McDonagh, Anthony

173 Pages·2017·7.9 MB·English

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Synthesis of novel glycolipids and investigation into the
Title
anomerisation of selenium glycosides
Author(s) McDonagh, Anthony W.
Publication
2016-07-14
Date
Item record http://hdl.handle.net/10379/5919
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Synthesis of Novel Glycolipids and Investigation into the Anomerisation of
Selenium Glycosides
By
Anthony W. McDonagh

A Thesis presented to
The National University of Ireland
For the degree of
Doctor of Philosophy

Based on the research carried out in the
School of Chemistry,
National University of Ireland,
Galway

Under the supervision and direction of
Prof. Paul V. Murphy
National University of Ireland,
Galway.
Date

Declaration

This thesis has not been submitted before, in whole or in part, to this or any other university
for any degree, and is, except where otherwise stated, the original work of the author.

_______________
Anthony McDonagh

i
For Mum & Dad

ii
Abstract
The first section of this thesis describes the synthesis of novel glycosphingolipids with an α-
triazole at the anomeric carbon. Glycosphingolipids are amphiphilic molecules containing a
carbohydrate head glycosidically linked to a sphingoid base. The α-linked derivatives
KRN7000 (α-GalCer) and PBS-59 are of particular interest, due to their ability to stimulate
iNKT cells and produce cytokines that can assist against various infections or alleviating the
effects of autoimmune diseases. The Murphy group has previously reported the synthesis of
α-O, α-SO and α-S PBS-59 analogues. Key to the success of each synthesis was a
2
stereoselective anomerisation reaction in forming the α-anomer. These anomerisation
reactions are promoted by either TiCl or SnCl and are successful in generating α-O and α-S-
4 4
glycosides from the corresponding β-anomer. A more recent development in the Murphy
group has illustrated the anomerisation for glycosyl azides. Therefore, chapter two is focused
on applying these α-glycosyl azides as intermediates to synthesise new PBS-59 analogues
with either a 1,5- or 1,4-triazole linkage.
Chapter 3 describes an investigation into the anomerisation of selenium glycosides. There are
various procedures in the literature for the synthesis of β-Se-glycosides and a lesser number
reported for α-Se-glycosides. It was therefore envisioned that Lewis acid promoted
anomerisation could give α-Se-glycosides from the corresponding β-anomer. The
anomerisation was successful for galacturonic acid derivatives with TiCl as the reaction
4
promoter. To investigate the substrate scope, various alkyl, alkenyl, alkynyl, saccharide and
steroid groups were attached to the anomeric selenium atom. The anomerisation was found
only to be unsuccessful for 1→4 linked disaccharides. Yields were higher when the reactions
were carried out at higher dilution. Increasing the complexity of the aglycon led to the
requirement to increase the amount of Lewis acid and/or temperature to ensure reaction
completion.
The selenium anomerisation was then applied to the first synthesis of selenoglycoside
analogues of the potent immunostimulant α-GalCer. Chapter four presents the synthesis of α-
Se-GalCer and analogues thereof. Synthetic challenges deemed the initial route involving an
azide intermediate to be unsuccessful. However, revising the retrosynthesis to omit the azido
gave a successful route to the target glycolipids.

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Table of Contents

Table of Contents iv
Symbols and Abbreviations vii
Chapter 1: Introduction to Glycosphingolipids
1.1 Structure of Glycosphingolipids 2
1.2 Biology of Invariant Natural Killer T (iNKT) Cells 3
1.3 KRN7000 (α-GalCer): Interaction with iNKT Cells 4
1.4 Analogues of KRN7000 and Promoting a Bias Cytokine Production 7
1.4.1 Modification of the Sugar Head Group. 8
1.4.2 Varying the Polar Portion of the Ceramide. 9
1.4.3 Substitution and Variating the Lipid Chains. 10
1.4.4 Modifying the Nature and Configuration (α or β) of the Anomeric Bond. 11
1.5 Bacterial Glycosphingolipids Stimulate NKT Cells 14
1.5.1 Stereoselective Synthesis of Bacterial Glycolipids 16
1.6 Aims of this Thesis and Target Compounds 20
1.7 References 21

Chapter 2: Synthesis of α-Galactosyl Ceramide Analogues with an α-
Triazole at the Anomeric Carbon
2.1 Retrosynthetic Analysis 28
2.2 Lewis Acid Promoted Anomerisation: An Overview 28
2.3 Synthesis of α-Glycosyl Azides 36
2.4 Synthesis of the Alkyne 37
2.5 Synthesis of α-Glycosyl Triazoles 39
2.5.1 Introduction to ‘Click’ Chemistry 39
2.5.2 Coupling of the Azide and the Alkyne 42
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2.6 Final Step: Deprotection 43
2.7 Biological Evaluation of AMD291 and AMD292 44
2.8 Conclusion 45
2.9 References 45

