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.

Chemoselective Heterogeneous Hydrogenation of Sulfur Containing Quinolines under Mild Conditions.

Sulfur, alongside oxygen and nitrogen, holds a prominent position as one of the key heteroatoms in nature and medicinal chemistry. Its significance stems from its ability to adopt different oxidation states, rendering it valuable as both a polarity handle and a hydrogen bond donor/acceptor. Nevertheless, the poisonous nature of its free electron pairs makes sulfur containing substrates inaccessible for many catalytic protocols. Strong and (at low temperatures) irreversible chemisorption to the catalyst's surface is in particular detrimental for heterogeneous catalysts, possessing only few catalytically active sites. Herein, we present a novel heterogeneous Ru-S catalyst that tolerates multiple sulfur functionalities, including thioethers, thiophenes, sulfoxides, sulfones, sulfonamides, and sulfoximines, in the hydrogenation of quinolines. The utility of the products was further demonstrated by subsequent diversifications of the sulfur functionalities.

Asymmetric arene hydrogenation: towards sustainability and application.

(Hetero)aromatic compounds are vastly available and easy to functionalise building blocks in the chemical industry. Asymmetric arene hydrogenation enables direct access to complex three-dimensional scaffolds with (multiple) defined stereocentres in a single catalytic process and, by this, the rapid installation of molecular complexity. The potential usage of hydrogen from renewable sources and perfect atom economy bears the potential for sustainable and broadly applicable transformations to valuable products. The aim of this review is to present the state-of-the-art in transition-metal catalysed asymmetric hydrogenation of (hetero)arenes, to highlight recent advances and important trends and to provide a broad overview for the reader.

Ligand switchable site selectivity in C-H alkenylation of thiophenes by turnover-limiting step control.

The origin of switchable site selectivity during Pd-catalysed C-H alkenylation of heteroarenes has been examined through More O'Ferrall-Jencks, isotope effect, and DFT computational analyses, which indicate substitution of ionic thioether for pyridine dative ligands induces a change from selectivity-determining C-H cleavage to C-C bond formation, respectively.

Ru-NHC-Catalyzed Asymmetric Hydrogenation of 2-Quinolones to Chiral 3,4-Dihydro-2-Quinolones.

Direct enantioselective hydrogenation of unsaturated compounds to generate chiral three-dimensional motifs is one of the most straightforward and important approaches in synthetic chemistry. We realized the Ru(II)-NHC-catalyzed asymmetric hydrogenation of 2-quinolones under mild reaction conditions. Alkyl-, aryl- and halogen-substituted optically active dihydro-2-quinolones were obtained in high yields with moderate to excellent enantioselectivities. The reaction provides an efficient and atom-economic pathway to construct simple chiral 3,4-dihydro-2-quinolones. The desired products could be further reduced to tetrahydroquinolines and octahydroquinolones.

Interrupted Pyridine Hydrogenation: Asymmetric Synthesis of δ-Lactams.

Metal-catalyzed hydrogenation is an effective method to transform readily available arenes into saturated motifs, however, current hydrogenation strategies are limited to the formation of C-H and N-H bonds. The stepwise addition of hydrogen yields reactive unsaturated intermediates that are rapidly reduced. In contrast, the interruption of complete hydrogenation by further functionalization of unsaturated intermediates offers great potential for increasing chemical complexity in a single reaction step. Overcoming the tenet of full reduction in arene hydrogenation has been seldom demonstrated. In this work we report the synthesis of sought-after, enantioenriched δ-lactams from oxazolidinone-substituted pyridines and water by an interrupted hydrogenation mechanism.

Diastereoselective Allylation of Aldehydes by Dual Photoredox and Chromium Catalysis.

Herein, we report the redox-neutral allylation of aldehydes with readily available electron-rich allyl (hetero-) arenes, ß-alkyl styrenes and allyl-diarylamines. This process was enabled by the combination of photoredox and chromium catalysis, which allowed a range of homoallylic alcohols to be prepared with high levels of selectivity for the anti diastereomer. Mechanistic investigations support the formation of an allyl chromium intermediate from allylic C(sp3)-H bonds and thus significantly extends the scope of the venerable Nozaki-Hiyama-Kishi reaction.