Combinatorial Optimization of Enantioselective Receptors

In the course of the preceding FWF project (P14179-CHE), dedicated to the combinatorial development of novel enantioselective receptors for pharmaceutically / biologically important amino acids, 9-epi-aminoquinine urea and mixed cinchona pyridazines could be identified as novel lead structures with receptor-like enantioselectivity for N- protected cyclic and beta-amino acids. E.g., the preliminary evaluation of covalently immobilized versions of these new receptors under chromatographic conditions provided enantioselectivity factors up to alpha > 30 for important beta amino acid derivatives. These unprecedented high levels of enantioselectivity and affinity in conjunction with the environmentally friendly hydro- organic operation conditions make these systems particularly attractive for the development of advanced enantiomer separation methodologies. In this sense, the objectives of the outlined following-up project are a rigorous optimization of the enantioselective binding properties of these highly promising receptor motifs and the elucidation of the molecular requirements that promote and control enantioselective binding of the target compounds. Receptor structure optimization will be achieved by a combinatorial approach, involving the generation of rationally designed receptor libraries by solid-phase parallel synthesis and dedicated target-specific screening protocols. To ensure a high quality of the libraries, the development as well as the generation of solid-phase bound receptors will be systematically monitored employing "on-bead" FT-IR spectroscopy as prime analytical tool. Enantioselectivity screening with capillary electrophoretic and solid-liquid extraction techniques will be performed at high levels of stringency to facilitate selection of the most efficient receptor systems. Subsequently, the optimized receptor structures will be prepared at gram-scale and evaluated for their applicability in traditional chromatographic, but also for innovative enantioseparation technologies, such as membrane, liquid-liquid extraction and batch-adsorption processes. The chiral recognition principles responsible for enantioselective binding will be studied at the molecular level for selected receptor-analyte combinations in solution by advanced 2D-NMR methodologies, and eventually on the basis of crystal structure data generated by X-ray analysis of corresponding receptor-analyte co-crystals.