Versatile and Practical Macrocyclic Reagent with Multiple Hydrogen-Bonding Sites for Chiral Discrimination in NMR

Abstract

Bifunctional macrocycles 1-4 and diamide 5 were designed and synthesized. NMR studies demonstrated that, among them, receptor 1 functions as the best chiral solvating agent (shift reagent), which is effective for a wide range of chiral compounds having a carboxylic acid, oxazolidinone, carbonate, lactone, alcohol, sulfoxide, sulfoximine, sulfinamide, isocyanate, or epoxide functionality. The addition of only 5 mol % (69 microg, 0.15 mM) of 1 splits the enantiomeric signals of sulfoxide 13. The excellent performance of 1 as a chiral solvating agent, such as versatility, signal sharpness, high splitting ability, high sensitivity, wide detection window, and synthetic accessibility, is reported. NMR studies revealed that the principal binding site of 1 is the two amide NH groups of the lower segment and that the additional binding site is the pyridyl nitrogen. The V-shaped arrangement of the two 2,6-diacylaminopyridine moieties as constructed in 1 was found to be much more effective for binding a variety of compounds than the parallel alignment of the two binding motifs as constructed in 4. The NO2 group in 1 enhanced not only the binding ability but also the degree of enantioselectivity. Unexpectedly, the comparisons between 1 and 3 enabled us to find the importance of the relative orientation of the binaphthyl moiety; the orthogonal disposition of the binaphthyl moiety in 1 most effectively brings about the differential ring-current effect on the chiral guest molecule bound, which leads to the high degree of chiral discrimination in NMR.