Synthesis Of Linearly Linked Multicalixarenes Consisting Of Calix[4]arene Units With Combined Axial Chirality And Inherent Chirality

Multicalixarenes are oligomers of defined molecular weight and architecture,formed by the covalent bonding of multiple calixarene units.The controlled synthesis of multicalixarenes usually relies on definite and highly efficient reactions such as etherification,esterification,amidation,Friedel-Crafts alkylation,Glaser coupling,Sonogashira coupling,Ring-Closing Metathesis（RCM）,Click reaction,etc.Recently,we have developed two stereoselective Williamson etherification on calix[4]arene.One is a highly efficient method for the generation of inherent chirality in calix[4]arene starting from a 1,2-substituted calix[4]crown containing an axially chiral BINOL moiety（reaction 1,condition:1 equiv of Cs₂CO₃,1 equiv of electrophile,DMF,60-80?C）.The other is the alkylation of tri-substituted cone calix[4]arene with an electrophile（reaction 2,condition:excess Cs₂CO₃,excess electrophile,DMF,60-80?C）,which highly stereoselectively furnishes the fully substituted partial cone products.We envisaged that reaction 1 is crucial to the covalent bonding of individual calix[4]arene units when R¹X is a（multi）calixarene-based electrophile,while reaction 2 is crucial to the formation of appropriate（multi）calixarene-based electrophiles R¹X for the purpose of linkage.Meanwhile,propargyl group can be introduced to calix[4]arenes via reaction 2,which is suitable for Glaser coupling.In this work,a linearly linked tetra-calix[4]arene 14,in which each calix[4]arene unit possesses both axial chirality and inherent chirality,was synthesized by repeated use of two stereoselective Williamson etherification on calix[4]arene.The use of Glaser coupling reaction allowed the synthesis of linearly linked tetra-calix[4]arene21 and hexa-calix[4]arene 23.（R）-BINOL-containingcalix[4]crown1underwentreaction1with BrCH₂CH₂CH₂CO₂Et,calix[4]arene electrophile 5,biscalix[4]arene electrophile 9 to produce the monocalix[4]arene cone conformer 2,biscalix[4]arene partial cone-cone conformer 6,triscalix[4]arene partial cone-partial cone-cone conformer 10 in 68%,47%,35%yield,respectively.With the increase of the number of calixarene units,the reaction was observed to become sluggish,and the isolation yield of the main products decreased gradually.The structures of all the new compounds were studied with NMR technology,mass spectrometry,elemental analysis,X-ray crystallography,and circular dichroism spectra.Single crystals of monocalix[4]arene partial cone conformers 3,4,and biscalix[4]arene partial cone-cone conformer 6 were cultivated,which are suitable for crystallographic study.Using the（R）-BINOL moiety as an internal reference,the absolute configuration concerning inherent chirality was assigned as cR in all cases.In the crystal lattice,there are alternate layers of biscalixarene molecules and solvent molecules in the ab plane,which is rarely seen in calixarene single crystals.This work demonstrated the power of jointly using two stereoselective calix[4]arene-related Williamson etherification to produce multicalix[4]arenes with both axial chirality and inherent chirality.It is highly probable that by varying the R¹and R² groups according to the need of molecular design,in conjunction with other highly efficient coupling reaction/RCM reaction/Click reaction/condensation reaction,the customized chiral multicalixarenes could be used in the construction of diverse novel chiral calixarene-based oligomeric/dendritic/polymeric architectures.