Enantioresolution of Substituted 2-Methoxy-6-oxo-1,4,5,6-tetrahydropyridine-3-carbonitriles on Macrocyclic Antibiotic and Cyclodextrin Stationary Phases

Abstract

Nine different 4−, or 5− substituted racemic pyridones were synthesized and resolved by reversed phase LC. Seven of the compounds showed complete or partial resolution on the vancomycin bonded phase column, while five compounds each were separated on both the teicoplanin and the β-cyclodextrin chiral stationary phase (CSPs). No enantioselective separations were obtained on α- or γ-cyclodextrin stationary phases. The antineoplastic agent methotrexate also was resolved. Structural factors that significantly altered enantioselectivity included: changing the pyridone substituent from the 4 to the 5 position or vice versa, changing the size of the substituent, changing the degree of unsaturation of the substituent and changing the nature and length of the substituent “tether”. The enantioselectivity of the two related macrocyclic antibiotic CSPs are somewhat similar but not identical. This provides a highly useful optimization approach for these columns. Frequently, when partial enantioresolution is obtained on one antibiotic CSP, a complete resolution is obtained on the related column using identical elution conditions. It is apparent that these separations (and CSPs) are highly complementary to each other.