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Chemical and Biological Approaches

Carbohydrate Chemistry
Volume 39


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A Specialist Periodical Report

Carbohydrate Chemistry
Chemical and Biological
Approaches
Volume 39
Editors
Amelia Pilar Rauter, Universidade de Lisboa, Portugal
Thisbe K. Lindhorst, Christiana Albertina University of Kiel,
Germany
Authors

Valquiria Araga˜o-Leoneti, Faculdade de Cieˆncias Farmaceˆuticas de Ribeira˜o
Preto, Sa˜o Paulo, Brazil
Binod K. Bharati, Indian Institute of Science, Bangalore, India
Vanessa Leiria Campo, Faculdade de Cieˆncias Farmaceˆuticas de Ribeira˜o
Preto, Sa˜o Paulo, Brazil
Ivone Carvalho, Faculdade de Cieˆncias Farmaceˆuticas de Ribeira˜o Preto,
Sa˜o Paulo, Brazil
Dipankar Chatterji, Indian Institute of Science, Bangalore, India
Darrell Cockburn, Technical University of Denmark, Lyngby, Denmark
Gabriele Cordara, University of Oslo, Oslo, Norway
Katalin Czifra´k, University of Debrecen, Hungary
N. Jayaraman, Indian Institute of Science, Bangalore, India
Ana R. Jesus, University of Lisbon, Portugal
Vladimı´r Krˇen, Academy of Sciences of the Czech Republic, Prague,
Czech Republic
Ute Krengel, University of Oslo, Oslo, Norway
Jian Liu, Eshelman School of Pharmacy, University of North Carolina,
USA
Kotari Naresh, Indian Institute of Science, Bangalore, India
Noe´ On˜a, University of Malaga, Spain
Amelia P. Rauter, University of Lisbon, Portugal
M. Soledad Pino-Gonza´lez, University of Malaga, Spain
Antonio Romero-Carrasco, University of Malaga, Spain
Kristy´na Sla´mova´, Academy of Sciences of the Czech Republic, Prague,
Czech Republic
La´szlo´ Somsa´k, University of Debrecen, Hungary
Arnold E. Stu¨tz, Technische Universita¨t Graz, Graz, Austria
Birte Svensson, Technical University of Denmark, Lyngby, Denmark



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Se´bastien Vidal, Universite´ Claude Bernard Lyon, Villeurbanne,
France
Shuai Wang, Universite´ Claude Bernard Lyon, Villeurbanne, France
Tanja M. Wrodnigg, Technische Universita¨t Graz, Graz, Austria


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If you buy this title on standing order, you will be given FREE access
to the chapters online. Please contact E-mail: with
proof of purchase to arrange access to be set up.

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Thank you.

ISBN: 978-1-84973-587-2
ISSN: 0306-0713
DOI: 10.1039/9781849737173
A catalogue record for this book is available from the British Library
& The Royal Society of Chemistry 2013
All rights reserved
Apart from fair dealing for the purposes of research or private study for
non-commercial purposes, or for private study, criticism or review, as

permitted under the Copyright, Designs and Patents Act, 1988 and the
Copyright and Related Rights Regulations 2003, this publication may not be
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prior permission in writing of The Royal Society of Chemistry, or in the case of
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be sent to The Royal Society of Chemistry at the address printed on this page.
Published by The Royal Society of Chemistry,
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Preface

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While this volume is mainly dedicated to the investigation and utilisation of

carbohydrate-specific enzymes, the reader will also find enzymology and
glycobiology combined with glycochemistry, demonstrating how the interdisciplinary approaches taken in the glycosciences contribute to the
increasingly important field of glycomics.
The first chapter of this book is dedicated to the radical bromination of
sugars, involving a broad range of substrates and their transformations. It
highlights the synthetic utility of this type of reactions and, in particular, the
uniqueness of carbohydrates as substrates, leading to a wide variety of
molecular tools for chemical glycobiology. Examples are given of acceptor
substrate analogues for glycosyltransferases, inhibitors of glycosidases,
compounds that inactivate retaining N-acetylglucosaminidases, amongst
many other bioactive compounds that were synthesized via radicalmediated halogenation of carbohydrates. While the first chapter is dedicated to synthetic organic glycochemistry, the second illustrates the
importance of enzymatic and chemoenzymatic syntheses for the production
of the polysaccharide heparin, marketed as anticoagulant agent. Recent
developments on synthetic glycolipids as ligands and as inhibitors of
mycobacterial cell wall components, biosynthesis and functions are described in chapter 3, also focusing on the inhibition of key glycosyltransferases
by glycolipids. The next chapters deal with carbohydrate-processing
enzymes and their inhibitors, most of them small molecule inhibitors.
Design and synthesis of glycosyltransferase and glycosidase inhibitors is
reviewed, paying particular attention to imino sugars and to carbohydrate
epoxides as synthetic key intermediates of this important class of therapeutic targets, with applications in the treatment of influenza infection,
cancer, AIDS, and diabetes. Also an overview on glycosidase metabolic
changes in diabetes is presented. The deficiency in humans of hexosaminidases causes severe neurodegenerative disorders, including the
Alzheimer’s disease. Hence a survey of the most efficient and selective
inhibitors of these glycosidases, required for the research of their physiological functions, is given in this volume. In recent years binding sites of
carbohydrate-specific enzymes have been investigated in greater detail, with
special focus on surface and secondary binding sites (SBS). SBS, playing
several supporting roles in enzyme function, are binding sites that are
located on the catalytic domain of a particular enzyme, but separate from
the enzyme’s main active site. Another chapter is devoted to this interesting
area of research that aims to modulate enzymatic behavior without altering

the enzyme active site, focusing on SBS potential roles, techniques for SBS
study and applications. The last but not the least, X-ray crystallography of
lectins is the subject of a chapter, emphasizing the characterization of lectincarbohydrate complexes with high precision, and revealing in detail the
underlying molecular recognition mechanisms.

