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.

Chiral trans-1,2-diaminocyclohexane derivatives as chiral solvating agents for carboxylic acids

“…6 Ideally, these diastereomeric species will show chemical shift nonequivalence of some of their NMR signals, allowing the determination of the enantiomeric composition of the substrate by the direct integration of these bands. 7 The advantage of using non-covalent chiral solvating agents relies on the possibility of carrying out the experiment in situ, without purification steps. 8 Besides the starting chiral materials, analytes and the CSA could be easily recovered after the measurement.…”

Chiral Heterocycle-Based Receptors for Enantioselective Recognition

“…However, in the case of macrocycles 67 and 69 fluorescence intensity decreases probably because nitrogen in the pyridine ring as a binding site interacts with proton by static force. Sakai et al [68] designed and synthesized a series of the pyridine incorporated chiral bifunctional macrocyclic hosts, 70-74 ( Figure 7) using two 2,6-diacylaminopyridine as binding units, chiral BINOL to provide an anisotropic ring-current effect, and amides giving rise to a V-shaped arrangement in 70-72, while a parallel alignment in 73. Out ofthe five chiral receptors, 70 was evaluated for the chiral discrimination ability using 1 H or 19 F NMR and was found to be an excellent versatile chiral solvating agent for a wide range of the chiral compounds ( Figure 8) having the following functionalities: carboxylic acid, oxazolidinone, lactone, alcohol, sulfoxide, sulfoximine, isocyanate, or epoxide.…”

Recent progress on using BINOLs in enantioselective molecular recognition

“…For example, the addition of only 5 mol % of (R)-83 resolves the enantiomeric signals of sulfoxide 1-methyl-4(methylsulfinyl)-benzene. 92 Compound (R)-84 (Fig. 37) containing 3,5-bis(trifluoromethyl) phenyl groups at the 3,3 0 -positions changes the size and shape of the chiral cavity of the macrocyclic receptor (R)-83.…”

“…1 The pioneering work conducted by Cram and co-workers is to immobilize bis-(1,1 0 -binaphthyl)-22-crown-6 on polystyrene or silica gel to afford CSPs, which shows reasonable resolution of racemic amines, a-amino acids and amino acid esters. 92,93 In order to improve the chiral recognition efficiency, the optically active (3,3 0 -diphenyl-1,1 0 -binaphthyl)-22-crown-6 is prepared and dynamically coated onto octadecylsilica gel to afford a successful CSP (R)-107 for various primary amino compounds (Fig. 52).…”