Expedient Methods for the Stereoselective Glycosylation of Carbohydrates

  • Ryan Williams

Student thesis: Doctoral ThesisDoctor of Philosophy (PhD)

Abstract

Carbohydrates are a widely abundant class of biological compounds that play pivotal roles in medicine, cellular function and nutrition. Despite the ubiquity of carbohydrates in living systems, their efficient synthesis presents a significant challenge. Major reasons for this include the difficulties in controlling the stereochemistry of the glycosylation reaction and the laborious, time-consuming nature of oligosaccharide preparation. This thesis describes efforts to overcome these challenges through new technologies that expedite glycosylation
reactions and subsequent product purification.

A library of glycosyl donors and acceptors was prepared. Using these substrates, a cooperative thiourea-Brønsted acid dual organocatalytic glycosylation strategy for the synthesis of 2-deoxyglycosides was probed. Experiments were performed to uncover mechanistic information about the organocatalytic reaction. Subsequently, a palladium catalysed glycosylation protocol for the preparation of 2-deoxyglycosides was developed. After optimisation of the model reaction, the tolerance of the method for various glycosyl acceptors was assessed through a substrate screen. Generally, high product yields were obtained with excellent α selectivity. A probable mechanism is discussed.

Continuous flow glycosylation reactions were then explored. Initially, a flow glycosylation protocol using a gold(I) catalyst was surveyed. Some promising results were discovered, however, the system proved inconsistent and ultimately unsuitable for the flow regime. Ionic liquid supported glycosylations in flow were then explored for the first time. After reaction optimisation, excellent yields of glycosylation product were obtained in just 15 seconds residence time, with no requirement for column chromatography. Application of the optimal reaction conditions to several other glycosyl donors and acceptors proved challenging due to unexpected protecting group reactivity leading to side products and irreproducibility of results. Nonetheless, mixtures of β-1,2-glucans were successfully prepared using this method, whilst a novel glycosyl donor featuring an orthogonal carbonate protecting group was identified as a key scaffold for the synthesis of β-1,6-glucans.
Date of Award23 Jan 2020
Original languageEnglish
Awarding Institution
  • The University of Bristol
SupervisorM C Galan (Supervisor)

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