Strong conformational preferences in the transition state and tetrahedral intermediates for the acylation reactions: Relevance to inhibitors of lipases and esterases

ORGN 405

Yu Takano and K. N. Houk. Department of Chemistry and Biochemistry, University of California Los Angeles, 405 Hilgard Ave., Los Angeles, CA 90095
Lipases and esterases are enzymes hydrolyzing a variety of different esters. X-ray crystallographic structures of lipases and esterases with bound inhibitors indicate that a specific conformation of the tetrahedral intermediate mimic is present. We have explored the mechanism of the base promoted transesterification involving methoxy and methyl acetate. A conformational analysis of the tetrahedral intermediate, 1,1-dimethoxyethoxide, has been performed with density functional theory. The geometries were fully optimized with B3LYP/6-31+G(d) calculations. Only the gauche+-anti (anti-gauche-) and gauche+-gauche+ minima are formed, and the gauche+-anti conformation is more stable by 2.9 kcal mol-1. The origin of the conformational preference was investigated from the viewpoint of the hyperconjugation, electrostatic, and steric effects. On the other hand, the gauche+-gauche- conformation is found to be a transition state connecting the gauche+-anti and anti-gauche- conformations.