Selective P450BM3 Hydroxylation of the Spiro[3.3]heptane Core as a Route to Potential Drug Fragment Molecules

Engineered P450_BM3 enzyme variants, developed from an initial screening panel of 42 enzymes, convert N-benzyl spiro[3.3]heptane-2-carboxamide into three distally monohydroxylated regioisomers with essentially complete enantioselectivity. Two α-hydroxyamide derivatives are also produced. Elaboration of the metabolites by tethered C-H amination leads to spiro[3.3]heptane motifs substituted with three different functional groups ready for further derivatization.