Synthesis and Evaluation of Chiral Selectors with Multiple Hydrogen-Bonding Sites in the Macrocyclic Cavities

Chiral macrocycles with the hydrogen bond donor/acceptor sites in the cavity were synthesized and covalently bonded to silica gel to give chiral stationary phases (CSPs), which showed excellent abilities to resolve various chiral compounds including ketones, esters, carboxylic acids, sulfoxides, amines, amino acid derivatives, and metal complexes. The effect of the linker connecting the macrocyclic moiety to silica was examined, and a more electronegative substituent was found to be better. Various organic solvents could be used as the mobile phase to optimize the resolution efficiency of the CSPs. Although the separation factors (alpha) tended to decrease with an increase in the solvent polarity, remarkable solvent tolerance was also observed. In some cases, even MeCN and MeOH could be used for the complete resolution of enantiomers. The MM calculations suggested that the chiral recognition of Co(acac)(3) is achieved by a combination of steric interactions and hydrogen bonds between the carbonyl O atom coordinated to the Co atom and the macrocyclic amide NH groups. The attachment of substituents to the 3,3'-positions of the binaphthyl moiety improved chiral HPLC performance in some cases. In particular, CSP-1d, having the Br atoms, showed the best performance for several analytes.