A Combinatorial Approach to Recognition of Chirality: Preparation of Highly Enantioselective Aryl-Dihydropyrimidine Selectors for Chiral HPLC

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Abstract
A parallel library of 108 4-aryl-1,4-dihydropyrimidine (DHPM) enantiomers, which are potential selectors for chiral HPLC separations, was synthesized using the single-step Biginelli multicomponent condensation. The individual compounds were screened by observing the enantioselectivity for resolution on a “brush-type” l-(3,5-dinitrobenzoyl)leucine-based chiral stationary phase, and separation factors α up to 12 were achieved. The best candidates from the library contained an ortho-substituted aromatic group at C4 carbon atom of the pyrimidine ring and an alkyl substituent at N1 nitrogen atom. Resolution of the enantiomers of the lead compound, 4-(9-phenanthryl)-DHPM 8, using semipreparative chiral HPLC followed by attachment to monodisperse macroporous aminomethacrylate beads, provided the novel polymer based chiral stationary phase with good enantioselectivities in the resolution of several π-acidic aryl-dihydropyrimidines and derivatized profens. In addition, 3,5-dinitrobenzamido derivatives of α-amino acids could be resolved under normal phase HPLC conditions with separation factors up to 8.