Chemo- and Atroposelective Boc Protection for Asymmetric Synthesis of NH2-Free Axially Chiral Biaryl Amino Phenols

Abstract

Enantioselective protection strategies have emerged as powerful tools for creating high-value optically active compounds. Herein, we report an efficient and direct Lewis base-catalyzed enantioselective tert-butoxycarbonyl (Boc) protection strategy for the construction of axial chirality. Employing a chiral isothiourea (ITU) catalyst, a series of amino bisphenols undergo chemo-and atroposelective O-Boc protection with Boc anhydride (Boc2O), delivering NH2-free axially chiral biaryl amino phenols with moderate yields and high enantioselectivities. This desymmetrization protocol is scalable to gram level and enables facile downstream transformations of the chiral products. Computational studies reveal that the amino (NH2) group on the naphthalene ring facilitates intramolecular proton transfer of the hydroxyl (OH) group. Moreover, an unprecedented S•••C-NH3+ electrostatic interaction, in combination with π-π stacking, is identified as a key stabilizing factor in the transition states.