Mechanistic study on the enantiodivergent kinetic resolution of axial chiral binaphthol via the peptide-phosphonium salt-catalyzed Atherton–Todd reaction

Abstract

Density functional theory calculations were conducted to elucidate the mechanism and stereoselectivity of the Atherton–Todd reaction-guided enantiodivergent kinetic resolution of axial chiral binaphthol catalyzed by peptide-phosphonium salts. The reaction involved the formation of two reactive phosphorus species: diphenylphosphinic chloride A and diphenylphosphinic anhydride B. Subsequent nucleophilic acylation of the deprotonated diol anion with A/B yielded chiral O-phosphorylation products. The hydrolysis of A was identified as the rate-determining step in the uncatalyzed reaction. Peptide-phosphonium salts accelerated the hydrolysis of A, reducing the energy barriers for the A → B transformation, for the two phosphonium salts with diverse side chains (P8 and P12). In the kinetic resolution process, the chiral peptide-phosphonium salt catalysts simultaneously activated the diol anion and A/B through ion-pairing and multiple hydrogen bonding interactions. P8 preferentially interacted with A and the R-diol anion via favorable π–π stacking, affording the R-product, while P12 exhibited higher affinity for B and the S-diol anion due to significant steric effects, leading to the formation of the S-atropisomer. Structural analysis of five representative catalysts revealed that silicon substituents, steric effects from Bn and Boc groups, and dipeptide skeletons collectively contributed to a well-defined chiral environment. These features enhanced the catalyst's rigidity and chiral recognition ability, enabling excellent enantioselectivity.