The object of this proposal is to prepare conformationally constrained analogs of biologically significant amino acids, aryl amines, and related structures. Alpha-functionalization, nitrone addition, and photochemical ring closure methods will be applied to the synthesis of methanopyrrolidines(2-azabicyclo[2.1.1]hexanes) with substituents at the bridgehead and methylene positions. Regioselectivity, stereoselectivity, and enantioselectivity in these reactions will be exploited to prepare novel structures with substituents in spatially defined orientations. Target molecules will include fluoro- and hydroxymethanoprolines to improve our understanding of substituent effects on collagen stability and perhaps lead to stronger collagen mimics. Methanonicotines and related molecules will be prepared as new antinociceptive nicotinic receptor agonists.
With this award, the Organic and Macromolecular Chemistry Program is supporting the research of Dr. Grant R. Krow of the Department of Chemistry at Temple University. Professor Krow and his students are synthesizing molecules that display particular geometrical and chemical bonding preferences, permitting an analysis of the factors controlling the structure and stability of biological polymers, including the structural protein, collagen. These studies are providing fundamental information about the structures of these important biomaterials, and may lead to the development of stronger collagen mimics. There is additional potential for polymers prepared from the targeted class of molecules to inhibit specific protein-protein interactions, and to have useful biological applications coupled with likely resistance to enzyme degradation.