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Published on 23 September 2016 on http://pubs.rsc.org | doi:10.1039/9781782626657-FP001
Carbohydrate Chemistry
Volume 42
Published on 23 September 2016 on http://pubs.rsc.org | doi:10.1039/9781782626657-FP001 View Online
View Online
A Specialist Periodical Report
Carbohydrate Chemistry
Volume 42
Editors
Amelia Pilar Rauter, Universidade de Lisboa, Portugal
Thisbe K. Lindhorst, Christiana Albertina University of Kiel,
Germany
Yves Queneau, Université de Lyon, France
Authors
Mohammed Ahmar, University of Lyon, France
Ana Ardá, CIC bioGUNE, Derio, Spain
Jacqueline Bezençon, University of Basel, Switzerland
Roman Bielski, Wilkes University, Wilkes-Barre, PA, USA
F. Javier Cañada, CIB-CSIC, Madrid, Spain
Stéphane Chambert, University of Lyon, France
Helena Coelho, CIC bioGUNE, Derio, Spain
Stephen J. Cowling, The University of York, UK
Gour Chand Daskhan, Indian Institute of Science, Bangalore, India
Simone Dedola, Iceni Diagnostics Ltd, Norwich, UK
Deniz Eris, University of Basel, Switzerland
Beat Ernst, University of Basel, Switzerland
Beatriz Fernández de Toro, CIB-CSIC, Madrid, Spain
Robert A. Field, John Innes Centre and Iceni Diagnostics Ltd,
Norwich, UK
Silvia Galante, CIB-CSIC, Madrid, Spain
Ana Gimeno, CIC bioGUNE, Derio, Spain
Ana M. Gómez, Instituto de Quı́mica Orgánica General, Madrid, Spain
John W. Goodby, The University of York, UK
Sławomir Jarosz, Institute of Organic Chemistry, Polish Academy of
Sciences, Warsaw, Poland
N. Jayaraman, Indian Institute of Science, Bangalore, India
Jesús Jiménez-Barbero, CIC bioGUNE, Derio, Spain and Ikerbasque,
Bilbao, Spain
Simon Kleeb, University of Basel, Switzerland
Paul Kosma, University of Natural Resources and Life Sciences-Vienna,
Austria
Pavol Kováč, NIDDK, LBC, National Institutes of Health, Bethesda, MD, USA
J. Cristobal López, Instituto de Quı́mica Orgánica General, Madrid, Spain
Grahame Mackenzie, University of Hull, UK
Krishnagopal Maiti, Indian Institute of Science, Bangalore, India
View Online
Michał Malik, Institute of Organic Chemistry, Polish Academy of Sciences,

Warsaw, Poland
Silvia Miranda, Instituto de Quı́mica Orgánica General, Madrid, Spain
Lijuan Pang, University of Basel, Switzerland
Giulia Pergolizzi, John Innes Centre, Norwich, UK
Yves Queneau, University of Lyon, France and University of Hull, UK
Ana Poveda, CIC bioGUNE, Derio, Spain
Said Rabbani, University of Basel, Switzerland

Christoph P. Sager, University of Basel, Switzerland
Gopal Kumar Samanta, Indian Institute of Science, Bangalore, India
Javier Sastre, CIB-CSIC, Madrid, Spain
Oliver Schwardt, University of Basel, Switzerland
Anja Sigl, University of Basel, Switzerland
Martin Smiesko, University of Basel, Switzerland
Laurent Soulère, University of Lyon, France
Luca Unione, CIC bioGUNE, Derio, Spain
Pablo Valverde, CIC bioGUNE, Derio, Spain
Zbigniew J. Witczak, Wilkes University, Wilkes-Barre, PA, USA
Peng Xu, NIDDK, LBC, National Institutes of Health, Bethesda, MD, USA
Rui Xu, University of Lyon, France
Zonglong Yang, University of Lyon, France
ISBN: 978-1-78262-538-4
PDF eISBN: 978-1-78262-665-7
EPUB eISBN: 978-1-78262-974-0
ISSN: 0306-0713
DOI: 10.1039/9781782626657
A catalogue record for this book is available from the British Library
r The Royal Society of Chemistry 2017
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Preface
DOI: 10.1039/9781782626657-FP007
This volume is dedicated to the memory of Derek Horton, a scientist that

has shown to the world the importance of the glycosciences for societal
and industrial innovation. With more than 500 publications and

numerous patents, he was also well known in the carbohydrate com-
munity for his editorial activities: he was a founder and editor of the
leading journal Carbohydrate Research, and the editor of Advances in
Carbohydrate Chemistry and Biochemistry, formerly known as Advances
in Carbohydrate Chemistry, a book series containing peer reviewed
contributions covering all areas of glycosciences.
In our memory remains his enthusiasm to find new topics and new
authors, encouraging researchers, including the younger ones, to submit
their contributions to the Advances, in recognition of their excellence
and novelty. He loved challenges, and another of his passions was
the nomenclature of carbohydrates. Indeed, he was a reference in this
domain, and nomenclature experts always wanted to hear his voice on
the matter! He was always first when giving a compound name, and a
more complex structure was a bigger challenge and a joy for him! He
chaired the American Chemical Society Committee for Carbohydrate
Nomenclature and belonged to the expert panel of the Recommendations
1996 for the Nomenclature of Carbohydrates. Since then, as a member of
the IUPAC Joint Commission of Biochemical Nomenclature and as a task
group member of the IUPAC project dedicated to the revision of the
Nomenclature of Carbohydrates, he honored us with his outstanding
contributions to carbohydrate nomenclature.
Derek Horton was a Fellow of both the American Society of Chemistry
(ACS) and the Royal Society of Chemistry (RSC), and received numerous
awards, to name the Haworth Medal from the RSC, the Wolfrom Award
and the Claude S. Hudson Award from the ACS. He held the Isbell Chair
of Carbohydrate and Natural Product Chemistry at American University
(1993–2009) and his love for teaching and research can be demonstrated
by the number of students that have learnt how to study and how to
investigate with him. This book contains contributions of some of his
friends, who wish to dedicate this work to him and to the friendship they
chaired in life.
Glycoconjugation and glycoside chemistry are the major topics of this
volume. Chapter 1, authored by Rob Field, provides a critical survey of
glycoconjugation methodologies, relevant to access homogenous natural
glycoproteins and analogues thereof, emphasizing recent progress in the
area. In this chapter, chemical and chemo-enzymatic glycoconjugation
methods are described, along with illustrations of typical applications.
These methods are unique tools to access glycoproteins for understanding
the role of each glycan in glycoprotein structure–function relationships.
In Chapter 2, the application of solution NMR to the study of con-
formation, dynamics of molecules embodying sugars in their structure
Carbohydr. Chem., 2017, 42, vii–ix | vii

c The Royal Society of Chemistry 2017
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(oligo and polysaccharides, glycopeptides and glycomimetics) and to the

investigation of glycan-related molecular recognition events is authored
by Jesús Jiménez-Barbero and coworkers (Chapter 4). They present recent
selected examples for analysing saccharide conformation, and for
describing key structural features of glycan molecular recognition events
with different natural and synthetic receptors.
In Chapter 3 the evolution of methodologies for the conjugation of
single amino group-containing carbohydrates to protein carriers is

described by Pavol Kováč and his coworker. They present the squaric
acid-based method as the most efficient one for converting proteins to
glycoconjugates with predictable carbohydrate-carrier ratios, and give
examples of proven protocols for the conjugation of low- and high-
molecular-weight carbohydrates.
Paul Kosma contribution describes the latest findings in Kdo
glycosidation, a demanding research area for the development of
glycoarrays, immunoreagents and vaccines that can be accessed by
reading Chapter 4.
Cyclic oligosaccharides have attracted the interest of glycochemists
as a result of their immense industrial importance arising from their
molecular and supramolecular properties. As opposed to the production
of cyclic oligosaccharides biosynthetically, their chemical synthesis
remains a challenge. In this Chapter 5, authored by N. Jarayaman and
coworkers, advances in cyclic oligosaccharide synthesis are compiled,
particularly those described over the last decade, with emphasis on
modifications of glycosidic bonds or individual sugar moieties.
The developments in the Ferrier rearrangement reported in the last
three years are the subject of the critical review authored by Ana Gómez
and Cristobal López (Chapter 6), who demonstrate the usefulness of
glycals to the synthesis of glycosides bearing a 2,3-unsaturated glycosyl
group and the various reaction conditions described for stereoselectivity
control. In addition, S-, N- and C-glycosylation starting from glycals is
also presented and discussed.
In Chapter 7, authored by Beat Ernst and coworker, they report their
original work on how to improve solubility, metabolic stability as well as
passive permeability of mannoside antagonists of the mannose-binding
adhesin FimH, by modifying the substitution pattern and by introducing
heteroatoms at the aglycone. These molecules may give an important
contribution to an efficient non-antibiotic strategy to overcome antibiotic
resistance in urinary tract infections.
An overview of steroid glycoside synthetic methodologies is given in
Chapter 8, authored by Yves Queneau and coworkers, who highlight their
nature as amphiphilic systems and their ability to interact with other
biomolecules within cell membranes and to contribute to organized
molecular and supramolecular systems.
Recent advances in the synthesis of imino sugars, comprising the
preparation of five- and six-membered heterocycles containing an en-
docyclic nitrogen atom, authored by Slawomir Jarosz and coworker
(Chapter 9) and amino sugar synthesis, with emphasis on diastereo- and
enantioselectivity (Chapter 10) authored by Zbigniew Witczak and Roman
viii | Carbohydr. Chem., 2017, 42, vii–ix

