Late-Stage Saturation of Drug Molecules.

The available methods of chemical synthesis have arguably contributed to the prevalence of aromatic rings, such as benzene, toluene, xylene, or pyridine, in modern pharmaceuticals. Many such sp2-carbon-rich fragments are now easy to synthesize using high-quality cross-coupling reactions that click together an ever-expanding menu of commercially available building blocks, but the products are flat and lipophilic, decreasing their odds of becoming marketed drugs. Converting flat aromatic molecules into saturated analogues with a higher fraction of sp3 carbons could improve their medicinal properties and facilitate the invention of safe, efficacious, metabolically stable, and soluble medicines. In this study, we show that aromatic and heteroaromatic drugs can be readily saturated under exceptionally mild rhodium-catalyzed hydrogenation, acid-mediated reduction, or photocatalyzed-hydrogenation conditions, converting sp2 carbon atoms into sp3 carbon atoms and leading to saturated molecules with improved medicinal properties. These methods are productive in diverse pockets of chemical space, producing complex saturated pharmaceuticals bearing a variety of functional groups and three-dimensional architectures. The rhodium-catalyzed method tolerates traces of dimethyl sulfoxide (DMSO) or water, meaning that pharmaceutical compound collections, which are typically stored in wet DMSO, can finally be reformatted for use as substrates for chemical synthesis. This latter application is demonstrated through the late-stage saturation (LSS) of 768 complex and densely functionalized small-molecule drugs.

Recent Advances in Dearomative Partial Reduction of Benzenoid Arenes.

Dearomative partial reduction is an extraordinary approach for transforming benzenoid arenes and has been well-known for many decades, as exemplified by the dehydrogenation of Birch reduction and the hydroarylation of Crich addition. Despite its remarkable importance in synthesis, this field has experienced slow progress over the last half-century. However, a revival has been observed with the recent introduction of electrochemical and photochemical methods. In this Minireview, we summarize the recent advancements in dearomative partial reduction of benzenoid arenes, including dihydrogenation, hydroalkylation, arylation, alkenylation, amination, borylation and others. Further, the intriguing utilization of dearomative partial reduction in the synthesis of natural products is also emphasized. It is anticipated that this Minireview will stimulate further progress in arene dearomative transformations.

Chemoselective Quinoline and Isoquinoline Reduction by Energy Transfer Catalysis Enabled Hydrogen Atom Transfer.

(Hetero)arene reduction is one of the key avenues for synthesizing related cyclic alkenes and alkanes. While catalytic hydrogenation and Birch reduction are the two broadly utilized approaches for (hetero)arene reduction across academia and industry over the last century, both methods have encountered significant chemoselectivity challenges. We hereby introduce a highly chemoselective quinoline and isoquinoline reduction protocol operating through selective energy transfer (EnT) catalysis, which enables subsequent hydrogen atom transfer (HAT). The design of this protocol bypasses the conventional metric of reduction reaction, that is, the reductive potential, and instead relies on the triplet energies of the chemical moieties and the kinetic barriers of energy and hydrogen atom transfer events. Many reducing labile functional groups, which were incompatible with previous (hetero)arene reduction reactions, are retained in this reaction. We anticipate that this protocol will trigger the further advancement of chemoselective arene reduction and enable the current arene-rich drug space to escape from flatland.