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

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 (Delta H double dagger) and entropies (Delta S double dagger) 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 angstrom (such as chlorine) and r(w) = 1.47 angstrom (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 angstrom (such as chlorine) and r(w) = 1.85 angstrom (such as bromine) gave rise to an immobilized 1,3-alternate conformation up to 180 degrees C.