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Bielski complete this volume 42 of the Specialist Periodical Reports –

Carbohydrate Chemistry: Chemical and Biological Approaches.
We hope the readers enjoy this selection of contributions that focus on
the progress of synthetic methodologies for small molecule amino and
imino sugars, glycoconjugation and glycosylation of a variety of acceptors
leading to molecules with a diversity of medicinal properties. Insights
onto molecular recognition studies by NMR also enrich the content and
multidisciplinarity of this volume.
Amelia P. Rauter
Thisbe K. Lindhorst
Yves Queneau
Carbohydr. Chem., 2017, 42, vii–ix | ix

CONTENTS
Cover
Tetrahydropyran-enclosed ball-and-
stick depiction of a glucose
molecule, and (in the background)

part of an a-glycosyl-(1-4)-D-glucose
oligosaccharide and a glycosidase, all
representative of the topics covered
in Carbohydrate Chemistry Chemical
and Biological Approaches.
Cover prepared by R. G. dos Santos.
Preface vii
Amelia P. Rauter, Thisbe K. Lindhorst and Yves Queneau
Contemporary glycoconjugation chemistry 1

Giulia Pergolizzi, Simone Dedola and Robert A. Field
1 Introduction 1
2 Established chemical methodologies 3
3 Newer chemical methodologies 8
4 Newer enzymatic methodologies 22
5 Conclusions and future perspective 41
Acknowledgements 41
References 41
Recent advances in the application of NMR methods to uncover 47

the conformation and recognition features of glycans
Ana Ardá, Helena Coelho, Beatriz Fernández de Toro, Silvia Galante,
Ana Gimeno, Ana Poveda, Javier Sastre, Luca Unione,
Pablo Valverde, F. Javier Cañada and Jesús Jiménez-Barbero
1 Introduction 47
2 Mono-, oligo- and poly-saccharides. Conformation and 47
dynamics in solution
3 The bound state 52
4 Oligosaccharide–protein interactions: lectins 53
5 Oligosaccharide–protein interactions: antibodies 57
Carbohydr. Chem., 2017, 42, xi–xiv | xi

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6 Oligosaccharide–protein interactions: enzymes 58

7 Polysaccharide interactions 59
8 Glycopeptides. The free state 60
9 Glycopeptide–antibody interactions 61
10 Glycopeptide–lectin interactions 62
11 Glycomimetics: structural and conformational features 63
12 Glycomimetic interactions: lectins and enzymes 64

13 Other interactions. Artificial receptors for carbohydrates 69
14 Cyclodextrins 72
15 Carbohydrate–nucleic acid interactions 74
16 Concluding remarks 74
Acknowledgements 74
References 75
Controlled and highly efficient preparation of carbohydrate-based 83

vaccines: squaric acid chemistry is the way to go
Pavol Kováč and Peng Xu
1 Introduction 83
2 The early days 84
3 More recent conjugations of synthetic oligosaccharides 85
4 Conjugation of bacterial polysaccharides 99
5 The road to the present state of the art 101
6 Practical considerations 103
7 Suggested conjugation protocols 106
Acknowledgements 111
References 111
Recent advances in Kdo-glycoside formation 116

Paul Kosma
1 Introduction 116
2 Chemistry of Kdo glycoside formation 117
3 Conclusions and outlook 157
Abbreviations 160
References 161
Chemical and enzymatic approaches to the synthesis of cyclic 165

oligosaccharides
Krishnagopal Maiti, Gopal Kumar Samanta, Gour Chand Daskhan
and N. Jayaraman
1 Introduction 165
2 Cyclic oligosaccharides retained with glycosidic oxygen 169
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3 Linear oligosaccharides formed through glycosidic bond 186

cleavage of native CDs and subsequent cyclization to cyclic
oligosaccharides
4 Polycondensation of designed oligosaccharide monomers 189
5 Enzymatic methods to prepare cyclic oligosaccharides 202
6 Conclusion 205
Abbreviations 206
References 207
Ferrier rearrangement: an update on recent developments 210

Ana M. Gómez, Silvia Miranda and J. Cristobal López
1 Introduction 210
2 Pd-catalyzed Ferrier rearrangement 210
3 Lewis-acid catalyzed Ferrier rearrangement 222
4 Ferrier rearrangement mediated by acids 229
5 Oxidative promoters 230
6 Miscellaneous activation protocols 231
7 Miscellaneous transformations of glycals 233
8 Ferrier rearrangement on C-1 or C-2 substituted glycal systems 236
9 Polarity inversion in the Ferrier rearrangement 243
10 Conclusion 244
References 245
FimH antagonists – solubility vs. permeability 248

Lijuan Pang, Jacqueline Bezençon, Simon Kleeb, Said Rabbani,
Anja Sigl, Martin Smiesko, Christoph P. Sager, Deniz Eris,
Oliver Schwardt and Beat Ernst
1 Introduction 248
2 Results and discussion 249
3 Conclusions 268
Abbreviations 269
References 269
Carbohydrate steroid hybrid architectures: the viewpoint of 274

amphiphilicity and self-organisation
Zonglong Yang, Rui Xu, Stéphane Chambert, Laurent Soulère,
Mohammed Ahmar, Grahame Mackenzie, Stephen J. Cowling,
John W. Goodby and Yves Queneau
1 Introduction 274
Carbohydr. Chem., 2017, 42, xi–xiv | xiii

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2 The different classes of glycosteroids, classified by 277

molecular shape
3 Investigations on supramolecular systems made of 296
glycosteroids
4 Conclusion 307
References 307
Recent advances in the synthesis of imino sugars. An insight 313

into the cascade addition of Grignard reagents to
halonitriles/cyclization
Michał Malik and Sławomir Jarosz
1 Introduction 313
2 SN2 cyclizations 314
3 Reactions of cyclic imines 319
4 Cascade addition of Grignard reagents to 324
halonitriles/cyclization
5 Reactions of cyclic nitrones 331
6 Ring-closing metathesis 335
7 Miscellaneous 338
8 Conclusions 340
References 340
Recent examples of novel synthetic approaches to diverse 344

amino sugars
Zbigniew J. Witczak and Roman Bielski
1 Introduction 344
2 Synthetic strategies for the preparation of C-1 amino sugars 346
5 Novel synthetic strategies for the preparation of C-4 357
amino sugars
6 Synthetic strategies for the preparation of C 5-amino sugars 358
7 Synthetic strategies for the preparation 6-amino-6-deoxy 361
sugars
8 Synthetic strategies for the preparation of branched 365
amino sugars
9 Conclusions and future prospects 365
References 366
xiv | Carbohydr. Chem., 2017, 42, xi–xiv

Contemporary glycoconjugation
chemistry
Giulia Pergolizzi,a Simone Dedolab and Robert A. Field*a,b
DOI: 10.1039/9781782626657-00001
Published on 23 September 2016 on http://pubs.rsc.org | doi:10.1039/9781782626657-00001
Glycoproteins are typically expressed in nature with heterogeneous glycan components;

understanding glycoprotein structure–function relationships is therefore challenging. This
has been the driving force for increasing investigation for glycoconjugation techniques,
in order to access homogenous natural glycoproteins and analogues thereof. These
tools will be invaluable in efforts to unveil the precise role of each glycan structure. This
mini-review provides a critical survey of glycoconjugation methodologies, with an
emphasis on more recent progress in the field. Chemical and chemo-enzymatic glyco-
conjugation methods will be described, along with illustrations of typical applications.
1 Introduction
It is now almost redundant to state that carbohydrates are crucial
molecules in nature, taking part in a wide variety of biological process:1,2
prevalent on cell surfaces, carbohydrates are involved in cell–cell sig-
nalling events and regulate the interaction with extracellular matrix;
oligosaccharides modulate glycoprotein folding in the ER and are sub-
sequently modified to achieve fully functional mature glycoproteins;3,4
recognition of carbohydrates by lectins forms the basis for inflammatory
and immune responses, as well as for the adhesion and infection pro-
cesses of pathogenic microorganisms. Surprisingly therefore, the
importance of glycan structure in biology has been underestimated in the
past and this class of molecule is only now gaining recognition for its
significant role on the crowded stage of scientific understanding (for
context, see Fig. 1).
The level of diversity5 present in glycan structures can be over-
whelming due to the intrinsic nature of carbohydrates. A detailed theo-
retical examination of all the possible monosaccharide combinations
that can give rise to disaccharides through hexasaccharides estimated an
astonishing 1012 possible structures.6 Based on biosynthesis consider-
ations, refinement of this number arrived at a projected number of
mammalian glycans of just over than 3000, to which may be added other
4000 estimated glycosaminoglycans.7 So, a projected B7000 mammalian
glycans overall, requiring overall the action of B700 enzymes for their
biosynthesis.7 The study of such a complex set of carbohydrates, known
as the ‘‘glycome’’, and its relation to biological processes is referred to as
‘‘glycomics’’;8 the latter has seen increasing attention in recent years
thanks to the development of glycan microarrays,9–12 nanoparticle13–15 and
biosensors,13,16–19 and improvements in glycoanalysis techniques.20,21
a
Department of Biological Chemistry, John Innes Centre, Norwich NR4 7UH, UK.
E-mail: rob.field@jic.ac.uk
b
Iceni Diagnostics Ltd, Norwich Research Park, Norwich NR4 7UH, UK
Carbohydr. Chem., 2017, 42, 1–46 | 1

