Combinatorial Approach to Chiral Receptors for Amino Acids

Research project P 14179 Combinatorial Approach to Chirale Receptors for Amino Acids Wolfgang LINDNER 08.05.2000 Molecular systems displaying enantioselective binding properties (chiral selectors, SOs) are of central importance for analytical and preparative enantioseparation of biorelevant chiral compounds (drugs, agrochemicals, aroma compounds etc.). Innovative applications, e.g. development of economic industrial-scale enantioseparation processes, diagnostic assays, analytical sensor devices and chiral catalysts call for target-specific SOs exhibiting high, quasi "receptor-like" levels of enantioselectivity (a>20). However, design, synthesis, evaluation and in particular optimization of SOs using conventional preparative and analytical "step-by-step" procedures are laborious and time-consuming. The use of parallel strategies for synthesis and evaluation of novel SOs may stimulate significant progress in terms of selectivity, efficiency and productivity. In this project the utility of combinatorial strategies for the development of novel cinchonan derived, target-specific SOs for a -, b -amino acids and their N-acyl and Ncarbarnoyl derivatives is put on test. In the first task, multi-member libraries of SOs are created by parallel synthesis using resin-bonded appropriately functionalized cinchonan scaffolds. Defined molecular diversity results as a consequence of sequential functionalization of the 06/09-centers of the cinchonan building block. Structural modification of the resin-bonded cinchonan scaffolds is performed with appropriate functionalized reagents to allow the focused introduction of new, synergistically operating interaction sites in a modular fashion. Subsequently, these SO libraries will be characterized using chromatographic, IR-spectroscopic and mass spectrometric techniques, and, if essential, purified by semipreparative chromatography prior to screening. As the second task and parallel to library generation, target-specific screening procedures for SO evaluation will be elaborated and optimized. These water-compatible techniques will be based on electrophoretic, chromatographic and liquid-solid extraction principles. They allow to evaluate SOarget interactions both with soluble and resin- bonded versions of the SOs. After screening, the promising SO lead candidates will be further optimized by structural "fine-tuning". This optimization process involves the generation of relatively small SO libraries of limited molecular diversity, centered around the lead structures. An additional screening cycle will be used to identify optimized SO structures. Third, for comprehensive evaluation of the optimized SOs, convenient synthetic procedures for these compounds will be developed using conventional solution phase chemistry. The scope of applications of these SOs will be assessed with a large set of acidic analytes using capillary electrophoretic and chromatographic techniques. Forth, the underlying chiral recognition mechanisms of SAarget combinations displaying outstanding levels of enantioselectivities will be studied by advanced 2D NMR spectroscopic techniques. These studies will provide a wealth of information, including complexation stoichiometry, associations constants, low-energy conformations of SO and SA in free and complexed state, including complex geometry and nature of the complex stabilizing noncovalent interaction. To confirm and complement these data, SAarget co-crystals and crystals of the separate components will also be subjected of X-ray structure determination. The presented project is of interdisciplinary nature as it combines elements of i) traditional solution phase chemistry; ii) innovative solid-supported parallel synthesis; iii) development of target-specific screening techniques; iv) advanced NMR spectroscopic and v) solid-phase structure elucidation techniques.