselective Synthesis of Aminals Through Enzyme‐Catalyzed Intermolecular C(sp 3 )‐H Amidation of Azacycles

ABSTRACT Stereogenic aminals are widespread in natural products, pharmaceuticals, and biologically active compounds, including important classes of antibiotics. Methodologies for asymmetric synthesis of aminals are therefore highly desirable, yet they remain scarce and mostly rely on C─N bond formation at functionalized carbon centers such as carbonyls. Here we report the development of a strategy for asymmetric synthesis of aminals via direct, stereoselective C(sp 3 )–H functionalization of cyclic amines via an enzyme‐catalyzed intermolecular nitrene transfer reaction with dioxazolones. Using engineered variants of thermophilic cytochrome P450 (CYP119) from Sulfolobus solfataricus as catalysts, this approach enables the synthesis of a diverse set of indoline‐based aminals in good to high yields, excellent regio‐ and chemoselectivity, and with enantioselectivity up to >99% ee . This methodology could be further extended to pyrrolidines, piperidines, or morpholines as well as different dioxazolone reagents, yielding a diverse range of enantioenriched aminal scaffolds. This work expands the scope of abiological intermolecular C(sp 3 )–H amination reactions accessible through biocatalysis and provides a convenient, new route to the synthesis of enantioenriched aminal compounds.