Published on 23 September 2016 on http://pubs.rsc.org | doi:10.1039/9781782626657-00001 View Online
Fig. 1 Glycoconjugates and their biological relevance.
However, in the absence of the biological context – conjugated to protein

or lipids, for instance – the true function of glycans may be lost. There is
therefore a pressing need for efficient methods to prepare natural,
homogenous glycoproteins, or structural mimetics thereof.
An ideal glycoconjugation method should fulfil a series of require-
ments. Very often either the protein or the carbohydrate moieties are not
available in large quantities, so conjugation methods should be highly
efficient to avoid the loss of valuable material. Related to this issue, the
possibility of recovering the starting materials in a usable form is very
much desirable. For glycoconjugation applied to glycoprotein synthesis
the reaction conditions should ideally involve neutral pH, performed at
room temperature, and generally mild so as not to disrupt the protein
structure/activity. Most of the glycoconjugation methods used to date
to generate non-native glycan–protein conjugates have relied on the
random modification of one or more of the amino acid side chains of
lysine, cysteine or tyrosine.
It is clear that glycoconjugates have a crucial role in fundamental
biology, with scope for application as therapeutics.17,22,23 Given the
complexity and variety of carbohydrates, and the difficulties in obtaining
homogeneous forms of glycans and glycoproteins from natural sources,
efficient methods for the preparation of homogeneous glycoconjugates are
key. With regard to natural glycoproteins,2 glycans may be connected to
polypeptides via the amide bond of the side chain of Asn, (N-glycans),24,25
via glycosidic bonds to the side chain of Ser or Thr (O-glycans),26–28 or via
an ethanolamine phosphate linkage that bridges a protein C-terminus to
a glycolipid, as in glycosylphosphatidylinositol (GPI) anchors.29 Recent
2 | Carbohydr. Chem., 2017, 42, 1–46

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progress in the field chemical synthesis of glycoproteins has been exten-

sively reported,30–32 highlighting powerful approaches to accurately control
the site and nature of glycosylation. Recent example of homogeneous
glycoproteins obtained by chemical means are, among the others, the total
synthesis of EPO,33,34 interferon b,35 MCP-3,36 homogeneous antifreeze
glycoprotein,37 the a and b subunit of human glycoprotein hormone.38,39
In term of non-natural glycoconjugates, linkers that permit glycan coup-
ling to the reactive side chains lysine and cysteine have traditionally
been popular.30,40 In addition, where chemical synthesis fails to afford
reasonable yields, the synthesis of natural and unnatural oligosaccharides
and their conjugation to proteins can be achieved by chemo-enzymatic
methods, which have become a valuable approach to tackle difficult syn-
theses of less straightforward oligosaccharide conjugates.41
As summarised above, it is evident that the structural diversity and
potential heterogeneity of natural glycoproteins makes deciphering
structure–function relationships a challenging task – one that may be
overcome by the preparation of homogeneous glycoproteins by means of
chemical or biological methods, or more often these days by a combination
of both. Likewise, efficient conjugation methods that are tolerant of diverse
glycan and protein structures will open new avenues for conjugate vac-
cines.42 The conjugation of carbohydrates to proteins, in particular, may be
achieved by a range of approaches that have been extensively reviewed in
the past.30,43,44 Herein we illustrate a range of newer methodologies and
their applications, with reference to some of the classic methods that
provided the inspiration for continued method development.
2 Established chemical methodologies

The definition of a ‘‘glycoconjugate’’ is rather broad and comprises
classes of molecules where a carbohydrate unit is covalently linked to
another molecule, generally a protein. Conjugation of carbohydrates to
proteins has been a challenging task, tackled in classic work performed
by Pauly, which dates back to the beginning of the twentieth century,
where he was able to couple glucose and galactose to serum globulin.45
His seminal work inspired later work by Avery and Goebel in the 1930s,46
which described the synthesis of diazonium salt derivatives of glucose
and galactose and their conjugation to serum globulin for use in a series
of immunological studies. The reaction of diazonium sugar derivatives
with proteins is non-specific resulting in indiscriminate modification of
tyrosine, histidine, lysine and, if used in large excess, with tryptophan
and arginine.47–50 Since then, efforts at improving the production of
glycoconjugates have been unceasing.
Synthetic carbohydrates generally have the reducing end available for
conjugation; on the other hand, carbohydrates from natural sources may
have the reducing end available or not, depending on the nature of the
glycan concerned. There are a variety of well-established reducing end
conjugations that exploit the reactivity of the exposed aldehyde of ring-
open reducing sugars towards amines.51 A classic approach involves the
reductive amination of a reducing sugar with the amino group of lysine
Carbohydr. Chem., 2017, 42, 1–46 | 3

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11,52,53
with cyanoborohydride, giving secondary amines that are stable to
hydrolysis. The aldehyde form of reducing sugars can also react with
hydrazines, hydrazides or aminooxy-functionalised proteins to give
hydrazones or oximes11 (Fig. 2a). Where the reducing end of a glycan is
not available for coupling, internal sugar units or the non-reducing
terminus may be oxidised with periodate to generate aldehydes that can
undergo reductive amination (Fig. 2b).
Alternatively, the reducing end or specific functional groups, such as

carboxylic acid in uronic acids or amine in amino sugars, can be
selectively modified by the use of heterobifunctional cross-linkers
introducing a variety of functional groups11,51 (Fig. 2c), such as amine,
hydrazine or thiol, which can react with N-hydroxy-succinimide (NHS)
ester- or maleimide-functionalised proteins. In the opposite sense, the
carbohydrate can be functionalised with linkers carrying NHS-ester, para-
nitrophenyl ester, squarate,54 maleimide, isocyanate, isothiocyanate or
acyl azide55 (Fig. 2c–d) to react with lysine and cysteine of the protein, or
with amine, thiol, or hydrazine-functionalised proteins.51 The hydroxyl
groups of carbohydrate moiety can also be traditionally activated by
cyanogen bromide (CNBr)56 or carbonyldiimidazole (CDI)57 to react with
amino groups of the proteins and generate isourea and carbamate bonds,
respectively (Fig. 2e–f). If the carboxylic groups on the sugar or proteins
are free and not activated by NHS-ester, they can be activated in situ with
water soluble carbodiimide,58 forming an O-acylisourea active ester that
can be attacked by amino groups forming an amide bond.
Historically, some of the most important glycan–protein conjugates
investigated have been non-natural materials, created as potential anti-
microbial vaccines. Vaccination has had a major impact in improving
human health, eliminating various diseases, such as pneumonia, influ-
enza, typhoid fever, pertussis, measles and smallpox, which have caused
millions of deaths in the past.59,60 Glycoconjugate vaccines are particu-
larly effective in this context; while the Haemophilus influenza type B (Hib)
capsular polysaccharide alone is poor at inducing an immune response,
immunogenicity was triggered by conjugation of the polysaccharide to
a carrier protein.61 In this instance, protein–glycan conjugation was
achieved through the bifunctional linker adipic acid dihydrazide (ADH),
which provides access to a protein acyl hydrazide by EDC coupling with
glutamate or aspartate through one end; CNBr activation of the hydroxyl
groups of the polysaccharide then allows isourea bond formation
through the other end of the adipic acid linker, as illustrated in Fig. 3.
The Hib vaccines have been further improved by Verez-Bencomo et al.62
using a synthetically prepared capsular polysaccharide, obtained with a
controlled degree of polymerization, which enabled the production of a
homogeneous glycoconjugate in a cost efficient manner. This example
paved the way for the development of glycoconjugate vaccines against
Neisseria meningitides, Salmonella typhi and Streptococcus pneumoniae.63
Pozsgay et al.64 have applied well-known oxime formation to obtain
glycoconjugates. The approach consists of a two-step functionalization of
BSA (Fig. 4): first, the protein is treated with the commercially available
succinimidyl 3-(bromoacetamido)propionate 2.1. The conjugation yield
4 | Carbohydr. Chem., 2017, 42, 1–46

Published on 23 September 2016 on http://pubs.rsc.org | Carbohydr. Chem., 2017, 42, 1–46 | 5
Fig. 2 Overview of established chemical methodologies for glycoconjugation.

