Construction of Axial Chirality via Amino-Acid-Catalyzed Asymmetric Reductive Desymmetrization of 2-Aryl-isophthalaldehydes

Abstract

Chiral biaryls with active ortho-substitutions are important building blocks for industrial and academic applications like ligands, catalysts, pharmaceuticals, and materials. Presently, there is high demand for the stereoselective synthesis of both (r)- and (s)-enantiomers of configurationally stable, axially chiral compounds with high rotational energy barriers (ΔG‡ > 30 kcal/mol) and multiple reactive sites for further post-synthetic modifications. Herein, we report a single amino-acid-catalyzed asymmetric desymmetrization of prochiral 2-aryl-isophthalaldehydes with CH-acids and 1,4-dihydropyridine (1,4-DHP) to construct a reductive alkylation product in high yield and enantioselectivity. The (s)- or (r)-indoline-2-carboxylic acid (H-L-Idc-OH) is able to do desymmetric activation of the pair of aldehydes in diverse tri/tetra-ortho-substituted 2-aryl-isophthalaldehydes through iminium ion formation, followed by sequential Knoevenagel condensation with CH-acids and transfer hydrogenation with 1,4-DHP to deliver axially chiral aldehydes with very good enantiocontrol. The generality of the reductive coupling strategy for the axially chiral C-C bond formation was further confirmed with various functionalized isophthalaldehydes and CH-acids to produce optically active enantiomers with dual chirality. Axially chiral aldehydes were further exploited for various post-synthetic transformations to produce functionally rich axially chiral biaryls for future applications. The absolute configuration, half-life, and rotational barriers were confirmed, and the mechanism was proved based on the control experiments and DFT calculations.