Biocatalytic C–H Oxidation Meets Radical Cross-Coupling: Simplifying Complex Piperidine Synthesis

Medicinal chemists in the modern era are targeting molecules with greater complexity to address increasingly challenging biological targets, a drive to enhance on-target specificity as well as physiochemical properties. As such, structures with greater fraction sp3 (Fsp3) character, reminiscent to those found in nature, are being synthesized. Many decades of synthetic methodology development have democratized access to flat, high sp2 (for example biaryl linkages) which has led to the commercialization of innumerable medicines. Those approaches rely heavily on electrophilic aromatic substitution (such as halogenation) followed by Pd-based cross coupling. In contrast, methods and strategies that allow for similarly modular and rapid construction of three-dimensional saturated molecules are less well developed. Here we exemplify a new approach for the rapid, modular, enantioselective construction of piperidine frameworks (the saturated analog of pyridine) that combines robust, tunable, and scalable biocatalytic methods with the logic of radical cross coupling. Thus, a set of reliable enzymatic systems (analogous to site-selective aromatic functionalization) provides scalable access to enantiopure hydroxyacid- containing piperidine derivatives that can be utilized to dramatically simplify routes to medicinally important molecules and natural products by employing recently developed electrocatalytic couplings (analogous to Pd-based cross couplings in aromatic systems). This study points to a different approach to rapidly access complex architectures that may appeal to both medicinal and process chemists alike.