ART─An Amino Radical Transfer Strategy for C(sp2)-C(sp3) Coupling Reactions, Enabled by Dual Photo/Nickel Catalysis.

Introducing the novel concept of amino radical transfer (ART) enables the use of easily accessible and commercially available alkyl boronic esters as cross-coupling partners for aryl halides in dual photoredox/nickel catalysis mediated by visible light. Activation of otherwise photochemically innocent boronic esters by radicals generated from primary or secondary alkylamines gives rise to an outstanding functional group tolerance in a mild, fast, and air-stable reaction. As shown in more than 50 examples including unprotected alcohols, amines, and carboxylic acids, this reaction allows quick access to relevant scaffolds for organic synthesis and medicinal chemistry. In comparison with existing methods for C(sp2)-C(sp3) couplings an extraordinary generality could be realized via the ART concept, employing a single set of optimized reaction conditions. Due to its selectivity, the transformation can also be used for late-stage functionalization, as demonstrated with three exemplary syntheses of drug molecules. Furthermore, the successful one-to-one scalability of this reaction up to gram scale without the necessity of any further precautions or flow systems is demonstrated.

A high-throughput screening assay for mutant isocitrate dehydrogenase 1 using acoustic droplet ejection mass spectrometry.

Acoustic droplet ejection mass spectrometry (ADE-MS) has recently emerged as a promising label-free, MS-based readout method for high throughput screening (HTS) campaigns in early pharmaceutical drug discovery, since it enables high-speed analysis directly from 384- or 1536-well plates. In this manuscript we describe our characterization of an ADE-MS based high sample content enzymatic assay for mutant isocitrate dehydrogenase 1 (IDH1) R132H with a strong focus on assay development. IDH1 R132H has become a very attractive therapeutic target in the field of antitumor drug discovery, and several pharmaceutical companies have attempted to develop novel small molecule inhibitors against mutant IDH1. With the development of an mIDH1 ADE-MS based HTS assay and a detailed comparison of this new readout technique to the commonly used fluorescence intensity mIDH1 assay, we demonstrated good correlation of both methods and were able to identify new potent inhibitors of mIDH1.

Catalytic enantioselective O-H insertion reactions.

The first effective method for catalytic enantioselective insertions into O-H bonds has been developed. Specifically, a copper/bisazaferrocene catalyst couples alcohols such as 2-trimethylsilylethanol with alpha-aryl-alpha-diazo esters in high yield and good ee.