Allan J. B. Watson

Evaluation of alternative solvents in common amide coupling reactions: replacement of dichloromethane and N,N-dimethylformamide

formation is the single most common synthetic transformation used within medicinal chemistry. Indeed, several studies have demonstrated the prevalence of this particular transformation within the pharmaceutical sector: MacDonald’s analysis of the GlaxoSmithKline (GSK) Respiratory Centre of Excellence for Drug Discovery revealed that 17% of all reaction types conducted in array (focused library) format were to prepare amide or sulfonamide moieties. 3 Similarly, Roughley’s analysis of the most common reactions used within synthetic medicinal chemistry research across three of the largest pharmaceutical companies (GSK, AstraZeneca, and Pfizer) indicated that N-acylation to prepare amides ranked 1st for frequency of use, accounting for 16% of all reactions performed and with the amide linkage present in 54% of the compound set analysed. 4

Spectroscopic Studies of the Chan–Lam Amination: A Mechanism-Inspired Solution to Boronic Ester Reactivity

We report an investigation of the Chan-Lam amination reaction. A combination of spectroscopy, computational modeling, and crystallography has identified the structures of key intermediates and allowed a complete mechanistic description to be presented, including off-cycle inhibitory processes, the source of amine and organoboron reactivity issues, and the origin of competing oxidation/protodeboronation side reactions. Identification of key mechanistic events has allowed the development of a simple solution to these issues: manipulating Cu(I) → Cu(II) oxidation and exploiting three synergistic roles of boric acid has allowed the development of a general catalytic Chan-Lam amination, overcoming long-standing and unsolved amine and organoboron limitations of this valuable transformation.

Chan–Evans–Lam Amination of Boronic Acid Pinacol (BPin) Esters: Overcoming the Aryl Amine Problem

The Chan-Evans-Lam reaction is a valuable C-N bond forming process. However, aryl boronic acid pinacol (BPin) ester reagents can be difficult coupling partners that often deliver low yields, in particular in reactions with aryl amines. Herein, we report effective reaction conditions for the Chan-Evans-Lam amination of aryl BPin with alkyl and aryl amines. A mixed MeCN/EtOH solvent system was found to enable effective C-N bond formation using aryl amines while EtOH is not required for the coupling of alkyl amines.

Tandem chemoselective Suzuki-Miyaura cross-coupling enabled by nucleophile speciation control

Control of boronic acid speciation is presented as a strategy to achieve nucleophile chemoselectivity in the Suzuki-Miyaura reaction. Combined with simultaneous control of oxidative addition and transmetalation, this enables chemoselective formation of two C-C bonds in a single operation, providing a method for the rapid preparation of highly functionalized carbogenic frameworks.

Chemoselective Boronic Ester Synthesis by Controlled Speciation

Control of boronic acid solution speciation is presented as a new strategy for the chemoselective synthesis of boronic esters. Manipulation of the solution equilibria within a cross-coupling milieu enables the formal homologation of aryl and alkenyl boronic acid pinacol esters. The generation of a new, reactive boronic ester in the presence of an active palladium catalyst also facilitates streamlined iterative catalytic C=C bond formation and provides a method for the controlled oligomerization of sp2-hybridized boronic esters.

Development of Autotaxin Inhibitors: An Overview of the Patent and Primary Literature

The autotaxin-lysophophatidic acid (ATX-LPA) signaling pathway is implicated in a variety of human disease states including angiogenesis, autoimmune diseases, cancer, fibrotic diseases, inflammation, neurodegeneration, and neuropathic pain, among others. As a result, ATX-LPA has become of significant interest within both the industrial and the academic communities. This review aims to provide a concise overview of the development of novel ATX inhibitors, including the disclosure of the first ATX clinical trial data.

Synthesis of functionalised 4H-quinolizin-4-ones via tandem Horner-Wadsworth-Emmons olefination/ cyclisation†

4H-Quinolizin-4-ones are a unique class of heterocycle with valuable physicochemical properties and which are emerging as key pharmacophores for a range of biological targets. A tandem Horner-Wadsworth-Emmons olefination/cyclisation method has been developed to allow facile access to substituted 4H-quinolizin-4-ones encoded with a range of functional groups.

GSK6853, a Chemical Probe for Inhibition of the BRPF1 Bromodomain

The BRPF (Bromodomain and PHD Finger-containing) protein family are important scaffolding proteins for assembly of MYST histone acetyltransferase complexes. A selective benzimidazolone BRPF1 inhibitor showing micromolar activity in a cellular target engagement assay was recently described. Herein, we report the optimization of this series leading to the identification of a superior BRPF1 inhibitor suitable for in vivo studies.

Chemoselective Suzuki-Miyaura cross-coupling via kinetic transmetallation

Chemoselective Suzuki-Miyaura cross-coupling generally requires a designed deactivation of one nucleophile towards transmetallation. Here we show that boronic acids can be chemoselectively reacted in the presence of ostensibly equivalently reactive boronic acid pinacol (BPin) esters by kinetic discrimination during transmetallation. Simultaneous electrophile control allows sequential chemoselective cross-couplings in a single operation in the absence of protecting groups.

Development of a solvent selection guide for aldehyde-based direct reductive amination processes

A range of alternative, more environmentally conservative solvents have been evaluated for use within the direct reductive amination reactions of aldehydes using borane-based reductants. The data generated has been used to develop a guide to facilitate replacement of less desirable chlorinated solvents, such as DCE, from these widely used synthetic processes.