Computationally Guided Ligand Discovery from Compound Libraries and Discovery of a New Class of Ligands for Ni-Catalyzed Cross-Electrophile Coupling of Challenging Quinoline Halides.

Although screening technology has heavily impacted the fields of metal catalysis and drug discovery, its application to the discovery of new catalyst classes has been limited. The diversity of on- and off-cycle pathways, combined with incomplete mechanistic understanding, means that screens of potential new ligands have thus far been guided by intuitive analysis of the metal binding potential. This has resulted in the discovery of new classes of ligands, but the low hit rates have limited the use of this strategy because large screens require considerable cost and effort.

Synthetic Approaches to the New Drugs Approved During 2021.

Each year, new drugs are introduced to the market, representing structures that have affinity for biological targets implicated in human diseases and conditions. These new chemical entities (NCEs), particularly small molecules and antibody-drug conjugates, provide insight into molecular recognition and serve as potential leads for the design of future medicines. This annual review is part of a continuing series highlighting the most likely process-scale synthetic approaches to 35 NCEs that were first approved anywhere in the world during 2021.

Nucleophilic Transformations of Lewis Acid-Activated Disubstituted Epoxides with Catalyst-Controlled Regioselectivity.

Due to their inherent ring strain and electrophilicity, epoxides are highly attractive building blocks for fundamental organic reactions. However, controlling the regioselectivity of disubstituted epoxide transformations is often particularly challenging. Most Lewis acid-mediated processes take advantage of intrinsic steric or electronic substrate bias to influence the site of nucleophilic attack.

Carbonylative, Catalytic Deoxygenation of 2,3-Disubstituted Epoxides with Inversion of Stereochemistry: An Alternative Alkene Isomerization Method.

Reactions facilitating inversion of alkene stereochemistry are rare, sought-after transformations in the field of modern organic synthesis. Although a number of isomerization reactions exist, most methods require specific, highly activated substrates to achieve appreciable conversion without side product formation. Motivated by stereoinvertive epoxide carbonylation reactions, we developed a two-step epoxidation/deoxygenation process that results in overall inversion of alkene stereochemistry.

Regioselective Carbonylation of 2,2-Disubstituted Epoxides: An Alternative Route to Ketone-Based Aldol Products.

We report the regioselective carbonylation of 2,2-disubstituted epoxides to β,β-disubstituted β-lactones. Mechanistic studies revealed epoxide ring-opening as the turnover limiting step, an insight that facilitated the development of improved reaction conditions using weakly donating, ethereal solvents. A wide range of epoxides can be carbonylated to β-lactones, which are subsequently ring-opened to produce ketone-based aldol adducts, providing an alternative to the Mukaiyama aldol reaction.