Fig. 3 First fully synthetic glycoconjugate vaccine against Haemophilus influenza type B.61
was estimated to be 80–90%, with MALDI-TOF analysis confirming an

average of 30–35 Lys residues functionalised. In a second step, the
chemically modified BSA was reacted with a bifunctional linker con-
taining thiol and aminooxy groups. With the aminooxy functionalized
protein in hand, the authors successfully incorporated a range of
L-rhamnose derivatives (2.7a–2.7d) bearing either an aldehyde or a
ketone, including the keto-ribitol 2.8 and the keto-tetrasaccharide 2.5
(Fig. 4), which yielded the BSA glycoconjugate 2.6.
Lysine on BSA was also targeted for glycoconjugation by Kovac et al.
by using a series of squarate derivative installed on Vibrio cholerae
polysaccharide fragments,65 of which an example (2.10) is shown in
Fig. 5. Also in this case, the advantage of using squarate derivatives as
2.9 is that it can be used in excess and the unreacted material can be
recovered.
A remarkable example of classic methodology has been recently
reported by the Davis group, which relates to a new approach in anti-
bacterial vaccines design.66 The Hep2KDO2 tetrasaccharide in Fig. 6 was
obtained by a new synthetic strategy starting from mannose; it was
then coupled via the well-established isothiocyanate methodology to a
6 | Carbohydr. Chem., 2017, 42, 1–46

Fig. 4 Preparation of aminooxylated BSA and conjugation with keto-tetrasaccharide 2.5 via oxime formation.64
Fig. 5 Conjugation of hexasaccharide fragment 2.9 of Vibrio cholerae polysaccharide to

BSA protein carrier.65
diphtheria toxin mutant. The tetrasaccharide mimics a common inner

core of bacterial capsular polysaccharide (CPS). Access to the inner core is
usually prevented by the presence of the outer core polysaccharide, but
using g-cyclodextrin as a co-administered inhibitor of the outer poly-
saccharide transporter, results in exposure of the inner core part on the
bacteria LPS. At this stage, the bacteria can be targeted by antibodies
previously raised against the Hep2KDO2-functionalized DT-carrier protein.
This innovative approach could pave the way to a new concepts for the
design of anti-bacterial vaccines, avoiding the challenging task of decor-
ating carrier protein with limited accessibility O-antigen polysaccharides.67
Several others glycoconjugate vaccines are in Phase I–III trials,
including against groups A and B streptococci, breast cancer, prostate
cancer and HIV-1.63
3 Newer chemical methodologies

After its discovery in 2002, the copper-catalysed azide–alkyne dipolar
cycloaddition (CuAAC) click reaction68,69 has found widespread appli-
cation in glycoscience70–73 due to its broad tolerance of functional
groups, offering high specificity and yield. It has found application in
glycoproteins synthesis as well, for instance, in the transformation of the
amine sidechain of lysine into an azide by treatment with imidazole-1-
sulfonyl azide for subsequent CuAAC modification. Such methodology
8 | Carbohydr. Chem., 2017, 42, 1–46

Fig. 6 An initial treatment (A) with DT-mutant decorated with the inner core mimic Hep2KDO2 will raise antibody (B) against the inner-core carbohydrate portion of
bacterial polysaccharide. Successively, g-cyclodextrin are used to inhibit Wza, which is the outer core polysaccharide transporter, exposing the inner core to the
antibody and generating the immune response (C) to kill the bacteria.66,67
View Online
74
have been applied by Lipinski et al. en route to the preparation of a
vaccine against Candida albicans. Of the 40 surface amino groups present
on the chicken serum albumin (CSA) surface, about half were converted
into azide form (Fig. 7). Subsequent CuAAC reaction gave an average of 17
and 19 oligosaccharides per protein from sugar alkynes 3.1 and 3.2,
respectively. In a first attempt towards the generation of the vaccines, the
authors analysed these two different linkers construction in order to
compare the influence of an unstructured versus a structured linker: the

former appears to decrease undesired immunogenic responses against
the non-carbohydrate portion of the conjugate.
Later work from the same authors generated tetanus toxoid glyco-
conjugate vaccines bearing two different oligosaccharides installed in
orthogonal method on the carrier protein (Fig. 8).75 Firstly, they trans-
formed the exposed amine of lysine side chains of the carrier protein
into azide, not only providing a handle for the CuAAC glycoconjugation,
but also preventing the cross-coupling in the second step, where the
carboxylic acid on the side chain of aspartic acid and glutamic acid were
activated for the formation of an amide bond with an amino terminal
functionalized b-mannan trisaccharide. The last step of the protocol
was the CuAAC of an alkyne-laminarin derivative, followed by the re-
conversion of the unreacted azide to amine. A comparison between the
two vaccine candidates with and without the laminarin hapten confirmed
a better efficiency of the former.
Functionalisation of protein lysine side chains was also achieved by
Crotti et al.76 with a two-step conjugation protocol. Diphtheria toxin
mutant, CRM197, often used as a carrier in commercial conjugate vaccines,
was firstly functionalized at lysine with either an alkyne or an azide,
installed via the azido/alkyne N-hydroxysuccinimide derivatives in Fig. 9b.
Secondly, the functionalized CRM197 was reacted with the respective azido
or alkyne sugar counterpart (Fig. 9a) by CuAAC chemistry.
The authors observed a low coupling efficiency, leaving unreacted
azide or alkyne functional groups on the protein surface. By carefully
mapping the functionalized lysine residues, the more exposed sites were
identified, leading to the conclusion that the installation of three to six
sugar haptens on the protein represented a practical maximum. This was
borne out by limiting the number of functional alkyne/azide on the
protein to three–six, when the efficiency of the CuAAC conjugation was
raised from 5–20% to495%, and it was possible to predict the position of
the each hapten installed (Fig. 10).
In 2010, Barbas77 group developed a new reagent, the 4-phenyl-1,2,4-
triazoline-3,5-dione (PTAD), for the site-specific modification of Tyr side
chains. Berti et al. optimized the application of PTAD to functionalize
CRM197 either with azide78,79 or alkyne;80 the latter aimed to prepare a
vaccines against candidiasis, with a b-(1,3) hexasaccharide azide, yielding an
average of 3.5 hexasaccharide units per protein (Fig. 11), followed by more
in-depth structural/immunological studies of a series of glycoconjugates
obtained by defined conjugation (PTAD) and random conjugation.81
The great potential of CuAAC for glycoconjugate synthesis was enhanced
by Shoda’s method82 for the direct preparation of sugar anomeric azides
10 | Carbohydr. Chem., 2017, 42, 1–46

Fig. 7 Conversion of side chain amine groups into azide followed by CuAAC reaction with the stereo-diversified glycoconjugate 3.1 and the structurally defined
glycoconjugate 3.2.74
Fig. 8 Bifunctionalized tetanus toxoid carrier protein bearing b-mannan trisaccharide

and laminarin installed in a two-step protocol showed better binding to Dectin-1 on
dendritic cells than the conjugate with only the b-mannan.75
directly from unprotected carbohydrates. Such methodology offers the

obvious advantages of avoiding protective group manipulation of complex
carbohydrates, which are often expensive or obtained in small amount by
isolation from natural products. The method has been applied, among
others, by Fairbanks et al.83 who prepared a number of different carbo-
hydrate azides and employed CuAAC to couple them with a synthetic
peptide fragment of MUC1 obtaining the glycopeptide with high efficiency
(Fig. 12).
Shoda’s method was also applied by Winssinger et al.84 who
successively coupled the resulting sugar azides by CuAAC to a short linker
containing a tetrazine moiety, followed by conjugation to a protein
containing either a trans-cyclooctene (Fig. 13, route 1) or a bicyclononyne
(Fig. 13, route 2) ring via an inverse-electron-demand Diels–
Alder strain-promoted cycloaddition reaction85 between the tetrazine/
strained-ring couple, representative examples of glycans conjugated with
this methodology are shown in the box in Fig. 13. The advantage of
this two-step approach is that it provides an opportunity to remove the
potentially toxic CuI well ahead of the final glycoconjugation.
In the course of developing vaccines against Salmonella, Micoli
et al.86,87 installed the lipopolysaccharide O-antigen on CRM197 protein
carrier using different methodologies, combining new developed methods
with well-established one (Fig. 14). Of the newer methods, partial disulfide
bond reduction of CRM197 with TCEP gave access to co-localised cysteine
modification sites that are reactive towards 1,2-dichloracetone, resulting in
the installation of a ketone for oxime ligation. In contrast, a pH-controlled
transglutaminase-catalysed reaction modified only at lysine, resulting in
transfer of Cbz-Gln-Gly-Peg3-azide on one/two lysine residue depending on
12 | Carbohydr. Chem., 2017, 42, 1–46

