Mechanistic investigation of organocatalysis
- Author(s): Zhu, Hui
- Advisor(s): Kelley, Anne Myers
- et al.
Active pharmaceutical ingredients (APIs) are often chiral. In many cases, different stereoisomers have significantly different physiological effects. As a result, the FDA requires clinical testing of each stereoisomer in any stereoisomeric mixture submitted as a candidate therapeutic and testing of the proposed mixture. As a result, clinical testing of any new stereoisomeric mixture requires three separate clinical trials. This process is cost-prohibitive. As a result, chiral pharmaceuticals are almost exclusively produced as single stereoisomers. Racemic production of chiral APIs limits production to an absolute maximum of 50% yield. A more atom-economical approach is asymmetric synthesis, which makes use of reactions that produce predominately or even exclusively one enantiomer. In recent years, organocatalysis has attracted attention as a potential tool for drug development. Organocatalysts avoid the usage of hazardous metals that can persist as trace contaminants in pharmaceuticals. Many organocatalytic systems have been developed in the past years with outstanding yields and selectivities. However, the mechanistic details for most of those reactions are still not well understood. In this dissertation, the author will first discuss the mechanism of Hajos-Parrish reaction, a proline-catalyzed intramolecular aldol reaction by performing kinetic isotope effect (KIE) study and ab initio density functional theory calculation. Secondly, the author will present the mechanistic study of asymmetric borane reduction catalyzed by Corey-Bakshi-Shibata (CBS) catalyst, and demonstrate the significance of steric effects in asymmetric reactions by measuring steric isotope effects. Additionally, two related fundamental studies on the Alpine-borane reduction and Friedel-Crafts acylation reaction will be presented as they are united with the main subjects covered in this dissertation.