Enantioselective synthesis of vicinal amino alcohols promoted by fluorine-containing counteranions

Abstract

Chiral vicinal amino alcohols are pivotal building blocks in organic synthesis and pharmaceutical research. Herein, we report a chiral copper-catalyzed two-step one-pot strategy for the efficient synthesis of diaryl chiral vicinal amino alcohols, featuring excellent diastereoselectivity (>99 : 1 dr) and enantioselectivity (up to 99.5% ee). A key discovery is the critical role of fluorinated counteranions, which significantly enhance both reactivity and stereocontrol—an underappreciated effect in copper-catalyzed asymmetric reactions. DFT calculations reveal that secondary Cu–F interactions, combined with the spatial confinement of hexafluorophosphate, fine-tune the catalytic chiral environment, enabling precise stereocontrol via modulation of π–π stacking and weak non-covalent interactions. This strategy exhibits broad substrate scope, accommodating diverse aryl, heteroaryl, and functionalized substituents, and allows gram-scale synthesis with facile deprotection to free amino alcohols. The mechanistic insights into counterion effects highlight counterion engineering as a powerful tool for optimizing asymmetric catalysis.