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The bromodomain and extra terminal (BET) family of proteins are an integral part of human epigenome regulation, the dysregulation of which is implicated in multiple oncology and inflammatory diseases. Disrupting the BET family bromodomain acetyl-lysine (KAc) histone protein-protein interaction with small-molecule KAc mimetics has proven to be a disease-relevant mechanism of action, and multiple molecules are currently undergoing oncology clinical trials. This work describes an efficiency analysis of published GSK pan-BET bromodomain inhibitors, which drove a strategic choice to focus on the identification of a ligand-efficient KAc mimetic with the hypothesis that lipophilic efficiency could be drastically improved during optimization. This focus drove the discovery of the highly ligand-efficient and structurally distinct benzoazepinone KAc mimetic. Following crystallography to identify suitable growth vectors, the benzoazepinone core was optimized through an explore-exploit structure-activity relationship (SAR) approach while carefully monitoring lipophilic efficiency to deliver I-BET432 (

Developments in synthetic chemistry are increasingly driven by improvements in the selectivity and sustainability of transformations. Bifunctional reagents, either as dual coupling partners or as a coupling partner in combination with an activating species, offer an atom-economic approach to chemical complexity, while suppressing the formation of waste. These reagents are employed in organic synthesis thanks to their ability to form complex organic architectures and empower novel reaction pathways. This Review describes several key bifunctional reagents by showcasing selected cornerstone research areas and examples, including radical reactions, C–H functionalization, cross-coupling, organocatalysis and cyclization reactions. Developments in synthetic chemistry are increasingly driven by attempts to improve both selectivity and sustainability. This Review highlights the versatility of bifunctional reagents in generating chemical complexity with enhanced atom-economy-leveraging radical reactions, C–H functionalizations, cross-couplings, organocatalysed processes and cyclizations.

Hydroarylation is an effective strategy to rapidly increase the complexity of organic structures by transforming flat alkene moieties into three-dimensional frameworks. Many strategies have already been developed to achieve the hydroarylation of styrenes, however most of these reports examine the hydroarylation of unpolar, β-mono- or β-unsubstituted styrenes, while exploring mainly electron-rich benzene nucleophiles. Herein, we report a mild and general catalytic system for the selective hydroheteroarylation of multiply substituted styrenes and heteroaromatic styrenes. Mechanistic analysis of the reaction led to the discovery of commercially available 2,2':5',2''-terthiophene as a key reagent.

Since the definition of the “12 Principles of Green Chemistry” more than 20 years ago, chemists have become increasingly mindful of the need to conserve natural resources and protect the environment through the judicious choice of synthetic routes and materials. The direct activation and functionalization of C–H bonds, bypassing intermediate functional group installation is, in abstracto, step and atom economic, but numerous factors still hinder the sustainability of large-scale applications. In this Outlook, we highlight the research areas seeking to overcome the sustainability challenges of C–H activation: the pursuit of abundant metal catalysts, the avoidance of static directing groups, the replacement of metal oxidants, and the introduction of bioderived solvents. We close by examining the progress made in the subfield of aryl C–H borylation from its origins, through highly efficient but precious Ir-based systems, to emerging 3d metal catalysts. The future growth of this field will depend on industrial uptake, and thus we urge researchers to strive toward sustainable C–H activation., Applications of C−H activation face a sustainability challenge. This Outlook discusses progress in areas such as 3d metal catalysis, alternative oxidation, green solvents, and undirected systems.

A highly selective Mn(I)-catalyzed alkenylation of arenes and heteroarenes with 1,3-diynes is described. The reported transformation overcomes regio-, chemo-, and stereoselectivity challenges assoc...

Summary The catalytic dearomatization of pyridines, accessing medicinally relevant N-heterocycles, is of high interest. Currently direct, dearomative strategies rely generally on reduction or nucleophilic addition, thus limiting the architecture of the dearomatized products to a six-membered ring. We herein introduce a catalytic, dearomative cycloaddition reaction with pyridines using photoinduced energy transfer catalysis, thereby advancing dearomatization methodology and increasing the topology of pyridine dearomatization products. This unprecedented method features high yields, broad substrate scope (44 examples), excellent functional group tolerance, and facile scalability. Furthermore, a recyclable and sustainable polymer immobilized photocatalyst was employed. Computational and experimental investigations support a mechanism in which a cinnamyl moiety is promoted to its corresponding excited triplet state through visible-light-mediated energy transfer catalysis, followed by a regioselective and dearomative [4+2] cycloaddition to pyridines. This work demonstrates the contribution of visible light catalysis toward enabling thermally challenging organic transformations.

Arene hydrogenation provides direct access to saturated carbo- and heterocycles and thus its strategic application may be used to shorten synthetic routes. This powerful transformation is widely applied in industry and is expected to facilitate major breakthroughs in the applied sciences. The ability to overcome aromaticity while controlling diastereo-, enantio-, and chemoselectivity is central to the use of hydrogenation in the preparation of complex molecules. In general, the hydrogenation of multisubstituted arenes yields predominantly the cis isomer. Enantiocontrol is imparted by chiral auxiliaries, Brønsted acids, or transition-metal catalysts. Recent studies have demonstrated that highly chemoselective transformations are possible. Such methods and the underlying strategies are reviewed herein, with an emphasis on synthetically useful examples that employ readily available catalysts.

Herein, we present a mild Cp*RhIII-catalyzed Suzuki–Miyaura-type allyl–aryl coupling of readily accessible arylboron reagents with a broad range of olefins. Allylic arylation was achieved without the need for prefunctionalized alkenes, and the general Heck-type reactivity between olefins and arenes was not observed. Mechanistic studies indicate that the reaction was enabled through the fast generation of a RhIII–allyl species via undirected C(sp3)–H activation. Moreover, the developed protocol was applied to the highly concise synthesis of the anti-inflammatory drug flurbiprofen.

C−H activation reactions with high catalyst turnover numbers are still very rare in the literature and 10 mol % is a common catalyst loading in this field. We offer a representative overview of efficient C−H activation catalysis to highlight this neglected aspect of catalysis development and inspire future effort towards more efficient C−H activation. Examples ranging from palladium catalysis, Cp*Rh III - and Cp*Co III -catalysis, the C−H borylation and silylation to methane C−H activation are presented. In these reactions, up to tens of thousands of catalyst turnovers have been observed.

Flow chemistry has been successfully integrated into the synthesis of a series of cyclooligomeric depsipeptides of three different ring sizes including the natural products beauvericin (1 a), bassianolide (2 b) and enniatin C (1 b). A reliable flow chemistry protocol was established for the coupling and macrocyclisation to form challenging N‐methylated amides. This flexible approach has allowed the rapid synthesis of both natural and unnatural depsipeptides in high yields, enabling further exploration of their promising biological activity.

Here we report on measurements of the absolute absorption and dispersion of light in a dense rubidium vapour on the D2 line in the weak-probe regime with an applied magnetic field. A model for the electric susceptibility of the vapour is presented which includes both dipole-dipole interactions and the Zeeman effect. The predicted susceptibility is comprehensively tested by comparison to experimental spectra for fields up to 800 G. The dispersive properties of the medium are tested by comparison between experimental measurements and theoretical prediction of the Stokes parameters as a function of the atom-light detuning.

We present the physics underlying the transmission of light through a dense atomic vapour, accounting for self-broadening and the application of a large axial magnetic field.