Enantioselective oxidation of unactivated C–H bonds in cyclic amines by iterative docking-guided mutagenesis of P450BM3 (CYP102A1)

Selective oxidation of ring C–H bonds is an attractive route to functionalized cyclic amines, which are versatile intermediates in drug synthesis and important fragment molecules discovery. Here we report a combined substrate enzyme engineering approach achieve enantioselective functionalization all unactivated azepane, azocane, 7-azabicyclo[2.2.1]heptane 8-azaspiro[4.5]decane by cytochrome P450BM3 (CYP102A1). Different N-modifying groups provide product diversity at high enantioselectivity (up 99% e.e.) from panel just 48 variants P450BM3. Substrate docking into molecular-dynamics-simulated structures shown be useful for designing mutations increase disfavouring binding poses leading the unwanted enantiomer, enzymatic activity non-productive ten or so per generation. The synthetic application remote activation within amines exemplified anisodamine via hydroxylation N-Boc-nortropinone. synthesis. Now, engineered P450 enzymes, designed with computational guidance disfavour undesired products, reported oxidize selectivity.