Carbohydr. Chem., 2013, 39, vii–viii | vii

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Volume 39 contains chapters covering chemical, biochemical and biological approaches that demonstrate, in a meaningful way, how interdisciplinary approaches in the glycosciences help to advance and appreciate
our understanding of the biological processes involving carbohydrates that
may be controlled to promote health and prevent disease.

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Ame´lia Pilar Rauter
Thisbe K. Lindhorst

viii | Carbohydr. Chem., 2013, 39, vii–viii


CONTENTS

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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
Ame´lia Pilar Rauter and Thisbe K. Lindhorst

Radical-mediated brominations at ring-positions of carbohydrates –
35 years later
La´szlo´
1
2
3
4

Somsa´k and Katalin Czifra´k
Introduction
Radical-mediated brominations
Transformations of the brominated compounds
Biological effects of and/or studies with compounds
obtained via the brominated sugars and their ensuing

products
5 Conclusion
Acknowledgement
References

vii

1

1
2
16
31

33
33
33

Recent advances in enzymatic synthesis of heparin

38

Ana R. Jesus, Ame´lia P. Rauter and Jian Liu
1 Introduction
2 Enzymatic synthesis of heparin
3 Conclusions
Acknowledgments
References

38

43
55
55
55

Carbohydr. Chem., 2013, 39, ix–xii | ix

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Synthetic arabinan, arabinomannan glycolipids and their effects on
mycobacterial growth, sliding motility and biofilm formation
Binod K. Bharati, Kotari Naresh, Dipankar Chatterji and N. Jayaraman
1 Introduction
2 Development of synthetic glycolipid inhibitors
3 Biological studies of modified arabinose oligosaccharides
4 Biological studies of iminosugar-arabinan oligosaccharide
conjugates
5 Effects of synthetic mannose oligosaccharides on
mannosyltransferase (ManT) enzyme
6 Studies of linear and branched arabinan and
arabinomannan glycolipids
7 Conclusion and perspectives

Acknowledgements
References

Recent design of glycosyltransferase inhibitors
Shuai Wang and Se´bastien Vidal
1 Introduction
2 Inhibitors of galactosyltransferases (GalT)
3 Inhibitors of O-linked N-acetylglucosamine transferase (OGT)
4 Conclusion and perspectives
Acknowledgements
References

58

58
61
63
65
65
67
74
75
75

78
78
80
92
96
97

97

b-N-Acetylhexosaminidases: group-specific inhibitors wanted
Kristy´na Sla´mova´ and Vladimı´r Krˇen
1 Introduction
2 b-N-Acetylhexosaminidases: properties and physiology
3 Inhibitors of b-N-acetylhexosaminidases
4 Conclusions
Acknowledgements
References

102

Positive attitude, shape, flexibility, added-value accessories or ‘‘just
being different’’: how to attract a glycosidase
Arnold E. Stu¨tz and Tanja M. Wrodnigg
1 Introduction
2 Positive attitude - not always necessary
3 Good shape and flexibility - catering for quite diverse
requirements

120

x | Carbohydr. Chem., 2013, 39, ix–xii

102
103
105
115
115

115

120
127
130


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Added-value accessories – addressing and exploiting
cooperative binding
5 Or just being different – uncommon and non-natural
configurations address selectivity
References

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4

133
139
142

Epoxy carbohydrate derivatives and analogues as useful intermediates 150
in the synthesis of glycosidase inhibitors
M. Soledad Pino-Gonza´lez, Antonio Romero-Carrasco and Noe´ On˜a
1 Introduction
2 Imino sugars and aza sugars
3 Carbasugars and aminocyclitols

4 Thio sugars
5 Amino sugars
6 Pyranoses fused to heterocycles
7 Miscellaneous
8 Concluding remarks
References

Glycosidases and diabetes: metabolic changes, mode of action and
therapeutic perspectives
Vanessa Leiria Campo, Valquiria Araga˜o-Leoneti and Ivone Carvalho
1 Introduction
2 Glycosidase metabolic changes in diabetes
3 Glycosidase mode of action
4 Glycosidase inhibitors
References

Surface binding sites in carbohydrate active enzymes: an emerging
picture of structural and functional diversity
Darrell Cockburn and Birte Svensson
1 Introduction
2 Structural diversity of SBS containing enzymes
3 Potential roles of SBSs
4 Techniques for studying SBSs
5 Applications of SBSs
6 Conclusions
Abbreviations
Acknowledgements
References

150

151
165
171
171
172
174
176
176

181

181
184
190
192
200

204

204
206
210
213
216
218
218
219
219

Carbohydr. Chem., 2013, 39, ix–xii | xi



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Structure determination of lectins by x-ray crystallography –
a hands-on approach
Gabriele Cordara and Ute Krengel
1 Introduction
2 Materials
3 Methods
Acknowledgements
References

xii | Carbohydr. Chem., 2013, 39, ix–xii

222

222
225
226
242
242


Radical-mediated brominations at ringpositions of carbohydrates – 35 years later
La´szlo´ Somsa´k* and Katalin Czifra´k


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The unique ability of sugar derivatives to undergo bromination at ring positions by a
radical mechanism is surveyed more than three decades after the discovery of the
reaction. The range of substrates as well as their transformations have been enormously extended, and many of the ensuing products have proven valuable tools for
chemical glycobiology.

