Novel Ionic Organocatalysts for Asymmetric Peptide Synthesis and Plastic Recycling

Abstract

In the past century, peptide therapeutics have been introduced as a powerful alternative to small molecule drugs; their ability to form strong interactions with proteins has led to their use in the treatment of many diseases. While the advantages of peptide-based drugs are evident, complexities involving their synthesis can often detract from their viability. For example, incorporation of unnatural amino acids can be costly, and racemisation of activated N-acyl amino acids can occur through the formation of cyclic azlactones. These azlactones exhibit high α-position acidity and can be readily deprotonated, resulting in stereoablation, and can also be ring- opened by nucleophiles. If racemisation occurs, and simultaneously a chiral catalyst is used to promote the nucleophilic ring-opening of the azlactone, a dynamic kinetic resolution (DKR) can be achieved. Though previously unsuccessful, the DKR of azlactones to orthogonally protected dipeptides may address synthetic challenges within peptide synthesis. In this work, ionic phase-transfer catalysts (PTCs) based on Cinchona alkaloids were developed to promote the ring-opening of azlactones to enantioenriched active ester products. Deuterium incorporation experiments were utilised to ensure racemisation of these active esters was limited and subsequently an effective amine quench was devised. The further screening of PTCs led to the discovery of relatively acidic acetamide-based Cinchonium species which promoted the DKR process with higher degrees of enantiocontrol than was previously possible. The development of phenolate ion-pair catalysts led to significant rate enhancements and further screening of substrates and conditions was carried out. Furthermore, the synthesis and investigation of novel quininium- based betaine catalysts allowed for relatively high throughput screening of pronucleophiles, leading to further enhancement of enantiocontrol. Finally, the process was used to synthesise an enantioenriched orthogonally protected dipeptide product. Separately, an assessment of previously reported studies on the PTC catalysed alkaline hydrolysis of poly(ethylene terephthalate) (PET) revealed a limited understanding of the influence of catalyst structure on activity. The seemingly similar yet practically diverse conditions used in these studies made the determination of catalyst structure activity relationships difficult. Furthermore, the reported processes often lacked practicality due to the use of PET particle sizes considerably smaller than flakes commonly used in industrial recycling. As such, classes of ammonium- and phosphonium-based PTCs were synthesised and screened for their ability to promote the alkaline hydrolysis of PET flakes cut from waste water bottles. Consistent and industrially relevant conditions were selected, and assessments of catalyst solubility/lipophilicity were made throughout, which proved instrumental in the clarification of catalyst structure activity relationships. The development of a greener process for the alkaline hydrolysis of PET was then carried out and quantitative recycling of the polymer was achieved. The effect of increased particle size on the rate of reaction was also investigated, counterintuitively leading to higher catalyst activity in a number of cases. Insights garnered from the alkaline hydrolysis study were then applied to a related neutral hydrolysis process.