Development of Biocatalytic Cascades for the Synthesis of Bioactive Compounds

Abstract

Iminosugars and aminopolyols are highly sought-after pharmaceutical targets, with rich oxyfunctionalisation, hydrophilicity and stereochemical density. These factors complicate their discovery and isolation from natural sources and their chemical synthesis but grant tremendous potential as bioactives. Biocatalytic routes towards these compounds offer a viable alternative to traditional synthesis, with enzymatic cascades allowing for natural levels of selectivity, efficacy and molecular complexity whilst enabling process intensification for use in organic synthesis. The aim of this project was to develop de novo biocatalytic cascades towards bioactive iminosugars and aminopolyols using newly identified enzyme activities and investigate the process intensification of these cascades using enzyme immobilisation and flow biocatalysis. With the assistance of computer-aided synthesis planning, enzyme cascades for the synthesis of valuable iminosugars and chiral (amino)-polyol fragments were devised. Primarily, a Galactose oxidase (GOase)-shikimate dehydrogenase (SkDH) cascade was implemented for the synthesis of piperidine and azepane iminosugars from sugar derived aminopolyols. This work exploited a newly identified reactivity of shikimate dehydrogenases, which had previously only been utilized on substrates closely related to the natural compound. The use of D-fructose-6-phosphate aldolase (FSA) in cascades towards amino-polyols was also investigated, with the intention of enabling protection group-free synthesis of chiral products from achiral precursors. Accordingly, an FSA-imine reductase (IRED) cascade was developed and provided diverse linear amino-diols and triols. Finally, FSA has been applied to generate versatile 2,3-dihydroxy-1,4-dicarbonyl synthons with the potential to be diversified into 2-aryl iminosugar derivatives in cascade with transaminase or IRED biocatalysts.

Date of Award	1 Aug 2024
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Sabine Flitsch (Supervisor) & Perdita Barran (Supervisor)