Data Science-Enabled Palladium-Catalyzed Enantioselective Aryl-Carbonylation of Sulfonimidamides.

New methods for the general asymmetric synthesis of sulfonimidamides are of great interest due to their applications in medicinal chemistry, agrochemical discovery, and academic research. We report a palladium-catalyzed cross-coupling method for the enantioselective aryl-carbonylation of sulfonimidamides. Using data science techniques, a virtual library of calculated bisphosphine ligand descriptors was used to guide reaction optimization by effectively sampling the catalyst chemical space. The optimized conditions identified using this approach provided the desired product in excellent yield and enantioselectivity. As the next step, a data science-driven strategy was also used to explore a diverse set of aryl and heteroaryl iodides, providing key information about the scope and limitations of the method. Furthermore, we tested a range of racemic sulfonimidamides for compatibility of this coupling partner. The developed method offers a general and efficient strategy for accessing enantioenriched sulfonimidamides, which should facilitate their application in industrial and academic settings.

Data-Driven Multi-Objective Optimization Tactics for Catalytic Asymmetric Reactions Using Bisphosphine Ligands.

Optimization of the catalyst structure to simultaneously improve multiple reaction objectives (e.g., yield, enantioselectivity, and regioselectivity) remains a formidable challenge. Herein, we describe a machine learning workflow for the multi-objective optimization of catalytic reactions that employ chiral bisphosphine ligands. This was demonstrated through the optimization of two sequential reactions required in the asymmetric synthesis of an active pharmaceutical ingredient. To accomplish this, a density functional theory-derived database of >550 bisphosphine ligands was constructed, and a designer chemical space mapping technique was established. The protocol used classification methods to identify active catalysts, followed by linear regression to model reaction selectivity. This led to the prediction and validation of significantly improved ligands for all reaction outputs, suggesting a general strategy that can be readily implemented for reaction optimizations where performance is controlled by bisphosphine ligands.

A catalytic asymmetric cross-coupling approach to the synthesis of cyclobutanes.

Stereodefined four-membered rings are common motifs in bioactive molecules and versatile intermediates in organic synthesis. However, the synthesis of complex, chiral cyclobutanes is a largely unsolved problem and there is a need for general and modular synthetic methods. Here we report a series of asymmetric cross-coupling reactions between cyclobutenes and arylboronic acids which are initiated by Rh-catalysed asymmetric carbometallation. After the initial carborhodation, Rh-cyclobutyl intermediates undergo chain-walking or C-H insertion so that overall a variety of additions such as reductive Heck reactions, 1,5-addition and homoallylic substitution are observed. The synthetic applicability of these highly stereoselective transformations is demonstrated in the concise syntheses of the drug candidates Belaperidone and PF-04862853. We anticipate this approach will be widely adopted by synthetic and medicinal chemists. While the carbometallation approach reported here is exemplified with Rh and arylboronic acids, it is likely to be applicable to other metals and nucleophiles.

Highly enantioselective rhodium-catalyzed cross-coupling of boronic acids and racemic allyl halides.

Although Csp2-Csp2 Suzuki-Miyaura couplings (SMCs) are widely used in small-molecule synthesis, related methods that allow the incorporation of Csp3-hybridized coupling partners, particularly in an asymmetric manner, are less developed. This protocol describes catalytic asymmetric SMC reactions that provide access to enantiomerically enriched cyclic allylic products. The method couples racemic allyl halide starting materials with sp2-hybridized boronic acid derivatives and is compatible with heterocyclic coupling partners. These reactions are catalyzed by a rhodium-ligand complex and typically display very high levels of enantioselectivity (>95% enantiomeric excess (ee)). In this protocol, we detail a procedure using a dihydropyridine-derived allyl chloride for the synthesis of (-)-(S)-tert-butyl-3-(4-bromophenyl)-3,6-dihydropyridine-1(2H)-carboxylate, an intermediate in the synthesis of the anticancer drug niraparib. This procedure affords 1.17 g (86% yield) of the coupling product with 96% ee. The initial experimental setup of the reaction takes 45-50 min, and the reaction is complete within 4-5 h.

Visible Light Photocatalysis of 6π Heterocyclization.

Photo-mediated 6π cyclization is a valuable method for the formation of fused heterocyclic systems. Here we demonstrate that irradiation of cyclic 2-aryloxyketones with blue LED light in the presence of an IrIII complex leads to efficient and high yielding arylation across a panoply of substrates by energy transfer. 2-Arylthioketones and 2-arylaminoketones also cyclize effectively under these conditions. Quantum calculation demonstrates that the reaction proceeds via conrotatory ring closure in the triplet excited state. Subsequent suprafacial 1,4-hydrogen shift and epimerization leads to the observed cis-fused products.