The long-term objective of this research is to learn how to design, prepare, and study synthetic organic host compounds that mimic some of the properties of enzymes, genes, and the self-organizing polymers of biological systems. The research tests the basic assumptions that the working sites of the biological systems can be collected and oriented on nonpeptide or nonnucleic acid support structures and yet retain some of the properties of the natural systems such as catalysis, self-assembly, and molecular recognition in complexation. The synthetic systems have support structures that are highly preorganized for self-assembly by complexation and(or) for attaching convergently arranged functional groups which act cooperatively to complex guests and catalysis their reaction. These convergent host sites are stereoelectronically complementary to potential guests' divergently arranged binding and reaction sites. Catalysis is realized by lowering the transition state free energies by complexation which, in effect, turns intermolecular into intracomplex, neighboring group reactions. Self-assembling polymers will be designed and studied whose component monomer units are held together by noncovalent attractions, and whose attached functional groups can act cooperatively in binding. The health relatedness of the project grows out of the central role that molecular recognition in complexation plays in life processes and, therefore, in medicine. Designed host-guest relationships model receptor- substrate (inhibitor) or antibody-antigen relationships. Self-assembling noncovalent polymers model the super-molecular aggregates of muscle, silk, double and triple helices, and membranes. The synthetic systems are designed with the help of Corey-Pauling-Koltun molecular models augmented occasionally by molecular mechanical calculations. The structures of synthetic complexes are determined by X-ray and NMR spectroscopy. Target systems are selected for their potential importance, the viability of their syntheses, and the knowledge yield expected from their investigation.
Specific aims i nvolve the study of: (a) a newly designed transacylase mimic for amides; (b) chiral bases for catalyzing by lipophilization organometallic addition reactions, and chiral acids for catalyzing glycoside hydrolyses; (c) a hydrolase of phosphate esters inspired by ribonuclease; (d) self-assembling polymers held together by noncovalent binding; (e) a host designed to show high chiral recognition in complexation of alpha-amino; (f) the complexing characteristics of cavitands based on cyclotriveratrylene-type structural units.
