Enzymatic catalysis meets radical coupling

Abstract

The first stage exploits enzyme-driven hydroxylation of carboxylated piperidine derivatives. The team engineered α-ketoglutarate (α-KG)-dependent dioxygenases (SaEctD), which binds to molecular oxygen to form a reactive iron-oxo centre capable of hydroxylating C–H bonds. Moreover, interactions between the substrate’s carboxylate group and specific active site residues, such as Gln127 and Arg280, align the substrate in a binding mode favourable to regioselective and stereospecific product formation.

The second stage capitalizes on radical reactivity to sequentially attach modules of interest to handle sites. Accordingly, as-synthesized hydroxylated carboxylate intermediates first undergo electrocatalytic decarboxylation, forming radicals via a single-electron transfer mechanism mediated by a nickel catalyst. These radicals then interact with electrophilic coupling partners, such as aryl halides. Simultaneously, the remaining hydroxyl group is converted into a more reactive functional handle, such as a redox-active ester or aldehyde. In a second electrocatalytic reaction, the transformed hydroxyl handle enables the addition of another module following an analogous radical-coupling pathway.