1

Introduction

The title reaction, namely the possibility for a direct replacement of a
hydrogen atom in a carbohydrate ring by bromine, was first reported by
Ferrier and Furneaux in 1977.1,2 The transformations need to be performed
under irradiaton or in the presence of radical initiators and can thus be
understood by a radical mechanism (Scheme 1). They are sometimes called
the ‘‘Ferrier photobromination’’. The resulting products contain the bromine
attached to carbons adjacent to the ring oxygen, i.e. the bonds formed are
either C-1–Br or C-5–Br/C-4–Br (pyranoid vs. furanoid rings); with certain
compounds competitive reactions to give C-1–Br and C-5–Br/C-4–Br derivatives can take place. Sporadically chlorinations have also been carried out.
The reactivity of several carbohydrate derivatives under such conditions
was tested and a comprehensive survey of these studies, including suggestions
for the rationalization of the observed regio- and stereoselectivities as well as
transformations of the primary brominated products, was also published in
1991.3 Since then the reaction has been extended to new types of substrates
and a broad range of subsequent transformations has led to various carbohydrate derivatives demonstrating the synthetic utility of this bromination.
The aim of the present article is to survey this type of functionalization of

carbohydrate derivatives and to update the previous review more than three
decades after finding the transformation. New developments in the reaction

Y

Y

5

O
Y
5

H

O 1 Z
H

Br
–HBr

Br

Br2
–Br

or/and

O 1 Z


H

Z

or/and

Y

Y
O

Z

5

Br
H

O 1 Z
H

Scheme 1 Bromination at ring-positions of carbohydrates (illustrated on pyranoid rings).

Department of Organic Chemistry, University of Debrecen, POB 20, H-4010 Debrecen,
Hungary. E-mail:

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conditions and protecting groups are summarized first, followed by the
brominations themselves. While in the 1991 review these reactions were
grouped somewhat arbitrarily, also considering historical and chronological
aspects, here the brominations are categorized according to substrate types
classified by exocyclic bonds of the C-1 centre (e.g. C-1–O, C-1–S, etc.). The
next part deals with the transformations of the brominated sugar derivatives
also outlining further synthetic uses of the obtained compounds. A brief
summary of those results covered in the first review introduces each of these
sections. The chapter is concluded with a tabular presentation of biological
activities and utilization of the synthesized compounds.
2

Radical-mediated brominations

2.1 General considerations
2.1.1 Reaction conditions. The reactions were originally performed
under the classical conditions for Wohl-Ziegler brominations,4,5 i.e. in
refluxing CCl4 with N-bromosuccinimide (NBS) or bromine as the reagents
in the presence of substoichiometric amounts of radical initiators like
dibenzoyl peroxide (Bz2O2) or azobisisobutyronitrile (AIBN) or/and with
irradiation. The use of ultrasound in place of the previous initiation
methods was reported to give higher yield and purity for the products in

slower reactions.6–10 Advantageous addition of CBrCl3 as a co-solvent was
mentioned in sporadic cases.3 Addition of BaCO3 or K2CO3 as acid scavangers especially in reactions with Br2 could be beneficial.
Due to its several hazardous effects (e.g. acute toxicity, specific organ
toxicity to liver, kidneys, eyes, and heart, carcinogenicity, aquatic toxicity,
ozone layer damages) the use of CCl4, being otherwise an ideal solvent for
these transformations, was seriously restricted, practically banned. Therefore, some research groups succesfully tried to replace CCl4 by Cl3CCH3
with NBS,11 and CHCl3 or CH2Cl2 with Br2.12 Another study13 showed that
benzotrifluoride (PhCF3, BTF) could be used as solvent in several cases, and
the unconventional bromination reagent system14 KBrO3–Na2S2O4 in
CH2Cl2–water biphasic solvent mixture proved also widely applicable. NBS
was also shown to perform well in the latter solvent system. For chlorinations SO2Cl2 in CCl4 with AIBN initiator was used.15
2.1.2 Protecting groups. Hydroxyl groups of the sugar derivatives are
generally protected by esters (benzoates preferred to acetates as the latter
can undergo bromination). Recently, the use of 4-bromobenzoate esters16
and carbonates17 was reported. From the ether type protective groups methyl
and trityl18 could be applied, but benzyl ether is sensitive towards bromine
radicals. The 2- and 4-trifluoromethylbenzyl ethers, which are stable under
some oxidative conditions,19 can, to a certain extent, survive NBS induced
cleavage of benzylidene acetals,20 but have, to the best of our knowledge,
never been used in radical-mediated brominations. The applicability of silyl
ethers will be illustrated in Section 2.6.1. Benzylidene- and other aldehydederived acetal protections are cleaved under the bromination conditions,
however, ketone-based derivatives have been used succesfully.
There are examples for bromination of compounds with a single free
OH21 (Section 2.6.1) and COOH30 (Section 2.2.1) groups. In other cases the
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presence of a free COOH group resulted in decomposition under the
bromination conditions22 (Section 2.6.1). For the protection of COOH
groups besides methyl also phenacyl23 esters were used (Section 2.7.1).
Compounds with primary carboxamide (CONH2) substituents can be
brominated without protection of the NH functionalities (Section 2.6.1).
Various data are available on brominations in the presence of secondary
amides (e.g. AcNH substituents) which were either masked as Ac2N,
phthalimido,24 or tetrachlorophthalimido25 moieties (Sections 2.2.1, 2.2.2,
2.7.1) or left unprotected26,27 (Sections 2.5, 2.7.1).
2.1.3 General rules governing regio- and stereoselectivity. In the 1991
review3 an attempt was made to rationalize the observed selectivities of the
reactions. Since then, no focused studies have been carried out to tackle these
points, nevertheless, those rules can be applied to explain new findings, as
well. To give a general frame for understanding the outcome of the reactions,
the factors determining selectivities are outlined here. As an illustration of
these considerations Table 1 summarizes the substrates studied so far in the
brominations and indicates the main products of the reactions.
Regioselectivity of the reactions is influenced by the ease of hydrogen
abstraction which is determined by radical stabilities as well as stereochemical
and steric effects. C-H bonds adjacent to ring oxygens are prone to homolysis,
which is reflected in the preponderant formation of a-bromoether type compounds (cf. Scheme 1). In addition, radical stability is influenced by the substituents Y and Z; a particularly stable radical is formed and the corresponding
site will be highly reactive if the so-called capto-dative substitution pattern is
present (Y or Z is an electron withdrawing group, cf Table 1). A numerical
estimate for the relevant sugar radical stabilities was given in the 1991 survey.3
An important stereochemical factor governing H-abstraction is the axial vs.
equatorial orientation of the hydrogen in pyranoid rings, the former being
significantly more reactive. The steric availability of the hydrogen atom to be
abstracted also contributes to the selectivity issues: bulky substituents e.g. in

