This proposal is concerned with the general topic of molecular recognition of biochemically important analytes by rationally designed, structurally well ordered molecular receptors. Specifically, it involves the development of stationary phases, based on zirconium phosphonates and related layered metal-organic compounds, for liquid chromatographic separations of enantiomers. Building a methods we have developed for growing metal-organic thin films containing molecule-size achiral binding sites, we propose to prepare """"""""chiral molecule sieves."""""""" These materials will be rationally designed and optimized for specific chiral separations problems. The size and shape of molecular binding sites will be controlled by the choice of the crystalline inorganic template, which determines the relative position of the organic groups within the film, and by the choice of chiral organic phosphonate and """"""""spacer"""""""" phosphonate functional groups. Particular emphasis will be placed on understanding the structure and chemical composition of the binding site, and the relation of these to the efficiency of chromatographic separations. Physical studies which measure the kinetics and thermodynamics of enantiomer binding, and which probe the structure of the host and host-guest complex spectroscopically, will be used in connection with molecular mechanics calculations. From these results and chromatographic data, the host-guest interaction will be understood and optimized iteratively by structural fine-tuning of chiral binding sites within the film. Molecular chirality plays a central role in almost all biochemical processes. Biological molecular receptors, e.g., enzyme active sites, are composed of optically active proteins and therefore interact differently with optical isomers of chiral chemical compounds. Many theraputically important drugs are available only as racemic mixtures of optical isomers, even though only chromatographic techniques are needed both for preparing pure optical isomers of these compounds, and for analyzing the optical purity of compounds derived from natural and synthetic sources. The proposed work will provide new materials and methods which will be of significant utility in the analytical and preparative separation of medically important chiral drugs and drug precursors.
