12/23/2022 – Congratulations to Myriam and Sara on their work on heteroarene hydrocarboxylation reaction that translates 2D heterocycles into versatile 3D analogs. Out on the rxiv now!

The rapid preparation of complex three-dimensional (3D) heterocyclic scaffolds is a key challenge in modern medicinal chemistry. Small molecule therapeutic candidates with increased 3D complexity, on average, possess a higher probability of clinical success. However, new drug targets remain dominated by flat molecules due the wealth of robust coupling reactions available for their construction. Heteroarene dearomatization reactions offer an ideal opportunity to transform readily accessible 2D structures into saturated analogs. Broadly employed heteroarene hydrogenation reactions rehybridize C(sp2) sites to C(sp3) without otherwise perturbing the molecular shape. In stark contrast, heteroarene difunctionalization strategies dramatically change the molecular structure. In principle, heteroarene hydrofunctionalization reactions constitute an elusive middle ground by disrupting aromaticity and introducing a single molecular vector. Unfortunately, dearomative hydrofunctionalization reactions remain limited. Herein, we report a new strategy to enable the dearomative hydrocarboxylation of indoles and related heterocycles. This reaction represents a rare example of a heteroarene hydrofunctionalization that meets the numerous requirements for broad implementation in drug discovery. The transformation is highly chemoselective, broad in scope, operationally simple, and readily amenable to high-throughput experimentation (HTE). Accordingly, this process will allow existing libraries of heteroaromatic compounds to be translated into diverse 3D analogs and enable exploration of new classes of medicinally relevant molecules.