place of Z (cf alkyl and aryl glycosides in Table 1) were shown to direct the
reaction to the C-5 centre, while axial substituents can slow down or even
totally hinder the abstraction of axial hydrogens on the same side of the ring.
This may result in considerable differences in reactivities of anomers.
The stereochemistry of the products is influenced by kinetic and thermodynamic anomeric effects, both in favour of the formation of axially
brominated compounds. Epimeric substrates can give common radicals
which result in the same product(s). Conformation of the intermediate
radicals is another important issue which can exert an effect on the formation of diastereomeric products. Glycosyl radical conformations and
their consequences for stereoselectivities cannot be treated here, the reader
is kindly referred to a review.28
2.2 Substrates with C-1–O bonds
2.2.1 Glycosides. Antecedents:3 Simple pyranosides with O-acyl protection having axial aglycons gave no isolable products. With equatorial
aglycons C-1-bromination (and subsequent reactions or decomposition)
occurred for methyl glucosides, while C-5 bromides were formed from
phenyl b-D-glucosides with increased yield for the 4-nitrophenyl derivative.
Carbohydr. Chem., 2013, 39, 1–37 | 3


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3

Table 1 Overview of the brominations with references to the 1991 review and to the sections
of this survey.
Starting compound
Y

Z
Y

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Y

O
H

Product(s)
Z

ensuing prod.*
–
–
–
–
–
–

–
þ
þ
þ
þ
þ
þ

*

–
–

þ
þ
–
þ

II. 10., VI. VI.
VI.
2.3.1.
2.3.2.
I.
-

H

OAlkyl
OAryl
H
OMe
OAryl
OAcyl
OAcyl

O

Z

the 1991
review
II. 9.
II. 9.

II. 2.
II. 2.
II. 3.
II. 2.

H

CH2OAcyl
H or CH2OAcyl
CO2Me
CO2Me
CO2Me
H or CH2OAcyl
CO2Me

Y

O

Z

Section in

Br

Br

H

CH2OAcyl

CH2OAcyl
CH2OAcyl
CH2OAcyl
CH2OAcyl
CO2Me

SPh
S(O)Ph
SO2Ph
SO2NH2
SC(=NOH)R
SPh

CH2OAcyl

NAryl

bromination in the aromatic ring -

CH2OAcyl

N Het

–

ensuing
ensuing
þ
þ
ensuing

ensuing

prod.
prod.*

prod.*
prod.*

*

this
survey
2.2.1.
2.2.1.
2.2.1.
2.2.2.

2.4.1.

þ

II. 11.

2.4.1.
2.4.1
2.4.2.,
2.4.3.

CH2OAcyl
CH2OAcyl


NHC(=NOH)R
Heterocumulenes
(N3, NCS)

ensuing prod.
ensuing prod.*

–
þ

VI.

CH2OAcyl

P(=O)(OR)2

þ

–

-

2.5.

H or CH2OAcyl CN
H or CH2OAcyl CONH2
H or CH2OAcyl COOR

þ

þ
þ

–
–
–

II. 6.
-

2.6.1.
2.6.1.
2.6.1.

H or CH2OAcyl

C Ar

þ

–

II. 7.

2.6.2.

CH2OAcyl
CO2Me
CH2OAcyl
H or CH2OAcyl


F
þ (minor)
F
Cl
þ (major)
Br (of 5-thiopyra- þ
nosyl derivatives)

þ (major)
þ
þ (minor)
þ

II. 8.
VI.
II. 8.
-

2.7.1.
2.7.1.
2.7.1.
2.7.2

II. 5.

2.8.

Y


Y

O
H

or C Het

H

ZH

H or CH2OAcyl O or N(OAcyl)
Y
H

O

O

H

H

H

O

H

Br Z

H

Z Br

þ
Y

Z

Y
H

–
O

Z
Br

Y
Br

O

Z
H

OAcyl

–


þ

II. 3.

2.2.2.

N Het

–

þ

II. 11.

2.4.1.

CN
þ
CH2OAcyl
CH2OAcyl
CONH2
þ
Bridged derivatives
Halogenation of exocyclic methylenes
Disaccharide substrates

–
–

II. 4.

II. 2.-5.

2.6.1.
2.6.1.
2.9.
2.10.
2.11.

CH2OAcyl
CH2OAcyl

*
The actually isolated compound was an ensuing product formed from the primary radical
intermediate or brominated derivative.

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Brominations of 4-methoxyphenyl- and 2,2,2-trichloroethyl 2-deoxy-2tetrachlorophthalimido-b-D-glucopyranosides were observed to take place
at both reactive centers, however, isolation in 43% yield of the 5-bromide 1
of the latter substrate was reported only.25 Phenyl b-D-xylopyranoside gave
2 (25%), but extended reaction times resulted in brominations of the OAc
and the phenyl groups, too.29 5-Bromides of uronic acid derivatives 3 and 4
were isolated in 39%30 and 65%31 yield, respectively.
AcO

AcO
AcO

O

AcO
AcO

O
OCH2CCl3

OPh
Br OAc

Br NTCP

1

HOOC
F
AcO

O
OPh
Br OAc

2

MeOOC
D

AcO

O

3

OC6H2Cl3(2,4,6)

