Desymmetric esterification catalysed by bifunctional chiral N-heterocyclic carbenes provides access to inherently chiral calix[4]arenes

Abstract

Calix[4]arenes display inherent chirality, with broad applications in synthetic and medicinal chemistry and in materials sciences. However, their use is hindered by their limited synthetic accessibility, primarily due to the lack of enantioselective methods for preparing chiral calix[4]arenes with an ABCC substitution pattern. Here, we address this challenge by presenting a simple, efficient, and metal-free protocol for organocatalytic desymmetrisation of prochiral diformylcalix[4]arenes. Through this highly effective and sustainable approach, we synthesize structurally unique products in gram-scale reactions. Accordingly, this method facilitates extensive post-functionalisations of the carbonyl groups, including for organocatalyst development. Furthermore, our experimental mechanistic studies demonstrate that desymmetrisation determines enantiocontrol in esterification reactions catalysed by N-heterocyclic carbenes. These findings underscore the broad potential of this method for providing versatile access to inherently chiral calix[4]arenes with an ABCC substitution pattern while offering a valuable platform for asymmetric molecular recognition and catalysis.

Fig. 1. Selected desymmetric approaches to compounds possessing various chirality elements, the main approaches to inherently chiral calix[4]arenes.

A Overview of NHC-mediated desymmetric esterification (highlighted in red). B Selected accesses to an inherently chiral calix[4]arenes (highlighted in blue). C Proposed approach (highlighted in green).

Fig. 2. Substrate scope of various calix[4]arenes and naphthols.

A Substitution of lower ring of calix[4]arene (highlighted in red). B Scope of naphthols (highlighted in blue). C Various nucleophiles (highlighted in green).

Fig. 3. Substrate scope of various phenols.

A Scope of substituted phenols (highlighted in red). B Scope of natural or bioactive phenols (highlighted in blue).

Fig. 4. Proposed reaction mechanism.

Catalytic cycle including the generation of NHC, formation of the Breslow intermediate, and following oxidative esterification.

Fig. 5. Mechanistic studies.

A Deuterium labeling experiments (highlighted in red). B Kinetic isotopic effect (highlighted in blue). C DFT calculations (highlighted in green). D Control experiments (highlighted in orange).

Fig. 6. Gram-scale desymmetrisation and synthetic utility demonstration.

A Gram-scale reaction (highlighted in red). B Follow-up transformations (highlighted in blue). C Organocatalyst development (highlighted in green). D Enantioselective recognition (highlighted in orange).