Translating Planar Heterocycles into Three-Dimensional Analogs by Photoinduced Hydrocarboxylation.

The rapid preparation of complex three-dimensional (3D) heterocyclic scaffolds is a key challenge in modern medicinal chemistry. Despite the increased probability of clinical success for small molecule therapeutic candidates with increased 3D complexity, new drug targets remain dominated by flat molecules due to the abundance of coupling reactions available for their construction. In principle, heteroarene hydrofunctionalization reactions offer an opportunity to transform readily accessible planar molecules into more three-dimensionally complex analogs through the introduction of 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.

Practical and General Alcohol Deoxygenation Protocol.

Herein, we describe a practical protocol for the removal of alcohol functional groups through reductive cleavage of their benzoate ester analogs. This transformation requires a strong single electron transfer (SET) reductant and a means to accelerate slow fragmentation following substrate reduction. To accomplish this, we developed a photocatalytic system that generates a potent reductant from formate salts alongside Brønsted or Lewis acids that promote fragmentation of the reduced intermediate. This deoxygenation procedure is effective across structurally and electronically diverse alcohols and enables a variety of difficult net transformations. This protocol requires no precautions to exclude air or moisture and remains efficient on multigram scale. Finally, the system can be adapted to a one-pot benzoylation-deoxygenation sequence to enable direct alcohol deletion. Mechanistic studies validate that the role of acidic additives is to promote the key C(sp3 )-O bond fragmentation step.

Chemoselective Oxidation of Equatorial Alcohols with N-Ligated λ3-Iodanes.

The site-selective and chemoselective functionalization of alcohols in complex polyols remains a formidable synthetic challenge. Whereas significant advancements have been made in selective derivatization at the oxygen center, chemoselective oxidation to the corresponding carbonyls is less developed. In cyclic systems, whereas the selective oxidation of axial alcohols is well known, a complementary equatorial selective process has not yet been reported. Herein we report the utility of nitrogen-ligated (bis)cationic λ3-iodanes (N-HVIs) for alcohol oxidation and their unprecedented levels of selectivity for the oxidation of equatorial over axial alcohols. The conditions are mild, and the simple pyridine-ligated reagent (Py-HVI) is readily synthesized from commercial PhI(OAc)2 and can be either isolated or generated in situ. Conformational selectivity is demonstrated in both flexible 1,2-substituted cyclohexanols and rigid polyol scaffolds, providing chemists with a novel tool for chemoselective oxidation.