This application describes experiments designed to test the utility of a model, developed in our laboratory, for relating molecular structure to reactivity within the class of erpicyclic reactions. The work will cover substituent effects on the Claisen rearrangement, control of reaction rates by utilization of through resonance between substituents, investigation of the mechanism of rearrangement of chorismic acid - with and without enzyme catalysis - and study of the feasibility of exploitation of the transient high acidity for certain rearranging alcohols as a means to the generation of high energy reactive intermediates. The goals of the work are: (1) further to establish the credentials of the model by subjecting it to additional experimental tests; (2) to utilize the model as a guide to the design of new reactions that could have application to the synthesis of pharmaceuticals - three new reactions of this type are included in the present proposal; (3) to investigate the mechanism of action of the enzyme chorismate mutase with a view to the design of inhibitors that should have antibiotic properties; (4) initial exploration of a new class of reactions, identified by application of the model, that could, in the long term, show """"""""enzyme-like"""""""" stereo- and regioselectivity in combination with a potent thermodynamic potential driving the reaction toward the generation of high energy intermediates.
