Access to enantioenriched atropisomers through biocatalytic deracemization

The ability to synthesize enantiopure materials is vital for pharmaceutical and agrochemical industries due to the inherently chiral nature of biological systems and the fact that two enantiomers can have drastically different biochemical properties within organisms and ecosystems. In particular, enantioselective preparation of atropisomers is of great interest due to their privileged status as chiral ligands and pharmacophores. Although chromatographic- or crystallization-based methods are commonly used to separate atropisomers, we urgently need more efficient and economical approaches to access enantioenriched atropisomers. The use of stereoconvergent methods to access molecules with point chirality is well established, but we have not yet tapped the potential of stereoconvergent catalytic methods to arrive at enantioenriched atropisomers. We recently discovered deracemization activity in a wild-type P450 enzyme and explored its ability to deliver a stereoconvergent route toward enantioenriched atropisomers. Using a curated set of P450 variants, we found that a wide variety of symmetric and non-symmetrically substituted 2,2ʹ-binaphthol (BINOL) building blocks can be deracemized to high enantiomeric purity. Further, we demonstrated that this deracemization activity is mechanistically distinct from activity of previously reported P450 enzymes, which operate through enantioselective bond formation to afford enantioenriched atropisomers, whereas, the deracemization process reported here is proposed to proceed through bond rotation. As engineered variants have complementary selectivity profiles and substrate scope, this biocatalytic platform should be readily tunable for any desired substitution pattern. We anticipate that these results will inspire new stereoconvergent approaches to synthesizing configurationally stable atropisomers.