4

Br OAc

2.2.2 Glycosyl esters. Antecedents:3 O-Peracylated aldopyranoses
underwent bromination at the C-5 centre: hexopyranoses (Y=CH2OAcyl)
gave axial 5-bromides (a-anomers gave lower yields than the b-anomers,
benzoates proved more stable than acetates), while the conformationally
more mobile tetra-O-acetyl-b-D-xylopyranose (Y=H) furnished C-5 epimeric
bromides with axial halogens in both compounds. Benzoylated furanosyl
acetate derivatives of D-glucose and D-ribose gave the corresponding C-4-Br
epimers. Anomeric esters of hexuronic acid derivatives (Y=COOR) of
b-D-gluco and a-L-ido configurations gave the same axial 5-bromide
of b-D-glucuronic acid. Both epimers of a formally 5-(2-cyanoethyl)substituted b-D-xylose tetraacetate gave the same C-5-bromide.
Bromination of O-per(4-bromobenzoylated) b-D-glucopyranose gave the
high melting C-5 bromide 5 in 83% yield.16 O-Peracetylated N-acetyl-Dglucosamine was reported to be incompatible with the bromination conditions. The N,N-diacetyl derivative gave an inseparable mixture of the C-1
and C-5 bromides, but tetrachlorophthaloyl (TCP) or phthaloyl (Pht)
protection could be applied to give 6 and 7, respectively. Interestingly, the
sterically more crowded 8 was obtained in higher yield than that of the
anomeric 6.25 a-D-Lyxopyranose tetraacetate gave the 5-bromide in 35%
yield, the formation of the possible other epimer was not mentioned.32
Methyl 1,2,3,4-tetra-O-acetyl-a-D-glucopyranuronate was brominated to

give 9 in a yield of 65–70%.33,34
RO
RO
RO

O
OR

AcO
AcO
AcO

O
OAc

5

BzO
OAc

Br

9

OAc
OAc

Br

AcO


OAc

10

OAc
NTCP

8 (52%)

O

O
Br

Br

6 (TCP, 35%)
7 (Pht, 66%)
AcO

MeOOC
AcO
AcO

O

Br N(TCP or Pht)

Br OR


(R = 4-BrC6H4CO)

AcO
AcO
AcO

R
O
BzO
CH2OBz

BzO

11

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Bromination of D-ribofuranose tetraacetate was mentioned to give the
corresponding 4-bromide 10 as the only product, however, no experimental
details were given.35 D-Fructofuranose pentabenzoate could not be brominated by NBS, however, Br2/hn furnished 11 in 52% yield.36
2.3 Substrates with C-1–S bonds
2.3.1 Thioglycosides, their oxidized derivatives, and glycosyl sulfonamides.
Antecedents:3 O-Perbenzoylated phenyl 1-thio-b-D-gluco- and galactopyranosides brominated at the anomeric centre and ensuing reactions gave isolated enone type compounds. O-Peracetates reacted similarly, however, these

reactions suffered from overbromination in the OAc protecting groups. The
a-D-gluco configured substrates reacted significantly slower to give the same
product. Bromination of O-peracetylated methyl (phenyl 1-thio-b-D-glucopyranoside)uronate took place both at C-1 and C-5 to yield the above enone
type compound and the 5-bromide, respectively. O-Peracetylated b-D-glucopyranosyl phenyl sulfoxide gave acetobromoglucose on bromination, while
the corresponding sulfone furnished both C-1-Br and C-5-Br derivatives in an
almost equal ratio.
Bromination of O-peracetylated b-D-gluco- and b-D-galactopyranosyl
methoxycarbonylethyl sulfones gave moderate yields of both C-1-Br and
C-5-Br derivatives 12–15, respectively (Table 2). b-D-Glycopyranosyl sulfonamides brominated similarly to give 16 and 17 of D-gluco as well as 18
and 19 of D-galacto configuration in low isolated yields together with significant amounts of the corresponding glycosyl bromides. A mechanistic
rationale, based on relative radical stabilities and b-fragmentation of sulfonamidyl radicals, was proposed to explain the regioselectivities and the
formation of glycosyl bromides.37
2.3.2 Glycosyl thiohydroximates. Antecedents:3 none.
Under treatment by NBS and irradiation, glycosyl thiohydroximates
(Scheme 2, A2) undergo spirocyclization to give mixtures of epimeric oxathiazolines D2 and E2.38 This spirocyclization can be understood either by
the oxidative formation of biradical B2 to yield the major isomer by
recombination with the known axial preference of glycosyl radicals28 or by
bromination of A2 to intermediate C2 and subsequent intramolecular
nucleophilic substitution. The anomeric configuration of A2 had no influence on the reaction as neither the rate nor the stereoselectivity were significantly different.39
Table 2 Bromination of glycosyl sulfones and sulfonamides.

R

R

R

R2 OAc
O
R

R3
AcO
AcO
Br

AcO
H
AcO
H

H
AcO
H
AcO

SO2(CH2)2CO2Me
SO2(CH2)2CO2Me
SO2NH2
SO2NH2

12 (21%)
14 (43%)
16 (11%)
18*

1

*

2


3

1

R2 OAc
O

R1
AcO

13 (30%)
15 (27%)
17 (12%)
19*

Not isolated in pure state because of almost identical chromatographical mobility.

6 | Carbohydr. Chem., 2013, 39, 1–37

R3
Br OAc


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O

O
S
AcO

S
AcO

H

B2

R

O

SN1

R
N

major

D2

+

N

HO

O

O
S


A2
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AcO

N

O

O

S

R

AcO

Br

R

HO

O

SN2
AcO


N

N
minor

S

C2

E2

R

Scheme 2 Formation of glycitol-spiro-oxathiazolines.

