Unlocking Enantioselectivity: Synergy of 2-Pyridone and Chiral Amino Acids in Pd-Catalyzed β-C(sp 3 )-H Transformations.

Enantioselective C(sp 3 )-H activation has garnered significant attention in synthetic and computational chemistry. Chiral transient directing groups (TDGs) hold promise for enabling Pd(II)-catalyzed enantioselective C(sp 3 )-H functionalization. Despite the interest in this strategy, it presents a challenge because the stereogenic center on the chiral TDG is frequently distant from the C-H bond, leading to a mixture of functionalized products. Our computational study on Pd(II)-catalyzed enantioselective β-C(sp 3 )-H arylation of aliphatic ketone with chiral amino acids provides a sustainable route to synthesizing complex chiral molecular scaffolds. The cooperative action of 2-pyridone derivatives and chiral amino acids is crucial in promoting the enantio-discriminating C-H activation, oxidative addition, and reductive elimination steps. Using 5-nitro-2-pyridone as the optimal external ligand demonstrates its ability to achieve the highest level of enantioselection. In contrast, the modeled 3,5-di((trifluoromethyl)sulfonyl)-2-pyridone ligand facilitates the most straightforward C-H activation. This study underscores the pivotal role of the alkyl substituent at the α-position of the amino acid (TDG) in altering enantioselectivity.