Fig. 9 Functionalization of terminal amines of CRM197 and azide/alkyne sugar derivative building blocks for the subsequent CuAAC reaction with an example of
final glycoconjugate product.76
Published on 23 September 2016 on http://pubs.rsc.org | 14 | Carbohydr. Chem., 2017, 42, 1–46
Fig. 10 Cartoon representation of the optimized functionalization protocol for CuAAC conjugation of CRM197 alkyne derivative.76
Fig. 11 Glycoconjugation product originating from the PTAD-alkyne decorated CRM197 and successive CuAAC reaction.80
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Faustus, Dr (Marlowe), v. 202, 203, 206, 207, 247; vii. 36; x. 274.
Faux, Guy, iv. 249, 365; vii. 69, 129; x. 245; xi. 317; xii. 26, 37.
—— Moll, vi. 510, 511.
Fauxbourg St Germain, The, xi. 384.
Favourite Kitten (Miss Geddes’), xi. 245.
—— Lamb (Collins’s), xi. 191.
Fawcett, John, vi. 453; viii. 244, 251, 252, 262, 266, 291, 319, 386,
443; xi. 277, 304, 305, 370, 397, 402; xii. 140 n., 152 n.
—— Rev. Joseph, ii. 171 n.; iii. 337; iv. 210, 283 n.; vi. 224, 225, 304;
vii. 133.
—— Mrs, viii. 413, 426.
Fawn, The, or Parisitaster (Marston’s), v. 225, 226.
Fazio (by Milman), v. 147; viii. 416; xi. 419.
Fear of Death, On the, vi. 321.
—— Odes to (Collins), v. 116, 374.
Fears in Solitude (Coleridge’s), iii. 242.
Fearn, John, vi. 64, 65; xi. 181 n.; xii. 345.
Fearne, Charles, vii. 26.
Fearon, Miss, ix. 278.
Feast of the Poets (Leigh Hunt’s), i. 377; iv. 302, 361; v. 378.
Feeble (in Shakespeare’s Henry IV.), viii. 33.
Felice (in Marston’s Antonio and Mellida), v. 225.
Felix Mudberry (in Ups and Downs), xi. 387, 388.
Felton, John, ix. 354.
Female head (Leonardo da Vinci’s), ix. 35.
Female Seducers, Fable of the (Moore’s), vi. 368.
—— Vagrant, The (Wordsworth’s), viii. 233 n.
Fenella (in Scott’s Peveril of the Peak), xi. 537.
Fénélon (François de Salignac de la Motte), vii. 321; ix. 119; x. 323,
324.
Fennings, The, iii. 420.
Fenwick, Mr, ii. 173, 192, 205.
Ferdinand of Sicily, iii. 179; xii. 242, 446.
—— VII. of Spain, iii. 106, 119, 157, 158, 160, 290, 309; vi. 156; vii.
149; viii. 267; x. 316; xi. 339, 551, 558; xii. 104, 204.
—— the Beloved, viii. 539.
—— (a play). See Faulkener.
—— (in Scott’s Yellow Dwarf), xii. 246 n.
—— (in Shakespeare’s Tempest), vii. 213; xi. 417.
—— Count Fathom. See Count Fathom.
Fergusson, Robert, v. 139.
Feriole (town), ix. 278.
Ferrara (town), ix. 264, 265, 266, 277, 302.
—— Duke Hercules of, x. 69.
Ferraw (a knight) (from Ariosto), v. 224.
Ferrers, Lord, x. 168.
Ferret, Mr (in Cherry’s Soldier’s Daughter), xi. 298.
Ferrex and Porrex (Thomas Sackville’s), v. 193, 195.
Ferry-bridge, The Inn at, xii. 203.
Fesch, Cardinal, ix. 363 n.
Fesole (town), ix. 211, 217.
Fête Champêtre (Watteau’s), ix. 22.
—— —— See Carronside.
Feudal Times (George Colman, jnr.), ii. 228.
Fichte, Johann Gottlieb, iv. 218; x. 141, 145.
Fidelia (in Wycherley’s Plain Dealer), viii. 78.
Field, Master John, ii. 226.
Fielding, Anthony Vandyke Copley, ix. 127; xi. 245, 246, 248.
—— Henry, i. 28; ii. 171 n., 280, 391; iii. 234; iv. 365, 367; v. 284; vi.
225, 236, 413, 426, 448, 452, 457, 458; vii. 36, 214, 322, 363; viii.
79, 107, 110, 112, 113, 114, 115, 116, 117, 119, 133, 144, 158, 163, 287,
454, 506; ix. 78, 118, 243 n., 391; x. 27, 30, 31, 32, 33, 34, 35, 36,
37, 167, 168, 206, 328; xi. 223, 225, 273 n., 374, 403, 435, 501,
543; xii. 22, 32, 46, 63, 98, 155 n., 226, 274, 310, 364, 374.
—— William, Mr Justice, vii. 84.
—— and Walker (booksellers), ii. 95.
Fife, ii. 314.
Figalon (painter), ix. 128.
Figaro, The Marriage of, or The Follies of a Day (Holcroft’s), ii. 113;
viii. 355; xi. p. viii.
Fight, The, xii. 1.
Filch (in Gay’s The Beggar’s Opera), vi. 286; viii. 255, 315, 387; xi.
373; xii. 24.
Filmer, Sir Robert, iii. 240, 284.
Finch, Daniel (second Earl of Nottingham), iii. 402.
—— Sir Heneage, and his son, iii. 394, 399.
Finche dal Vino (a song), viii. 365.
Fine Arts, The, ix. 377;
also in ix. 408; xi. 195.
—— —— whether they are promoted by Academies, ix. 470.
—— —— British Institution, xi. 187.
—— —— The Louvre, xi. 195.
—— —— (E. B. Article), ix. 464; xi. 567, 568.
Fingal, The Son of (Ossian), xi. 300.
Finger-Post, The (a play), xi. 367.
Finland, iii. 158, 216.
Finnerty, Peter, iii. 236, 237; xii. 307.
Fire of London, vii. 69.
—— Famine, and Slaughter (Coleridge), iii. 157, 205; v. 166, 377.
Firense la bella, ix. 207.
Firmian, Joseph, Count de, ix. 419.
First Elements (Nicholson’s), ii. 173.
Firth of Forth, ii. 252, 314; iv. 244.
Fish-street-hill, xi. 385.
Fisher (Catherine Maria), ix. 473.
—— of Duke Street, vii. 486.
—— Mr, viii. 465, 513.
Fittler, James, ii. 201.
Fitzgerald, Thomas Judkin, iii. 237, 240, 241.
Fitzharding, Mr (in Smiles and Tears), viii. 266.
—— Miss (in Smiles and Tears), viii. 266.
Fitz-Osborn’s Letters (by William Melmoth the younger), i. 93.
Fitzpatrick, Mrs (Fielding’s Tom Jones), vi. 457; viii. 114, 115; x. 33.
Fitzwilliam (2nd Earl of) (Wentworth, Wm.), ii. 169, 225.
Five Patron-Saints of Bologna, Guido’s, ix. 206.
Fives Court, The, xii. 8, 325.
—— —— St Martin’s St., The, vi. 88.
Flageolet, The (in Liber Amoris), ii. 291.
Flamborough Family (in Goldsmith’s Vicar of Wakefield), v. 119; viii.
554.
Flamineo (in Webster’s White Devil), v. 243, 245.
Flaminius, ix. 262.
Flash, Theodore (? Theodore Hook), xii. 276.
Flaxman, John, vii. 90, 95; ix. 168, 490.
Flaxman’s Lectures on Sculpture, x. 330.
Flech Horr, The, ix. 279, 280.
Flecknoe (Marvell’s), viii. 54.
Fleet-Ditch, vii. 69.
—— Prison, ii. 216; v. 84 n.; vi. 89; viii. 463.
—— Street, iv. 342; vi. 59, 415; viii. 104; xii. 35 n.
Fleetwood (Godwin’s), iv. 209.
Flemish School, i. 26; ix. 314, 386.
Fletcher, Andrew (of Saltoun), iv. 98 n.
—— George, vii. 263, 504.
—— John, v. 248;
also referred to in iv. 367; v. 175, 176, 181, 189, 193, 224, 296, 297,
346; vi. 203, 218 n.; vii. 134, 229, 320, 321; viii. 48, 69, 89, 264,
353; x. 118, 205, 261; xii. 34.
—— P., v. 295, 311.
Fleur de Lys, Order of, viii. 20.
Fleuri, Joli de, iii. 290.
Flight into Egypt (Poussin’s), ix. 24.
—— —— (Rubens’s), ix. 72.
—— of Paris and Helen, The (Guido’s), vii. 283.
Flippanta (in Vanbrugh’s The Provoked Wife), viii. 80, 156.
Flitch of Bacon, The (Henry Bates’s), ii. 85; vi. 432.
Flora (the goddess), iv. 310; ix. 216.
—— (in Rowe’s Jane Shore), viii. 537.
—— (in Mrs Centlivre’s The Wonder), xi. 402; xii. 24.
—— MacIvor (in Scott’s Waverley), iii. 32; iv. 247; viii. 129.
Florence, i. 332; v. 189; vi. 353, 368, 404; vii. 369; ix. 111 n., 187, 197,
198, 207, 211, 212, 217, 218, 219, 221, 224, 227, 229, 233, 240, 241,
249, 256, 260, 262, 263, 277, 363 n., 409, 417, 429; x. 63, 68, 300,
301, 302, 354; xii. 20, 134, 172 n.
—— History of (Guicciardini’s), vii. 229.
Florentine Observer, The, x. 270.
—— School, ix. 222.
Florestan (early romance), x. 57.
Florid (Holcroft’s), ii. 191, 222.
Florimel (Spenser), ii. 347; v. 38; vii. 193; x. 81; xi. 235.
Floris (in Kinnaird’s Merchant of Bruges), viii. 265, 266.
Florismarte of Hircania (early romance), x. 57.
Florizel (in Shakespeare’s Winter’s Tale), viii. 354.
Floscel, Mr, ii. 114.
Flower, Benjamin, i. 423; ii. 177, 190.
—— and the Leaf (Chaucer’s), i. 162; v. 27, 82, 370; x. 75; xi. 269; xii.
327.
Flute (in Shakespeare’s Midsummer Night’s Dream), viii. 275.
Fly drowned in Treacle, Lines to a (Peter Pindar’s), xii. 350.
