Biocatalytic synthesis of heterobiaryl sulfoxides: A comparative study between Baeyer-Villiger monooxygenases and unspecific peroxygenases

The biocatalytic sulfoxidation of heterobiaryl indole- and pyrrole-based sulfides was investigated using unspecific peroxygenases (UPOs) and Baeyer-Villiger monooxygenases (BVMOs) as complementary oxidative biocatalysts. Among the UPOs tested, only the UPO from Marasmius rotula showed outstanding catalytic efficiency, reaching up to 99% conversion at substrate concentrations as high as 60 mM, with excellent chemoselectivity toward sulfoxides (>90%), albeit with moderate enantioselectivities (17-64% ee). In contrast, screening of a panel of BVMOs revealed superior stereochemical control: TmCHMO enabled the sulfoxidation of indole-based sulfides with enantioselectivities up to 94% ee, while OTEMO proved particularly effective for pyrrole-based substrates, affording sulfoxides in up to 90% ee. Reaction parameters such as temperature, pH, cosolvent and substrate loading have been optimized, allowing reaction rates of up to 22.4 mmol L -1 h -1 at 50 mM substrate concentration without enantioselectivity loss. Overall, pyrrole-based sulfides displayed higher optical purities than indole analogues under BVMO catalysis, whereas UPOs excelled in terms of productivity and operational simplicity. Selected BVMO- and UPO-catalyzed reactions were successfully scaled up, demonstrating the practical applicability of these biocatalytic systems. These results highlight the complementary strengths of UPOs and BVMOs for the efficient and selective synthesis of chiral heterobiaryl sulfoxides.