Synthesis and binding properties of chiral macrocyclic barbiturate receptors: application to nitrile oxide cyclizations

Abstract

A series of chiral macrocyclic receptors containing a barbiturate binding domain based on two 2,6-diaminopyridine groups has been synthesized with the purpose of exploiting these for asymmetric 1,3-dipolar cycloadditions. Each macrocyclic host was built possessing an (R)-BINOL or a modified deoxycholate moiety as the chiral unit connected to the barbiturate binding domain with varying lengths of spacer. All the hosts with the exception of one were found to effectively bind a barbiturate–cinnamic acid conjugate with association constants in the order of 10⁴ M⁻¹ in CDCl₃. The 1,3-dipolar cycloaddition between several arylnitrile oxides and the cinnamate conjugates were examined in the presence of stoichiometric amounts of a chiral receptor affording two regioisomeric isoxazolines. Enantiomeric excesses of up to 30% were obtained in one case for the major regioisomer. In most cases, the enantiomeric excesses could be measured directly from the crude ¹H-NMR spectra owing to the diastereomeric interaction between the isoxazoline cycloadduct and the chiral receptor. The relatively low enantiofacial selectivities at the CC double bond of the cinnamate were attributed to the non-planar orientation of the barbiturate–cinnamate conjugate with respect to the receptor, as previously noted for the binding of barbital to an achiral macrocyclic host (S.-K., Chang, E. Fan, D. Van Engen and A. D. Hamilton, J. Am. Chem. Soc., 1991, 113, 7640), directing the cinnamate unit away from the chiral unit.