Flying Mercury, John of Bologna’s, ix. 222.
Fodor, Madame Mainville, viii. 297, 327, 364, 370, 371; xi. 307, 308,
427, 500, 501.
Foe, Daniel (see Defoe).
—— James, x. 356, 357.
Foible (Congreve’s The Way of the World), viii. 75.
Foligno, ix. 260, 261, 365.
—— Picture, The (Raphael’s), ix. 240.
Folle par Amour, La (opera), ix. 174.
Follies of a Day (see Figaro), ii. 113; viii. 355; xi. p. viii.
Fontainebleau, ix. 175, 176.
Fontaine, Jean de la, i. 46; iv. 190; vi. 109; viii. 29; x. 109.
Fontenelle, Bernard le Bovier de, ii. 393; iii. 319 n.
Fonthill Abbey, ix. 348;
also referred to in vii. 135, 292; ix. 55, 56, 58, 60, 61; xii. 83.
Fool, The (in Shakespeare’s Lear), viii. 24.
—— of Quality, The (Henry Brooke’s), viii. 123 n.
Foote, Maria, viii. 196, 231, 266, 268, 275, 426, 428, 457, 540; xi.
207, 208, 364, 402.
Foote, Samuel, ii. 59, 60, 77 n., 87, 170; viii. 166, 167, 241, 242, 319.
——, Garrick, Letters of, xi. p. viii.
Footmen, xii. 131.
Force of Conscience. See Ravens.
—— of Ridicule, The (Holcroft’s), ii. 159.
Ford, John, v. 248;
also referred to in v. 193, 265 et seq., 268, 318; vi. 218 n.; vii. 134;
x. 205.
—— Mr, ii. 173.
—— (in Cooke’s Green’s Tu Quoque), v. 290.
—— Miss, xii. 122.
Foresight (in Congreve’s Love for Love), vi. 287; viii. 279.
—— (Munden’s), viii. 71, 72.
Forest of Merry Sherwood, The, viii. 425.
—— Scene (Stark’s), xi. 249.
Forester (the horse), ii. 31, 41.
Forli (town), vi. 238.
Fornarina (Raphael’s), i. 92; ix. 73, 223, 224; xii. 36, 332.
Forrest (in Shakespeare’s Richard III.), v. 188.
Forsyth, Joseph, ix. 221, 253.
Forth, The river, v. 300.
Fortunate Mistress. See Roxana.
Fortunatus’s Wishing Cap, vii. 221.
Fortune (Salvator Rosa’s), x. 301.
Fortune-Teller (Northcote’s), vi. 404.
Fortunes of Nigel (Scott’s), iv. 248; xi. 538.
Foster, James, iv. 204 n.; vi. 367.
—— Thomas, vi. 360, 509.
Fouché, Joseph, iii. 192.
Foulkes, Mr, ii. 145, 176, 183, 225.
—— Mrs, ii. 193, 194.
Foundling, History of a. See Tom Jones.
Four Ages (Titian’s), ix. 31, 38, 270.
Four Orations for the Oracles of God (Edward Irving’s), iv. 228.
—— P’s, The, v. 274.
—— Seasons of Life, The (Giorgioni’s), v. 321.
Fourth Estate, iv. 334.
Fox, Charles James, i. 103, 127, 384, 429; ii. 200, 217, 227, 374; iii. 15
n., 17, 108, 324, 328 n., 336, 337, 347 n., 349, 391, 416, 421, 424,
461, 466; iv. 190, 231–2, 237; vi. 109, 455; vii. 7, 8 n., 184, 200,
267, 269, 273, 274–5, 364; x. 151–2, 213, 232; xi. 436, 522–3; xii.
274, 292–3, 346, 369.
—— Character of Mr, iii. 337.
—— George, iii. 112; x. 145.
—— Henry (Lord Holland), iii. 416.
—— John, vi. 364, 365, 366.
—— Joseph, iii. 111.
—— William Johnson, iv. 227.
—— at the Point of Death, The (Gay’s), v. 107.
—— Dogs (Gainsborough’s), xi. 204.
—— hunted with Greyhounds (Gainsborough’s), xi. 203.
Foxe, John, vii. 129, 320; xi. 443.
Frail, Mrs (in Congreve’s Love for Love), viii. 72, 279.
Francanzani, Francesco, x. 283, 287.
France, iii. 6, 7, 11, 12, 13, 22, 31, 36, 52, 53, 55, 56, 59, 63, 65, 68, 71,
77, 78, 80, 81, 82, 83, 84, 86, 94, 95, 96, 97, 98, 99, 101, 102, 103,
104, 106, 108, 109, 111, 119, 129, 158, 164, 179, 180, 181, 216, 227,
240, 285, 290, 335, 347 n., 399, 415; iv. 93, 323; v. 354; xi. 184,
390.
—— and Italy, Notes on a Journey Through, ix. 83; xi. 568.
—— Travels in (Holcroft’s), ii. 232–4.
Francesca of Rimini (Dante), x. 405.
Francesca of Rimini (Leigh Hunt), x. 409.
Francesco (in Godwin’s Cloudesley), x. 391.
—— (in Massinger’s The Duke of Milan), v. 267; viii. 289, 290.
Francis I., i. 133.
—— Sir Philip, ii. 172, 182, 199.
Franciscan Friars, The, xii. 224.
Francken, Frans, ix. 354.
Frank Osbaldistone (in Scott’s Rob Roy), xii. 66.
—— and Clara (Holcroft’s), ii. 176, 182.
—— Henley (in Holcroft’s Anna St Ives), ii. 129, 131.
—— Jerningham (in Merry Devil), v. 293, 294.
Franks. See Francken, Frans.
Franks’s Hotel at Rome, ix. 231.
Frankelein, The (Chaucer), v. 24.
Frankenstein (Mrs Shelley), x. 311.
Frankford, Mrs (in Heywood’s A Woman Killed with Kindness), v.
212, 213.
Frankfort, ii. 187.
Franklin, Dr Benjamin, ii. 203, 205; iv. 9 n., 190; x. 251, 314; xi. 472
n.
Frascati (town), ix. 254.
Frates Poloni, The, i. 82; ii. 165; iii. 266.
Frati Church, in Venice, ix. 270.
Frazer, Mr, ii. 218.
Frederic (in The Poor Gentleman), xi. 376.
Frederick the Great, ii. 115, 116, 116 n., 179; iii. 106, 160; vi. 445.
—— William I., vi. 445.
Frederigo Alberigi. See Alberigi.
Free Admission, The, xii. 119.
—— Thoughts on Public Affairs in a letter addressed to a Member of
the Old Opposition, iii. 1;
also referred to in i. 383 n.
Freeman, Mr, of Bath, ii. 259–61, 266.
Freeman, Mr (in Double Gallant), viii. 361.
Freemasons, The, iii. 106.
Freethinkers, i. 48.
Frejus (town), i. p. xxxi.
French, The, viii. 309; ix. 80, 89, 138 et seq.; xi. 195, 196, 256, 258,
339, 353.
—— Academy, Discourses of the (Coypel’s), xi. 208 n.
—— Art, ix. 29, 389, 404, 407; xi. 188, 209, 220, 238, 240, 244.
—— Exhibition, ix. 108.
—— Opera, The, ix. 169.
—— Philosophy, xi. 162, 285.
—— Plays, xi. 352.
—— Poetry, xi. 162.
—— Revolution (Mignet’s), ix. 186.
—— —— The, i. 89 n., 105 n., 117, 138, 214, 427, 430; ii. 133, 156, 162,
176; iii. 32 n., 114, 116, 146, 157, 160, 169, 179, 205, 206, 210, 221,
246, 250, 279, 281, 302, 304, 343, 460; iv. 218, 237, 263, 282,
338; v. 83, 161, 359; vi. 55, 147, 150, 151, 155, 198; vii. 51, 240, 257;
viii. 309, 347, 416; x. 128, 150, 151; xi. 306, 311, 374, 418, 420; xii.
157, 170, 236, 269, 287, 288, 291, 459.
—— —— Reflections on (Burke’s), i. 71 n., 214; iii. 100, 170, 255, 335;
iv. 284 n.; vi. 33; vii. 118, 227–8, 247, 257; viii. 347; xi. 458; xii.
132.
—— Writers, iv. 277.
Frere, Mr, ii. 232.
Freres, The (Frere, John Hookham), x. 139.
Freybourg, ix. 298.
Friar, The (in Shakespeare’s Romeo and Juliet), viii. 199.
—— John (in Rabelais), i. 52, 131; v. 112, 113, 277; xii. 348.
—— Lawrence (in Shakespeare’s Romeo and Juliet), viii. 209.
—— Onion (in Rabelais), v. 277.
—— Tuck (in Scott’s Ivanhoe), iv. 223; viii. 424, 426.
Fribble (Miss in her Teens), ii. 80.
Fribourg, ix. 285.
Friedland, iii. 112.
Friend (Coleridge’s), iii. 130 n., 139, 159, 294 n.; vii. 374; x. 123, 135,
141, 150; xi. 452, 516.
—— Where to Find a, viii. 258.
Friends of Revolution, xi. p. vii.
Friendly Reproof to Ben Jonson (by Carew), v. 312.
Frightened to Death (Oulton’s), viii. 358.
Friscobaldo, Signor Orlando, vi. 192; vii. 121.
Froissart, Jean, i. 87, 100; vii. 229; xii. 16.
Frontiniac (a wine), xi. 487.
Frontispiece (Hogarth’s), ix. 357.
Fry, Mrs, ix. 91.
Fudge Family (Moore’s), iii. 311, 312; iv. 359, 360; vii. 380; viii. 176
n.; xi. 440.
—— —— in Paris, The, iii. 311.
Fuessly, Johann Heinrich. See Fuseli.
Fugitive Writings, xi. 1.
Fulham, ii. 221.
Fullarton (? William), ii. 186.
Fuller, Thomas, iv. 331, 365; vi. 245; vii. 16; xii. 137, 392.
Fulmer (in The West Indian), ii. 83.
Fulvia (in Shakespeare’s Antony and Cleopatra), i. 229.
Funeral, The (Donne’s poem), viii. 52.
—— (Steele’s), viii. 158.
Furies (in Æschylus), viii. 159; xi. 506.
Furor (Spenser’s), x. 245.
Fuseli, Henry, ii. 180; iv. 208 n., 233; vi. 10, 270, 296, 336, 340, 342,
363, 365, 379, 385, 389, 393, 400, 403, 428, 434; vii. 41, 89, 90,
93, 94, 104; viii. 99, 307; ix. 15, 131, 226, 427; x. 197, 200; xii. 168.
Fusina (town), ix. 266.
G.
G——, xii. 355, 369.

