Selective synthesis of N-Glycosyl Aziridines and their evaluation as Glycomimetics

Chapter 1 gives a brief introduction to topics which form the discussion in the later chapters. Carbohydrate structure, the anomeric/exo-anomeric effects, and examples of their application as chiral auxiliaries in asymmetric synthesis are briefly summarised. The Huisgen 1,3-dipolar cycloaddition, which forms an important part of this thesis work, is described: the reactivity of different dipolarophiles, along with existing experimentally-determined selectivity is discussed. Methods of aziridine synthesis commonly found in the literature, including examples of their synthesis from triazolines and through Lewis acid catalysis are introduced. A background to continuous flow chemistry is also provided in chapter 1, mentioning flow chemistry equipment, its advantages over batch reactions, and the application of cycloaddition and carbohydrate chemistry processes to flow methodology. Finally, an introduction to glycosyl hydrolases (glycosidases) and their inhibition is given. In Chapter 2, triazoline and aziridine derivatives were prepared via diastereoselective Huisgen 1,3-dipolar cycloaddition of 2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl azide 3 with the activated acyclic dipolarophile ethyl 4,4,4-trifluorocrotonate. Compared to a sealed tube reaction, conducting the cycloaddition reaction in a continuous-flow reactor shortened the reaction time and permitted the use of EtOAc as a greener solvent, improving overall safety. Thermolysis of the resulting trans-triazolines yielded trans-aziridines, whereas treatment with boron trifluoride diethyl etherate (BF3·OEt2) or benzyl triflate (BnOTf) stereospecifically produced cis-aziridine. X-ray crystallography and NMR spectroscopy facilitated the stereochemical assignments. Regioselective and stereoselective aziridine ring-opening with a nucleophile is also demonstrated Chapter 3 builds on the methodology established in chapter 2. However, it focuses on access to new N-glycosyl aziridines through the azide-alkene cycloaddition of N- phenylmaleimide, a strained cyclic alkene, with glycosyl azides. The synthesis of a fructopyranosyl aziridine and a galactopyranosyl aziridine from fructopyranosyl azide 20 and galactopyranosyl azide 3 respectively was achieved via thermolysis of diastereomeric triazoline intermediates. Continuous flow chemistry improved the intermolecular cycloaddition reaction time and facilitated tandem one-pot synthesis of the fructopyranosyl aziridine. Chapter 4 describes the stereoselective synthesis of a new N-galactosyl aziridine derivative of norbornene and its evaluation as a glycosyl hydrolase inhibitor (Michaelis-Menten enzyme kinetics is introduced in chapter 4). The Huisgen cycloaddition reaction of galactopyranosyl azide 3 with norbornene proceeded in a diastereoselective manner to give exo triazoline derivatives of norbornane. DFT-calculated 13C NMR spectra helped to further verify the observed diastereoselectivity. The removal of acetyl protecting groups from the galactopyranoside, followed by silica gel mediated decomposition of the intermediate triazolines gave exo N-galactopyranosyl norbornane aziridine (NGNA). NGNA displayed potent mixed inhibition of Aspergillus oryzae (A. oryzae) !-galactosidase and showed high selectivity as an inhibitor for A. oryzae !-galactosidase when compared to the "-galactosidase from green coffee beans. Irreversible inhibition causing enzyme inactivation was ruled out through a !-galactosidase incubation assay. The biological evaluation of derivatives of the N-galactosyl 2-trifluoromethyl-3- carboxylate aziridines synthesised previously is explored in Chapter 5. Their initial assessment as !-galactosidase inhibitors via a glycosidase inhibition assay showed them to be weak competitive inhibitors. This was followed by the synthesis of 3’-O-sulfated aziridine derivatives, targeting the inhibition of galectin-8N (Gal-8N; topic introduced in chapter 5). They were found to be relatively weak ligands compared to existing Gal-8N inhibitors. Molecular docking proposed improved affinity for the primary alcohol aziridine analogue, whose synthesis is demonstrated.

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University of Galway

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