Mechanism of a Metal Catalyzed Reaction from a Computational Quantum Mechanical Perspective

Abstract

A recent study reported an innovative approach to the synthesis of the pharmaceutical drug, Clinprost. The authors found that the introduction of a palladium catalyst into the reaction scheme helped reduce the overall synthesis from twenty steps down to just nine, affording significant overall savings. However, unable to account for how the palladium catalyst affects the chemical transformation in the decarboxylative coupling step, the authors contacted the Sargent group for help in determining the reaction mechanism by computational modeling. In order to get a better understanding of a key oxidative addition step in the reaction mechanism, a well-known related system, referred to as the Trost system, was investigated. This reaction utilizes charged species, much like the parent Clinprost system. In this system, acetate detaches from a cyclohexane ring and is replaced with dimethyl malonate. The computational modeling techniques encompass procedures to generate optimized chemical geometries of the stable intermediates along the reaction pathway, isolate the transition state species that connect these local minima, and compute the Gibbs free energies.