Accelerations in the Lactonization of Trimethyl Lock Systems are Due to Proximity Orientation and not to Strain Effects

Introduction e study of enzyme mechanisms is of vast importance and has become central to both bioorganic chemistry and computational chemistry. Studies in this eld by Bruice, Benkovic, Jencks, and Bender over the past 40 years have contributed largely to understanding the mode and scope by which certain enzymes achieve their catalytic activities [1]. ese and studies of many others have been carried out in order to understand enzymatic catalysis which is characterized by high substrate specicity, chemoselectivity, and stereospecicity along with large rate enhancements. Among these are (1) the proximity model of Bruice [2, 3] on the intramolecular cyclization of dicarboxylic semiesters, (2) the “orbital steering” theory suggested by Koshland [4, 5], (3) the “spatiotemporal hypothesis” devised by Menger [6-9] which describes the importance of the distance between the two reactive centers in determining whether a reaction is inter-or intramolecular, and (4) the gem-trimethyl lock (stereopopulation control) proposal of Cohen [10-12].