2.4 Substrates with C-1–N bonds
2.4.1 N-Glycosyl compounds and N-glycosylheterocycles. Antecedents:3
1,N-Dibenzoyl-2 0 ,3 0 ,5 0 -tri-O-benzoyladenosine was brominated in the 4 0 position.
O-Peracetates of some N-aryl-b-D-glucopyranosylamines were reacted
with NBS/Bz2O2, however, only aromatic brominations could be observed.
Similarly protected N-acetyl-N-aryl-b-D-glucopyranosylamines remained
intact under these conditions. Acetylated N-b-D-cellobiosylpiperidine, as an
aliphatic N-glycosidic substrate, gave the corresponding a-D-cellobiosyl
bromide.15
In an attempt to prepare glucitol spiro 1,2,4-oxadiazolines40 (as analogues of the spiro-oxathiazolines shown in Scheme 2) O-peracetylated b-Dglucopyranosylamidoximes (Scheme 3, A3) were treated with NBS under
irradiation. Various proportions of compounds C3–E3 could be isolated
whose formation can be explained by the oxidative milieu: C3 is a direct
oxidation product of A3; the expected B3 can be formed by a mechanism
similar to that depicted in Scheme 2, however, this compound undergoes a
tautomeric ring opening followed by aromatization of the heterocycle to

give D3 which is further oxidized to E3.
Bromination of a glucopyranosylpurine gave the 5 0 -bromo product 20,
while an unselective reaction was observed with 2 0 ,3 0 ,5 0 -tri-O-benzoyluridine.15 On the other hand, benzoylated 5-fluorouridine gave the 4 0 -bromide
21, and 4 0 -bromoadenosine 22 could also be isolated.41 Failure of attempts
to brominate 2 0 -deoxycitidine was reported.35
AcO
AcO
AcO

O

H
N

AcO
AcO
AcO

Ar

AcO

OAc

A3
AcO
AcO
AcO

O


HO

N

O

Ar
N

B3

O
N

Ar

AcO
AcO
AcO

N

AcO
AcO
AcO

OH
N
AcO


OAc

C3 O

H
N

O

D3

Ar
N

O
N
AcO

E3

O

Ar
N

Scheme 3 Transformation of glycosyl amidoximes by NBS and irradiation.

Carbohydr. Chem., 2013, 39, 1–37 | 7



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Cl
AcO
AcO
AcO

N

BzO

O
N

N

Br OAc

21 R =

R

O

F
NHBz

N

22 R =


BzO OBz

Cl

O

N

Br

N

20

H
N

O

Cl

N

N

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N


2.4.2 Glycosyl azides. Antecedents:3 none.
Reactions of variously protected glycosyl azides with NBS under irradiation or in the presence of Bz2O2 or AIBN (Scheme 4) resulted in the
rather labile bromoiminolactones 23–31.15,18,42 Anomeric configuration of
the starting azides had a considerable bearing on the rate (but not on the
yields) of the reactions:18 competitive experiments showed the relative
reaction times for O-peracetylated glycopyranosyl azides of b-D-manno, b-Dgluco, a-D-manno, and a-D-gluco configurations to be B2:3:6:15, respectively. In furanosyl azides the reactivities of the anomers were practically the
same. A detailed mechanistic proposal suggests the formation of an
anomeric radical as the initial step, which looses molecular nitrogen
and rearranges to an iminyl radical whose reaction with bromine gives the
final product.18 Contrary to bromination, radical-mediated chlorination of
O-peracetylated b-D-glucopyranosyl azide gave the C-5-chloro derivative 32
(Scheme 5).15

O

O
N3

RO
RO
RO

O

AcO
AcO
AcO

OR NBr


O

R

O

26
(α, 81%; β, quant.)

NBr

O O

O

OAc
O

O

O

O

NBr

23 R = Ac (α or β, 92%)
24 R = Bz (β, quant.)
25 R = Me (β, quant.)

R'

NBr 23–31

NBr

27
(β, quant.)

28 R = Me, R′ = AcO (α, 90%; β, 80%)
29 R = Me, R′ = N3 (α, 91%)
30 R = Me, R′ = TrO (β, quant.)
31 R,R = C5H10, R′ = AcO (α or β, quant.)

R

Scheme 4 Transformation of glycosyl azides under bromination conditions (anomeric configuration of the starting compound in parentheses).

AcO
AcO
AcO

O
X
OAc

SO2Cl2, AIBN
CCl4, reflux

AcO

AcO
AcO

O
X
Cl OAc

32 X = N3(55%)
33 X = NCS (60%)

Scheme 5 Chlorination of glucosyl azide and -isothiocyanate derivatives.

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2.4.3 Glycosyl isothiocyanates. Antecedents: none.
Bromination of O-peracetylated b-D-glucopyranosyl isothiocyanate
under several conditions gave acetobromoglucose and 2,3,4,6-tetra-Oacetyl-D-glucopyranose or an unsaturated lactone in varying yields and
ratios. On the contrary, chlorination resulted in the C-5-chloro product 33
(Scheme 5).15
2.5 Substrates with C-1–P bonds
Antecedents:3 none.
Diethyl 2,3,4,6-tetra-O-acetyl-a- and -b-D-glucopyranosylphosphonates
were brominated to give the same product 34 in 53% and 64% yields,

respectively.27 To get the 2-deoxy counterpart 35 (25% isolated by chromatography as a rather unstable syrup) an anomeric mixture of the corresponding phosphonate was used.43 Similarly, a mixture of both anomers
was reacted to furnish the sialic acid analogue bromide 36 in 45% yield
whereby 15% of the starting material was recovered.27 Possible different
reactivity of the anomers got no mention in these reports.
AcO
AcO
AcO