Gabriel, the Angel, xii. 199.
Gabrielle (in Morton’s Henri Quatre), viii. 443.
—— ix. 175.
Gadshill, i. 285; vi. 318, 403; viii. 33.
Gaffer Gray (in Holcroft’s Hugh Trevor), ii. 137, 138.
Gainsborough, Thomas, ii. 189; vi. 128, 129, 369, 437, 438; ix. 38,
395; xi. 202, 248.
Gainsborough’s Pictures, On, xi. 202.
Galaor (early romance), x. 57.
Galatea (Cervantes’), vii. 229; viii. 110.
—— (Raphael’s), i. 76, 134; ix. 239, 419, 429; x. 278.
Galba, ix. 221.
Galicia, xi. 317.
Galignani’s, vi. 422; ix. 287.
Galileo, vi. 466; vii. 306; ix. 211, 212 n., 429; xi. 424; xii. 134.
Gall, Dr, vii. 19, 137, 138, 144, 155, 231; ix. 206 n.
Gallantry, or Adventures at Madrid, viii. 399.
Gallaspy, Mr (in Amory’s John Buncle), i. 54; iii. 142.
Galley, Mdlle., i. 90.
Galt, John, vii. 134.
Gamaliel, iv. 202.
Gamble, Andrew (Irish boxer), xi. 487.
Gamester, The (E. Moore’s), ii. 265; v. 359; vii. 299; viii. 198.
Gammer Gurton’s Needle (John Still), v. 274;
also referred to in v. 286.
Gandy, William, vi. 21, 345, 367; x. 181.
Ganges, vi. 64.
Ganlesse (Scott’s Peveril of the Peak), xi. 540.
Ganymede (Titian’s), ix. 11 n.
Garat, Dominique Joseph Comte, ii. 180.
Garda, The Lake of, ix. 277.
Gardiner, Sir Allan, iv. 231, 232.
Gargantua (Rabelais), iii. 287 n.; v. 113; viii. 29, 200.
Garnish (in Kenney’s Touchstone), viii. 369.
Garofalo (Tisi, Benvenuto), ix. 238, 239.
Garrard, George, iii. 121 n.
Garrick, David, i. 156–8, 290, 335; ii. 72–80, 358, 367; iii. 389; vi. 46
n., 50, 273, 275, 301, 322, 342, 350, 399, 404, 405, 418, 438, 444,
453; vii. 305, 306; viii. 83, 103, 144, 163, 173, 174, 180, 198, 209,
261, 263, 273, 285, 313, 345, 384, 406, 429, 435, 443, 454, 514; ix.
46; xi. 349, 363, 393, 449; xii. 33, 34, 207.
—— (Gainsborough’s portrait of), xi. 203.
—— between Tragedy and Comedy (Reynolds’s), ix. 402.
Garrow, Sir William, ii. 186; iii. 164; xi. 476.
Gas Lights, i. 139.
—— Man, The, xii. 4 et seq.
Gasparo (Webster’s White Devil), v. 241, 245.
Gassendi, Peter, xi. 48.
Gaston de Foix (Giorgione’s), ix. 271.
Gate Beautiful (Raphael’s), viii. 147; ix. 47.
—— of Galienas, The (Verona), ix. 277.
Gates, General, iii. 422.
Gathering of Manna (Rubens’s), ix. 52.
Gatti, Signor, ix. 205.
Gattie, Henry, viii. 229, 245, 403.
Gatton, Borough of, ii. 154 n.
Gatty (actor), xi. 364.
Gaveston (in Marlowe’s Edward II.), v. 211.
Gay, John, i. 46, 65; iv. 365; v. 83, 98, 104, 106, 108, 129, 164, 369,
373; vi. 96, 367; vii. 36; viii. 56, 158, 193, 255, 256, 323; x. 375; xi.
273, 375; xii. 32, 35, 121, 355.
Gayrard, Raymond, ix. 168.
Gazette, The, x. 161.
Gazza Ladra, The (Rossini’s opera), ix. 174.
Gebir (Landor’s), x. 255.
Geddes, Dr, ii. 177, 178.
—— Miss, xi. 245.
Geese that cackled in the Capitol (bronze), ix. 239.
Geiseveiller, Mr, ii. 173, 178, 182, 183, 185, 186, 187, 188, 192, 193,
194, 195, 201.
Gelamont (a town), ix. 285, 287.
Gelling, Rev. Isaac, vi. 364.
General Advertiser, The (newspaper), ii. 92.
—— Savage (Wycherley’s School for Wives), ii. 83.
—— Torrington (in Leigh’s Where to Find a Friend), viii. 258, 259,
260.
—— Warrants, Lord Chatham’s speech on, iv. 210.
Genesis, v. 183.
Geneva, i. 92; ix. 182, 197, 280, 281, 285, 293, 294, 295, 296, 297; x.
45.
Genevieve (Coleridge’s), v. 377; xii. 436.
Genevra, The Story of, x. 56, 62, 62 n.
Genius and Common Sense, vi. 31, 42.
—— is Conscious of its Powers? Whether, vii. 117.
—— and Originality, On (Reynolds’ Discourse), xi. 210.
Genoa, iii. 158, 234; iv. 281; vi. 384, 385; ix. 198, 207, 267; xi. 467;
xii. 223.
Gensano Girls, vii. 175; ix. 236, 376.
Gentle Geordie (in Scott’s Heart of Midlothian), vii. 137; xi. 534
—— Shepherd (Allan Ramsay’s), ii. 77–8.
Gentleman Comedian, The, or Alwyn. See Alwyn.
—— Dancing Master, The (a farce), viii. 78.
—— On the Look of a, vii. 209.
Gentleman’s Magazine, i. 374, 376, iv. 365; x. 221, 222.
Geoffrey Crayon, iv. 362.
—— of Monmouth, x. 20.
George I., i. 425; iii. 405, 409; iv. 343 n.; v. 359; vi. 59 n., 445; xii.
269.
—— II., i. 25, 156; iii. 285 n., 414; vi. 445, 521; vii. 211; viii. 106, 121,
122, 134, 263; ix. 76; x. 26, 40; xii. 269.
—— III., iii. 114, 123, 221, 360, 445; vi. 322, 387; vii. 16, 88; viii. 122;
ix. 465; x. 40, 41, 152; xi. 555; xii. 24, 242.
—— IV., iv. 338; vi. 55, 482; xi. 547; xii. 56, 168, 249.
—— the Fourth, A Portrait of, ix. 367.
—— Prince, x. 377.
—— a Green, or The Pinner of Wakefield (by Robert Greene), v. 289,
294.
—— Barnwell (by George Lillo), viii. 268;
also referred to in i. 154.
—— Dandin (Molière’s), viii. 28.
—— of Douglas (Scott’s Abbot), iv. 248.
—— St., vi. 120.
Georges, Mademoiselle, ix. 154.
Georgics (Virgil’s), xi. 492; xii. 273.
Georgium Sidus, x. 331.
Gerald (in Kinnaird’s Merchant of Bruges), viii. 265, 266.
Geraldine (in Coleridge’s Christabel), x. 413.
Gérard, François Pascal Simon, Baron, ix. 123, 124, 125, 137.
Gerardeschi, The, ix. 211.
Gerat (the singer), viii. 363.
German Drama, contrasted with that of the Age of Elizabeth, On the,
v. 345.
German Hotel, The (a play from Brandes), ii. 116.
—— Painters, xi. 209.
—— Philosophy and Literature, Account of (Madame de Staël’s), xi.
162.
—— Play, The (Mr Canning’s), xi. 341.
—— Poetry, xi. 162.
—— School of Singing, xi. 428, 501.
Germany, iii. 53, 55; iv. 218; v. 182, 362; xi. 162, 289.
Gertrude (in Jonson, Marston, and Chapman’s Eastward Hoe), vi.
164, 165.
—— (in Cooke’s Green’s Tu Quoque), v. 290.
—— (in Kinnaird’s Merchant of Bruges), viii. 264, 265.
—— of Wyoming (Campbell’s), iv. 345, 346; v. 149, 150, 377; viii. 153;
x. 15; xii. 239.
Gerusalemme liberata, The (Ariosto’s), x. 14.
Gessner, Mr, ii. 186.
Ghengis Khan, xii. 37.
Ghent, ix. 302.
Ghetto Judaico, xii. 462.
Ghibellines, The, xi. 443.
Ghirlandaio, Domenico, iv. 217; vii. 254; ix. 205, 261, 409; xi. 238;
xii. 36, 38.
Ghost, The (in Shakespeare’s Hamlet), viii. 186, 188, 189.
—— of King of Ormus (in Fulke Greville’s Mustapha), vii. 255.
Giannuzzi, Giulio dei. See Romano, Julio.
Giant Despair (in Bunyan’s Pilgrim’s Progress), iv. 337; vi. 54; ix.
229.
Giant’s Causeway, xii. 273.
Giaour, The (Byron’s), v. 153.
Giardini, Felice, vi. 373.
Gib the Cat (in Still’s Gammer Gurton’s Needle), v. 286.
Gibbet (in Farquhar’s Beaux’ Stratagem), viii. 10.
Gibbon, Edward, i. 138; iii. 144; iv. 365; vi. 222; ix. 153 n., 375.
Gibbons, Grinling, ix. 67.
Gibbs, Vicary, ii. 147.
—— Mrs, viii. 251, 252, 319, 333, 465, 468; xi. 397, 402.
Gibby (in Mrs Centlivre’s The Wonder), viii. 156, 333; xi. 402.
Gibson’s Field, vi. 418.
Gifford, John, iii. 206, 295.
—— William, iv. 298;
also referred to in i. p. xxx., 166; iii. 45, 206, 219, 262, 295; iv. 421;
vi. 212, 475, 494; vii. 121, 207, 301, 516; ix. 247; x. 139, 228; xii.
324.
—— A Letter to William, i. 363.
Gil Blas (Le Sage’s), i. 12, 136, 138, 160; v. 91; vi. 118, 224–5, 457; vii.
33, 36, 74, 173, 303, 311, 380; viii. 111, 112, 116, 141, 151, 315; ix. 29,
99 n.; x. 30, 31, 34, 214; xi. 252, 458; xii. 141.
Giles (in Bickerstaffe’s Maid of the Mill), ii. 83.
—— Arbe (in Miss Burney’s The Wanderer), x. 44.
Gillies, Mr, ii. 176, 231.
Gilray, James, ii. 185; vi. 455; viii. 330, 400; xii. 20, 363.
Gin Lane (Hogarth’s), viii. 142; ix. 323; xii. 364.
Ginevra, a fragment (Shelley), x. 270, 271.
Giordano, Luca, vi. 128 n.; ix. 67.
Giorgione, vi. 11 n.; ix. 26, 31, 225, 226, 239, 271, 386; xii. 36.
Giotto, iv. 217; vii. 254; ix. 205, 206, 261; xii. 36, 38, 347.
Giovanni in London (Moncrieff’s), viii. 461, 462.
Girard & Co., ii. 113.
Girl with Beer (picture), ii. 228.
—— drawing with a Pencil (Reynolds’), ix. 399.
—— and Pigs (Gainsborough’s), xi. 204.
Girl feeding Pigs (Watteau’s), vi. 437.
—— Reading (Correggio’s), ix. 41.
—— going to the Well (Gainsborough’s), xi. 204.
—— at a Window (Rembrandt’s), ix. 22.
Girodet-Trioson, Anne Louis, vii. 331; ix. 131; xi. 241; xii. 190.

