Synthesis, Resolution, Structure, and Racemization of Inherently Chiral 1,3-Alternate Azacalix[4]pyrimidines: Quantification of Conformation Mobility

Abstract

The synthesis, resolution, structure, and racemization of inherently chiral 1,3-alternate azacalix[4]pyrimidine macrocycles are reported. Site-selective halogenations of monohalo-substituted azacalix[4]pyrimidines with NBS, NCS, and NFSI produced a number of the lower-rim dihalogenated 1,3-alternate azacalix[4]pyrimidines. 1,3-Alternate azacalix[4]pyrimidines bearing two proximal substituents were AABB-type and ABCC-type inherently chiral macrocycles, and three pairs of conformationally stable P and M enantiomers with >99.5% ee were obtained from the resolution of racemic samples by chiral HPLC. Absolute configurations were determined by X-ray crystallography and were correlated with their CD spectra. The rate constants for racemization of macrocycles were measured, and enthalpies (ΔH(‡)) and entropies (ΔS(‡)) of activation were determined by the Eyring plot method. The present study revealed that a combination of two proximal substituents larger than the van der Waals radii r(w) = 1.75 Å (such as chlorine) and r(w) = 1.47 Å (such as fluorine) at the lower rim was the minimum steric requirement for the resolution and isolation of conformationally stable inherently chiral enantiomers of 1,3-alternate azacalix[4]pyrimidines at room temperature, while a combination of two substituents larger than the van der Waals radii r(w) = 1.75 Å (such as chlorine) and r(w) = 1.85 Å (such as bromine) gave rise to an immobilized 1,3-alternate conformation up to 180 °C.