Chapter 3: Lewis Acid Induced Anomerisation of Selenium Glycosides
3.1 Selenium 49
3.2 Selenium in Carbohydrate Chemistry 50
3.2.1 Selenoether Pseudocarbohydrates 50
3.2.2 Selenosugars 53
3.2.3 Selenoglycosides 55
3.3 Aims and Objectives 58
3.4 Investigating the Anomerisation of Selenium Glycosides 59
3.5 Substrate Scope: Synthesis and Investigation 62
3.6 Conclusion 69
3.7 References 69

Chapter 4: Synthesis of α-Se-GalCer
4.1 Retrosynthetic Analysis 74
4.2 Synthesis 75
4.3 Revised Retrosynthetic Analysis 78
4.4 A Successful Route to α-Se-GalCer 79
4.5 Biological evaluation 81
4.6 Conclusion 81
4.7 A Note on Future Work 82
4.8 References 82

v
Chapter 5: Experimental
5.1 General Experimental Conditions 85
5.2 Chapter 2-Experimental 86
5.3 Chapter 3-Experimental 104
5.4 Chapter 4-Experimental 135
5.5 References 160

vi
Symbols and Abbreviations
α Alpha
Å Angstrom
Ac Acetyl
AcOH Acetic acid
Ac O Acetic anhydride
2
Ag OTf Silver trifluoromethanesulfonate
2
All Allyl
aq. Aqueous
Ar Aromatic
AraCer Arabinitolceramide
Arg Arginine
Asp Aspartic acid
β Beta
BAIB (Diacetoxyiodo)benzene
BH .THF Borane tetrahydrofuran complex
3
BF .Et O Boron trifluoride diethyl etherate
3 2
Bn Benzyl
Boc tert-butyloxycarbonyl
Boc O Di-tert-butyl dicarbonate
2
br s Broad singlet
Bu, n-Bu Normal (primary) butyl
Bu NCl Tetrabutylammonium chloride
4
t-Bu tert-butyl
t-BuOH tert-butanol
Bz Benzoyl
°C Degrees Celsius
CBr Tetrabromomethane
4
Cer Ceramide
CH Cl Dichloromethane
2 2
CH I Iodomethane
3
cm-1 Wavenumber
COSY Correlation Spectroscopy
Cp* Pentamethylcyclopentadienyl
Cs CO Cesium carbonate
2 3
CuI Copper iodide
CuSO Copper sulfate
4
Cy Cyclohexyl
δ Chemical shift in ppm downfield from TMS
d Doublet (spectral)
dd Doublet of doublets (spectral)
ddd Doublet of doublets of doublets (spectral)
D O Deuterium oxide
2
DCE 1,2-Dichloroethane
DEPT Distortionless Enhancement by Polarisation Transfer
DIPEA Diisopropylethylamine
DMA N,N-dimethylacetamide
DMAP 4-(Dimethylamino)pyridine
DMF N,N-dimethylformamide
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2,2-DMP 2,2-Dimethoxypropane
DMPU N,N′-Dimethylpropylene urea
DMSO Dimethylsulfoxide
DMTr Dimethoxytrityl
dt Doublet of triplets (spectral)
dr Diastereomeric ratio
E Trans
EDC N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide
eq. or equiv Equivalents
ES-HRMS High-Resolution Mass Spectrometry - Electrospray Ionization
Et Ethyl
EtOH Ethanol
EtSH Ethane thiol
Et O Diethylether
2
EtOAc Ethyl acetate
Gal Galactose
GalCer Galactosylceramide
Glc Glucose
Gly Glycine
GSL Glycosphingolipid
H O Hydrogen peroxide
2 2
h Hours
HCl Hydrochloric acid
HClO Perchloric acid
4
HCOOH Formic acid
HMBC Heteronuclear multiple bond correlation
HOBr Hypobromous acid
HOCl Hypochlorous acid
HOSCN Hypothiocyanous acid
HSQC Heteronuclear single quantum correlation
Hz Hertz
I Iodine
2
IFN-γ Interferon-γ
IL Interleukin
Im Imidazole
InI Indium(I) iodide
iNKT Invariant natural killer T
IR Infrared (spectroscopy)
J Coupling constant (nmr), in Hz
KBr Potassium bromide
K CO Potassium carbonate
2 3
KSAc Potassium thioacetate
LDA Lithium diisopropylamide
LiAlH(O-t-Bu) Lithium tri-tert-butoxyaluminum hydride
3
LiCl Lithium chloride
LiI Lithium iodide
LPS Lipopolysaccharide
m Multiplet
M Molar
M+ Mass of the molecular ion (mass spectrometry)
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