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Carbohydrate Chemistry Volume 42

Amelia Pilar Rauter

Carbohydrate chemistry: chemical and biological

Recent Trends in Carbohydrate Chemistry: Synthesis,

Recent Trends in Carbohydrate Chemistry: Synthesis and

Advances in Carbohydrate Chemistry and Biochemistry

Carbohydrate chemistry for food scientists Third Edtion

Carbohydrate chemistry for food scientists Third Edtion

Protecting Groups Strategies and Applications in

Plant breeding reviews: Volume 42 1st Edition Irwin

A Specialist Periodical Report

Michał Malik, Institute of Organic Chemistry, Polish Academy of Sciences,

Said Rabbani, University of Basel, Switzerland

r The Royal Society of Chemistry 2017

All rights reserved

Published by The Royal Society of Chemistry,

Registered Charity Number 207890

For further information see our web site at www.rsc.org

Printed in the United Kingdom by CPI Group (UK) Ltd, Croydon,

This volume is dedicated to the memory of Derek Horton, a scientist that

and industrial innovation. With more than 500 publications and

Carbohydr. Chem., 2017, 42, vii–ix | vii

(oligo and polysaccharides, glycopeptides and glycomimetics) and to the

single amino group-containing carbohydrates to protein carriers is

viii | Carbohydr. Chem., 2017, 42, vii–ix

Bielski complete this volume 42 of the Specialist Periodical Reports –

multidisciplinarity of this volume.

Carbohydr. Chem., 2017, 42, vii–ix | ix

molecule, and (in the background)

Contemporary glycoconjugation chemistry 1

Recent advances in the application of NMR methods to uncover 47

Carbohydr. Chem., 2017, 42, xi–xiv | xi

6 Oligosaccharide–protein interactions: enzymes 58

12 Glycomimetic interactions: lectins and enzymes 64

Controlled and highly eﬃcient preparation of carbohydrate-based 83

Recent advances in Kdo-glycoside formation 116

Chemical and enzymatic approaches to the synthesis of cyclic 165

xii | Carbohydr. Chem., 2017, 42, xi–xiv

3 Linear oligosaccharides formed through glycosidic bond 186

Ferrier rearrangement: an update on recent developments 210

FimH antagonists – solubility vs. permeability 248

Carbohydrate steroid hybrid architectures: the viewpoint of 274

Carbohydr. Chem., 2017, 42, xi–xiv | xiii

2 The diﬀerent classes of glycosteroids, classified by 277

Recent advances in the synthesis of imino sugars. An insight 313

Recent examples of novel synthetic approaches to diverse 344

xiv | Carbohydr. Chem., 2017, 42, xi–xiv

Glycoproteins are typically expressed in nature with heterogeneous glycan components;

Carbohydr. Chem., 2017, 42, 1–46 | 1

Fig. 1 Glycoconjugates and their biological relevance.

However, in the absence of the biological context – conjugated to protein

2 | Carbohydr. Chem., 2017, 42, 1–46

progress in the field chemical synthesis of glycoproteins has been exten-

2 Established chemical methodologies

Carbohydr. Chem., 2017, 42, 1–46 | 3

Alternatively, the reducing end or specific functional groups, such as

4 | Carbohydr. Chem., 2017, 42, 1–46

Fig. 2 Overview of established chemical methodologies for glycoconjugation.

was estimated to be 80–90%, with MALDI-TOF analysis confirming an

6 | Carbohydr. Chem., 2017, 42, 1–46

Fig. 5 Conjugation of hexasaccharide fragment 2.9 of Vibrio cholerae polysaccharide to

diphtheria toxin mutant. The tetrasaccharide mimics a common inner

3 Newer chemical methodologies

8 | Carbohydr. Chem., 2017, 42, 1–46