Discovery of IRAK4 Inhibitors BAY1834845 (Zabedosertib) and BAY1830839.

Interleukin-1 receptor-associated kinase 4 (IRAK4) plays a critical role in innate inflammatory processes. Here, we describe the discovery of two clinical candidate IRAK4 inhibitors, BAY1834845 (zabedosertib) and BAY1830839, starting from a high-throughput screening hit derived from Bayer's compound library. By exploiting binding site features distinct to IRAK4 using an in-house docking model, liabilities of the original hit could surprisingly be overcome to confer both candidates with a unique combination of good potency and selectivity. Favorable DMPK profiles and activity in animal inflammation models led to the selection of these two compounds for clinical development in patients.

Open-Source Chromatographic Data Analysis for Reaction Optimization and Screening.

Automation and digitalization solutions in the field of small molecule synthesis face new challenges for chemical reaction analysis, especially in the field of high-performance liquid chromatography (HPLC). Chromatographic data remains locked in vendors' hardware and software components, limiting their potential in automated workflows and data science applications. In this work, we present an open-source Python project called MOCCA for the analysis of HPLC-DAD (photodiode array detector) raw data. MOCCA provides a comprehensive set of data analysis features, including an automated peak deconvolution routine of known signals, even if overlapped with signals of unexpected impurities or side products. We highlight the broad applicability of MOCCA in four studies: (i) a simulation study to validate MOCCA's data analysis features; (ii) a reaction kinetics study on a Knoevenagel condensation reaction demonstrating MOCCA's peak deconvolution feature; (iii) a closed-loop optimization study for the alkylation of 2-pyridone without human control during data analysis; (iv) a well plate screening of categorical reaction parameters for a novel palladium-catalyzed cyanation of aryl halides employing O-protected cyanohydrins. By publishing MOCCA as a Python package with this work, we envision an open-source community project for chromatographic data analysis with the potential of further advancing its scope and capabilities.

Exploration of Biaryl Carboxylic Acids as Proton Shuttles for the Selective Functionalization of Indole C-H Bonds.

A survey of diversely substituted 2-arylbenzoic acids were synthesized and tested for use as proton shuttle in the direct arylation of indoles with bromobenzenes. It was found that 3-ethoxy-2-phenylbenzoic acid gives superior yield and selectivity for this class of substrates.

Advances in the development of catalytic tethering directing groups for C-H functionalization reactions.

Transition metal-catalyzed C-H bond insertion is one of the most straightforward strategies to introduce functionalities within a hydrocarbon microenvironment. For the past two decades, selective activation and functionalization of certain inert C-H bonds have been made possible with the help of directing groups (DGs). Despite the enormous advances in the field, an overwhelming majority of systems require two extra steps from their simple precursors: installation and removal of the DGs. Recently, traceless and multitasking groups were invented as a partial solution to DG release. However, installation remains largely unsolved. Ideally, a transient, catalytic DG would circumvent this problem and increase the step- and atom-economy of C-H functionalization processes. In this review, we summarize the recent development of the transient tethering strategy for C-H activation reactions.

Development of an iron(II)-catalyzed aerobic catechol cleavage and biomimetic synthesis of betanidin.

An aerobic iron(II)-catalyzed cleavage of catechols was developed. This reaction allows for the preparation of 2-methoxy-2 H-pyrans that can be employed as versatile building blocks for synthesis. The utility of this biomimetic oxidative cleavage is featured in the synthesis of betanidin, a natural colorant with antioxidant properties.

Catalysis through temporary intramolecularity: mechanistic investigations on aldehyde-catalyzed Cope-type hydroamination lead to the discovery of a more efficient tethering catalyst.

Mechanistic investigations on the aldehyde-catalyzed intermolecular hydroamination of allylic amines using N-alkylhydroxylamines are presented. Under the reaction conditions, the presence of a specific aldehyde catalyst allows formation of a mixed aminal intermediate, which permits intramolecular Cope-type hydroamination. The reaction was determined to be first-order in both the aldehyde catalyst (α-benzyloxyacetaldehyde) and the allylic amine. However, the reaction displays an inverse order behavior in benzylhydroxylamine, which reveals a significant off-cycle pathway and highlights the importance of an aldehyde catalyst that promotes a reversible aminal formation. Kinetic isotope effect experiments suggest that hydroamination is the rate-limiting step of this catalytic cycle. Overall, these results enabled the elaboration of a more accurate catalytic cycle and led to the development of a more efficient catalytic system for alkene hydroamination. The use of 5-10 mol % of paraformaldehyde proved more effective than the use of 20 mol % of α-benzyloxyacetaldehyde, leading to high yields of intermolecular hydroamination products within 24 h at 30 °C.

