Enantioselective C(sp³)−H activation has gained considerable attention from the synthetic chemistry community, however, the mechanisms responsible for enantioselection remain vague. Ligand development, combined with theoretical studies, has been instrumental in achieving stereocontrol in Pd-catalyzed C(sp³)−H activation.

In our studies, development of a new class of chiral Mono-acetyl Protected Amino Anilamide (MPAAn) ligands enabled β-desymmetrizing aryl thioether-directed C(sp³)–H arylation, while Mono-acetyl Protected Amino Acid (MPAA) ligands were most effective for α-desymmetrization. Quantitative structure-selectivity relationship (QSSR) analysis revealed extreme variation in sensitivity of two substrate classes to substituent effects of ligands and directing groups: whereas 3-pentylsulfides (prochiral α-center) responded positively to substitution on ligands and directing groups, isobutyl sulfides (prochiral β-center) were entirely insensitive. These unexpected results required extensive theoretical studies for new stereomodel development.

Large conformational space of the chiral ligands and transient sulfur chirality presented a significant challenge of an accurate description of both catalytic systems. High-throughput DFT computational studies with meta-dynamics sampling of the flexible chiral ligand scaffolds allowed to locate over 570 unique enantio-determining C(sp³)−H cleavage transition states, while statistical thermodynamics analysis identified the dominant TS ensembles and NCI analysis revealed key interactions responsibe for enantioinduction. In both systems, enantioselectivity is achieved through a ligand-through substrate stereoinduction relay via dispersion interactions with transiently chiral Ar group on sulfur. Consequently, two new stereomodels were proposed, highlighting the different approaches to achieving enantioselectivity in the two types of thioether substrates. This study will assist in improving the ongoing ligand design for such transformations and complement mechanistic understanding necessary for the development of new catalytic systems for enantioselective C(sp³)−H activation.

Jinquan Yu

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