Synthesis of Diverse 11- and 12-Membered Macrolactones from a Common Linear Substrate Using a Single Biocatalyst

[Image: see text] The diversification of late stage synthetic intermediates provides significant advantages in efficiency in comparison to conventional linear approaches. Despite these advantages, accessing varying ring scaffolds and functional group patterns from a common intermediate poses considerable challenges using existing methods. The combination of regiodivergent nickel-catalyzed C–C couplings and site-selective biocatalytic C–H oxidations using the cytochrome P450 enzyme PikC addresses this problem by enabling a single late-stage linear intermediate to be converted to macrolactones of differing ring size and with diverse patterns of oxidation. The approach is made possible by a novel strategy for site-selective biocatalytic oxidation using a single biocatalyst, with site selectivity being governed by a temporarily installed directing group. Site selectivities of C–H oxidation by this directed approach can overcome positional bias due to C–H bond strength, acidity, inductive influences, steric accessibility, or immediate proximity to the directing group, thus providing complementarity to existing approaches.