Rhodium(III)-catalyzed heterocycle synthesis using an internal oxidant: improved reactivity and mechanistic studies.

Directing groups that can act as internal oxidants have recently been shown to be beneficial in metal-catalyzed heterocycle syntheses that undergo C-H functionalization. Pursuant to the rhodium(III)-catalyzed redox-neutral isoquinolone synthesis that we recently reported, we present in this article the development of a more reactive internal oxidant/directing group that can promote the formation of a wide variety of isoquinolones at room temperature while employing low catalyst loadings (0.5 mol %). In contrast to previously reported oxidative rhodium(III)-catalyzed heterocycle syntheses, the new conditions allow for the first time the use of terminal alkynes. Also, it is shown that the use of alkenes, including ethylene, instead of alkynes leads to the room temperature formation of 3,4-dihydroisoquinolones. Mechanistic investigations of this new system point to a change in the turnover limiting step of the catalytic cycle relative to the previously reported conditions. Concerted metalation-deprotonation (CMD) is now proposed to be the turnover limiting step. In addition, DFT calculations conducted on this system agree with a stepwise C-N bond reductive elimination/N-O bond oxidative addition mechanism to afford the desired heterocycle. Concepts highlighted by the calculations were found to be consistent with experimental results.

Rhodium(III)-catalyzed isoquinolone synthesis: the N-O bond as a handle for C-N bond formation and catalyst turnover.

An external-oxidant-free process to access the isoquinolone motif via cross-coupling/cyclization of benzhydroxamic acid with alkynes is described. The reaction features a regioselective cleavage of a C-H bond on the benzhydroxamic acid coupling partner as well as a regioselective alkyne insertion. Mechanistic studies point out the important involvement of a N-O bond as a tool for C-N bond formation and catalyst turnover.

Palladium-catalyzed decarboxylative cross-coupling reaction between heteroaromatic carboxylic acids and aryl halides.

A full overview of the decarboxylative cross-coupling reaction between heteroaromatic carboxylic acids and aryl halides is described. This transformation employs palladium catalysts with short reaction times providing facile synthesis of aryl-substituted heteroaromatics. The effect of each reaction parameter including solvent, base, and additive employed as well as the full substrate scope of this transformation are reported. Mechanistic evidence is also disclosed that sheds light on possible reaction pathways.

Isoquinoline synthesis via rhodium-catalyzed oxidative cross-coupling/cyclization of aryl aldimines and alkynes.

A general rhodium-catalyzed oxidative coupling reaction between internal alkynes and aryl aldimines is described. This process affords 3,4-disubstituted isoquinolines in good yield and high regioselectivity. Preliminary mechanistic studies suggest that the C-N bond formation arises from the reductive elimination of a rhodium(III) species.

Palladium-catalyzed direct arylation of azine and azole N-oxides: reaction development, scope and applications in synthesis.

Palladium-catalyzed direct arylation reactions are described with a broad range of azine and azole N-oxides. In addition to aspects of functional group compatibility, issues of regioselectivity have been explored when nonsymmetrical azine N-oxides are used. In these cases, both the choice of ligand and the nature of the azine substituents play important roles in determining the regioisomeric distribution. When azole N-oxides are employed, preferential reaction is observed for arylation at C2 which occurs under very mild conditions. Subsequent reactions are observed to occur at C5 followed by arylation at C4. The potential utility of this methodology is illustrated by its use in the synthesis of a potent sodium channel inhibitor 1 and a Tie2 Tyrosine Kinase inhibitor 2.

Unexpected effect of the fluorine atom on the optimal ligand-to-palladium ratio in the enantioselective Pd-catalyzed allylation reaction of fluorinated enol carbonates.

The enantioselective Pd-catalyzed allylation reaction of fluorinated allyl enol carbonates is presented; a key feature of this transformation is the important effect of the ligand-to-palladium ratio on the enantioselectivity of the alpha-fluoroketones, since using a ligand excess (L/Pd ratio = 1.25 : 1) led to moderate results (30-76% ee), while using a L/Pd ratio <1 : 1.67 (to as low as 1 : 4) allowed the desired products to be obtained with high enantiopurity (up to 94% ee).