Accessing inherently chiral multifunctional structures by desymmetrization of a wide-rim calix[4]arene triamine

Abstract

An efficient strategy is presented for the synthesis of rare-type inherently chiral calix[4]arenes having an asymmetric arrangement of functional groups at the wide rim of the cone macrocycle and possessing virtually unlimited functionalization capabilities. Selective protection of two proximal amino groups in the C_s-symmetrical wide-rim calixarene triamine by tert-butoxycarbonyl groups is suggested as the key synthesis step, allowing desymmetrization of the core, the efficiency of which can be improved due to the facile recovery of the starting material from the mixture of reaction byproducts. The insertion of an auxiliary chiral unit into the remaining free amino group enables early-step separation of stereoisomers, which allows for further derivatization of the enantiopure calixarene cores without the need for any stereocontrol conditions. This derivatization may include, for instance, amine deprotection followed by acylation/sulfonylation, and/or conversion of amines into diazonium salts and azides, which can be further involved in a copper(I)-catalyzed azide–alkyne cycloaddition. As a proof of concept, three pairs of optically active enantiomers of inherently chiral calix[4]arenes bearing two proximal triazole groups accompanied by amine, sulfonamide or urea functionalities were prepared, and their high optical purity (>99% ee) was confirmed. Using 2D NMR data supported by quantum-chemical calculations, and X-ray diffraction data, the absolute stereoconfiguration of the inherently chiral calixarene core in these compounds was established. To evaluate the enantiodiscriminative capabilities of the asymmetrically arranged triazole groups and the asymmetric cavity (the permanent parts of the enantiomer structures), a qualitative NMR study was performed using an excess of selected chiral guest molecules. The study showed distinct complexation-induced spectral changes that were clearly different between (P)- and (M)-enantiomers of calixarenes, confirming that these structural elements may contribute to complexation provided by the ‘main’ receptor units. The latter can be easily varied in asymmetric calixarene cores using azide–alkyne cycloaddition and/or amine acylation/sulfonylation, enabling the design of multifunctional chiral host structures tailored to the functionality of the target chiral guest molecules.