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

Abstract

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.

Enantioselective Sulfonimidamide Acylation via a Cinchona Alkaloid-Catalyzed Desymmetrization: Scope, Data Science, and Mechanistic Investigation

“…We recently reported using chemical space visualization to qualitatively sample a diverse range of sulfonimidamide substrates, which was also deployed here (Figure B) . Examples were evaluated on bench-scale using the top-performing cinchona-phosphinate catalyst 3e (Figure A).…”

“…Willis and co-workers have reported an enantioselective alkylation of protected sulfonimidamides using cinchona alkaloid-derived phase-transfer catalysts . Additionally, we have recently disclosed an enantioselective Pd-catalyzed aryl-carbonylation of sulfonimidamides with aryl and heteroaryl iodides (Figure B) . This reaction leveraged the rapid tautomerization of the imido and amido nitrogen atoms on unprotected sulfonimidamide starting materials, which provided a unique opportunity to desymmetrize the prochiral nitrogen atoms via dynamic kinetic resolution.…”

“…This resolution of the two unprotected nitrogen nucleophiles on a single sulfur chiral center is challenging due to the tendency toward oligomerization and the lack of obvious structural differences required for effective catalyst recognition. Additionally, the nitrogens in both the starting material and monoacylated product are nucleophilic, which can result in competitive uncatalyzed reactions and the ability to form bis-acylated products (as observed in reported aryl-carbonylation reactions). , Related enantioselective acylation of nitrogen nucleophiles are sparse but include both enzymatic and small molecule catalysis, highlighted by independent efforts of the De and Seidel, Fu and co-workers, and Bode and co-workers teams.…”

Synthesis of Dihydropyrazoles via Palladium‐Catalyzed Cascade Heterocyclization/Carbonylation/Arylation of β,γ‐Unsaturated N‐Tosyl Hydrazones

“…[8] To retrospectively evaluate the structural diversity of our intuitively selected set we sought to compare this set to the vast catalog of available boronic acids. [15][16] A curated list of commercially available boronic acids from a previous study [15c] with our selected scope added was defined as our catalog and described using molecular parameters collected from the Mordred python package to generate a virtual database containing 543 descriptors. [17] Using Uniform Manifold Approximation and Projection (UMAP) to visualize this descriptor library, a 2D chemical space representation of more than 5000 compounds was developed.…”

Classification of Hemilabile Ligands Using Machine Learning

“…Normally, new reaction design or reactivity improvement involves screening a large number of ligands − or performing computational mechanistic studies. − While ligand hemilability is often used as a design principle, ,, such a principle mainly relies on a set of heuristic rules such as distinct donor properties of coordinating atoms, flexibility of the linker between metal-coordinating atoms, and steric crowding near the metal center. Determining whether or not a ligand is hemilabile in solution usually requires indirect kinetic measurements of reaction rates, − trapping of distinct complexes in crystal structures, or time-consuming computational mechanistic studies .…”