AcO
PO3Et2 AcO
AcO

O
AcO

34

AcO

O

AcHN

Br

Br

35

OAc

Br

PO3Me2

O

PO3Me2
OAc

AcO OAc

36

2.6 Substrates with C-1–C bonds
2.6.1 C-Glycosyl formic acid (anhydro-aldonic acid) derivatives.
Antecedents:3 Several O-peracetylated glycopyranosyl cyanides (2,6-anhydro-aldononitriles) were brominated. From the hexose-derived compounds
the b-D-gluco and a- and b-D-galacto configured ones gave the C-1-bromo
products (38 and 41) in yields above 80%. The a-D-manno substrate furnished the analogous axial bromide 42 in 49% yield. Among pentose
derivatives the a- and b-D-arabino compounds gave high yields of the same
C-1-bromide 44, while the b-D-xylo and b-D-ribo derivatives reacted to
mixtures of C-1-bromo epimers 43.
Since the first investigations a very large array of C-glycosyl formic acid
derivatives were studied under bromination conditions. Bromides 37–61
which were isolated in pure state are collected in Table 3 (for the sake of
completeness also including some compounds actually obtained by ionic
chemistry, but which could have been prepared by the radical method, too).
Table 4 contains non-isolated bromides 62–69 used immediately for further
transformations. Significant difference in reaction times of the a- and b-Dpyranosyl derivatives was observed to show a 10–12 times higher reactivity
for the equatorially substituted substrates leading to e.g. 37 and 41, while
the reactivity of the furanoid substrates was almost the same to give e.g.

product mixtures 45 and 46 or single product 53.
A specific course of the bromination of C-(2-deoxyglycopyranosyl)formates (Scheme 6, A6) was observed, namely the primary
Carbohydr. Chem., 2013, 39, 1–37 | 9


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Table 3 Isolated bromides of C-glycosyl formic acid derivatives.
R=CN
44

PGO
PGO
PGO

O
R
R′
Br

OAc
AcO

O
R

AcO

R′
Br

OAc
O

R′
AcO
AcO

R

37 R’=H, PG=Ac (60% from both anomers)
a-CN needed 12 times longer reaction time
38 R’=OAc, PG=Ac (83% from b-CN)3
39 R’=OBz, PG=Bz (80% from b-CN)12
40 R’=H (63% from a-CN)48
41 R’=OAc (88% from b-CN)3
a-CN reacted B10 times slower49

CONH2

COOR’’

47 R’=OAc, PG=Ac
(by hydration of 38)45
48 R’=OBz, PG=Bz
(89% from
b-CONH2)12,46 (also
by hydration of 39)12

49 R’=OAc (50% from
b-CONH2)50 (also by
hydration of 41)51

54 R’’=Me, R’=BzO, PG=Bz (80% from b-COOR’’)22
55 R’’=Me, R’=BnO, PG=Bn (by ionic bromination)47
56 R’’=tBu, R’=BzO, PG=Bz (83% from b-COOR’’)22
57 R’’=C6Cl5, R’=BzO, PG=Bz (89% from b-COOR’’)22
58 R’’=Me, R’=OAc (77% from b-COOR’’)22
59 R’’=tBu, R’=OAc (85% from b-COOR’’)22
60 R’’=C6Cl5, R’=OAc (77% from b-COOR’’)22

42 R’=OAc (49% from a-CN)3

Br
Br
H3C
AcO

OAc

OAc

Br

O

AcO

R

AcO

AcO

50 (quant. from
b-CONH2)52

R

O

Br

Br

R
OAc

O

43a
(D-xylo 56%)3
(D-ribo 50%)3

O
OAc
AcO
OAc

R


43b
(D-xylo 28%)3
(D-ribo 33%)3

51 (by hydration of
43a D-xylo)45

44 (85% from a-CN)3

52 (by hydration of 44)51

45 R’=H, PG=4-ClBz (82% a/b-Br mixture
from a/b-CN)54,55
46 R’=OBz, PG=Bz (93% a/b-Br B1:1 from
b-CN);56 isolated 27% a-Br, 62% b-Br57

53 R’=OBz, PG=Bz
(51% a-Br only from
b-CONH2)58

OAc
AcO

PGO

R

O


Br
PGO

R′

61 R’’=Me (by ionic reactions)53


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Table 4 Non-isolated bromides of C-glycosyl formates [(ulosylbromide)onic acid esters].
O

O

OTBS
CO2Me
O

O

OTBS
O
CO2Me

O
TBSO

Br

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O

O

O

CO2Me

Br

OTBS

63

11, 60, 61

6411
CO2Me

O

TBSO
O

CO2Me

TBSO O


Br

CO2Me

Br

H3C

Br

H 3C

TBSO

O O

TBSO

6511,62

6711, 63

6611

Br

O
HO
H 3C
O


O

Br

6259
TBSO

O

CO2Me

HO
H 3C
O

O

6821

AcO
AcO

CO2Me

O

O
H3C


O

O

6921

O
CO2Me

NBS
CCl4

AcO
AcO

OAc

CO2Me

O

Br
O

70

OAc

Br
O


AcO

OAc

O

AcO

CO2Me
Br

B6

A6

E6

CO2Me

NBS CCl4
OAc
AcO
AcO

O
CO2Me
OAc

AcO

AcO
OAc

Br

AcO

O

C6

AcO

Br
O
CO2Me

CO2Me

F6

D6

Br

Scheme 6 Bromination of C-(2-deoxyglycopyranosyl)formates.

N

S

Gly-CSNH2

KBrO3-Na2S2O4
CH2Cl2-H2O, rt

Gly

N

Gly

Scheme 7 Reaction of C-glycosyl thioformamides under bromination conditions.

brominated product C6 eliminated HBr to give glycal D6 which, after
bromine addition, furnished the isolated dibromide B6. Compound E6 gave
F6 as the major product with some identified by-products.64
Under usual bromination conditions (Br2/CHCl3-sunlight) 2,3,4,6-tetraO-acetyl-b-D-galactopyranosyl thioformamide gave the corresponding 3,5bis(glycosyl)-1,2,4-thiadiazole in 80% yield. More safely reproducible
results were achieved by using the non-conventional bromination reagent
system in Scheme 7 (Gly=Ac4-b-D-Glcp, 77%; Bz4-b-D-Glcp, 86%; Ac4-b65
D-Galp, 80%; Ac3-b-D-Xylp, 62%).
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AcO
AcO
AcO

~95%


O

Br2/hν
CCl4-H2O
3:2

AcO

A8

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~95%

OAc
O

AcO
AcO
AcO

e
a

C8

AcO
AcO
AcO


a: α-D-manno
e: β-D-manno

O

B8
AcO
AcO
AcO

a e
AcO Br
a: D-manno
e: D-gluco
O

D8

a e
AcO OH

Scheme 8 Bromination of glycopyranosylbenzenes in the presence of water.

