Enantio-, atrop-, and diastereoselective macrolactonization to access type III cyclophanes

Abstract

Abstract Although chiral substituents have been incorporated into ansa chains to stabilize the conformations of cyclophanes and modulate the biological activities of pharmaceuticals, the asymmetric syntheses of these atropisomers relies on substrate-induced diastereoselective macrocyclization. To the best of our knowledge, enantio-, atrop-, and diastereoselective macrocyclizations are yet to be reported. Herein, we describe an N-heterocyclic carbene (NHC) and chiral phosphoric acid (CPA) dual-catalytic process for the desymmetrization of 1,3-diols, to achieve macrocyclization and stereoselective control over two chiral elements. It is deduced that the hydrogen bonding of CPA with the 1,3-diols enhances the diastereoselectivity of the process. As a result, various planar-chiral cyclophanes bearing chiral ansa chains are synthesized. Thermodynamic experiments reveal that the presence of an all-carbon quaternary carbon center on the ansa chain significantly increases the rotational barriers of the cyclophanes. Moreover, density functional theory calculations suggest that the chiral substituent shrinks the ansa chain by compressing the bond angle, thereby rendering the conformational rotation reaction more challenging.