Progress toward for the development of biomimetic organocatalysts for acyl substitution

Abstract

Acyl substitution reactions such as transesterification or hydrolysis, though conceptually simple, hold significant potential for development and are widely used across diverse fields, including plastic degradation, biodiesel synthesis, native chemical ligation. To develop catalysts for this reaction, we aim to explore catalysts that mimic enzymes such as protease, which can cleave robust acyl functional groups like amide under physiological conditions. While enzymes offer high catalytic activity under mild condition, their reliance on maintaining a stable 3D structure presents practical limitations. Therefore, our goal is to develop organocatalysts that can mimic enzymatic activity while maintaining stability across varying pH, temperature, and solvent conditions. Protease active sites have the common features of stabilizing the oxyanion of tetrahedral intermediate formed during nucleophilic attack on the substrate's acyl carbon through hydrogen bonding. Active sites also contain activated nucleophilic OH or SH groups via deprotonation by adjacent base. In chapter 2, we applied this catalyst design for the glycolytic degradation of PET (polyethylene terephthalate), a polyester plastic. In glycolysis, ethylene glycol is used to break down PET via transesterification. Our initial screening identified arginine derivatives and biguanides as a particularly potent catalyst. Based on this observation, further investigations were conducted by synthesizing and studying more arginine derivatives for the better understanding of the degradation mechanism. Chapter 3 explored trans-thioesterification catalysts that facilitate native chemical ligation (NCL) in protein chemical synthesis. Using computational simulations, we designed and predicted optimal head groups and alkyl chain lengths for highly reactive catalysts, and these predictions were used as a blueprint for their synthesis. Catalysts with the same head group but varying alkyl chain lengths were compared to evaluate the effect of chain length on reactivity. Additionally, catalysts with identical alkyl chain lengths but different head groups were analyzed to determine the influence of the head group on reactivity. Unfortunately, the computational predictions do not align with the experimental results, prompting us to further refine the computational model to enhance its accuracy in predicting thioester reactivity.