2.6.2 C-Glycosyl homo- and heterocycles. Antecedents:3 Some observations on the possible formation of 2,3,4,6-tetra-O-acetyl-1-bromo-Dglucopyranosylbenzene (B8e in Scheme 8) were discussed. Brominatons of
O-peracetylated C-glycopyranosyl 1,3,4-oxadiazoles and benzothiazoles
were investigated with the b-D-galacto, b-D-xylo, and a-D-arabino configurations to give mostly isolable C-1-bromides.
Bromination of glycosylbenzenes (Scheme 8, A8 and C8) in the presence
of water allowed to isolate lactols D8 as products of hydrolysis of the primarily formed bromides B8. This finding demonstrated the highly selective
abstraction of hydrogen from the C-1 position of A8 and C8. A reactivity

order was also established by competitive experiments and the reaction
times (C8e:C8a:A8=15:40:85 min)66 reflected higher radical stabilization
by the axial 2-OAc substituent.28
2.7 Substrates with C-1–halogen bonds
2.7.1 Glycopyranosyl halides. Antecedents:3 O-Peracetylated glycopyranosyl chlorides of the b-D-gluco and b-D-manno configurations afforded
mixtures of separable C-1 and C-5 bromides in very good overall yields and
in a B5-6 to 1 ratio in favour of the C-1-Br. Chlorinations, carried out with
SO2Cl2/AIBN in CCl4, gave similar results. The a-D-gluco configured
chloride and bromide yielded a 1,2-dibromide presumably in a HXelimination–Br2-addition sequence (see also ref. 67). Tetra-O-acetyl-b-Dglucopyranosyl fluoride furnished the C-1- and C-5-brominated compounds
favouring the C-5-Br derivative in a ratio of B14 to 1. The corresponding
a-fluoride produced only the C-5-bromide.
It was shown later that the C-1-halogenated products isolated from the
bromination mixtures of the b-D-gluco, b-D-galacto, and b-D-manno configured glycopyranosyl chlorides also contained the corresponding 1,1dichlorides (r10%) besides the major 1-bromo-1-chloro compounds.
Formation of the minor products can be attributed to a Cl abstraction from
the solvent (CCl4). These mixtures were inseparable by chromatography,
but repeated crystallizations allowed to remove the dichlorides. No C-5bromide could be isolated from the reaction of the b-D-galacto substrate.68
O-Peracetylated 2-deoxy-2-fluoro-b-D-glucopyranosyl chloride expectedly
gave a mixture of C-1 (71) and C-5 (72) bromo derivatives which proved
inseparable.69
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AcO
AcO
AcO

AcO
AcO
AcO


O
Cl
F

Cl
Br F

Br

71

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O

72

Extensively studied brominations of several glycosyl fluorides were
reported to produce C-5-bromides but the possible formation of the C-1-Br
isomers was not mentioned (although such compounds might be present in
the obtained mixtures). Tetra-O-benzoyl-b-D-glucopyranosyl fluoride gave
73 in 84% yield, the a-anomer proved to be unreactive.16 O-Peracetylated
2-deoxy-2-fluoro-b-D-glycopyranosyl fluoride and 1-fluoro-b-D-glycopyranosyl fluoride produced 74 and 75, respectively, and the latter substrate
was reported to be extremely unreactive.69 b-Fluorides of O-peracetylated
N-acetyl- and N-phthaloyl-D-glucosamines afforded 7626 and 77,24 respectively. None of 74–77 was isolated in pure state.
BzO
BzO
BzO


AcO
AcO
AcO

O
F

O
F
Br F

Br OBz

73

74
AcO

O
F

AcO

AcO
Br
F

76 R = NHAc
77 R = NPht

R
O
F
Br OAc

80

AcO
AcO

OAc
O
Br

78

O
PhCOCH2O
AcO
AcO

F
AcO
Br
F

AcO
AcO
AcO


O

Br R

O

75

OAc
AcO
AcO
AcO

AcO
AcO
AcO

F

79
O
F

Br OAc

81 R = H
82 R = Br

O


AcO
AcO

Br
AcO F

83

Tetra-O-acetyl-a-D-galactopyranosyl fluoride gave 52% of 78,70 and the
a-D-manno derivative 79 was obtained in 53% yield.71 A phenacyl (b-Dglucopyranosyl fluoride)uronate furnished 80 (43%) selectively due to the
capto-dative nature of the C-5 centre.23 Interestingly, the formally also
capto-datively substituted CH2 moiety of the phenacyl protecting group was
not reported to be reactive, most probably indicating the smaller radical
stabilizing capacity of the O-acyl moiety compared to the O-alkyl one.
Bromination of tri-O-acetyl-b-D-xylopyranosyl fluoride allowed to isolate
the 5-bromide 81 (38%) and 5,5-dibromide 82 (19%), while the a-anomer
furnished 83 (20%).72
2.7.2 5-Thiopyranosyl bromides. Antecedents:3 none.
Prolonged bromination of an anomeric mixture of O-peracetylated
5-thio-D-glycopyranosyl bromides gave tribromide 84 in 30% yield. 5-Thiob-D-xylopyranosyl bromide afforded 90% of the anomeric dibromide 85 in a
short reaction time, while after longer treatment tribromide 86 also
appeared among the products (containing further minor polybrominated
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