Carbohydrate chemistry volume 39 chemical and biological approaches

Brominations of 4-methoxyphenyl- and 2,2,2-trichloroethyl tetrachlorophthalimido-b-D-glucopyranosides were observed to take place2-deoxy-2-at both reactive centers, however, isol2-deoxy-

Carbohydrate ChemistryChemical and Biological Approaches

Volume 39

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A Specialist Periodical Report

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˜oPreto, 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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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

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DOI: 10.1039/9781849737173-FP007

While this volume is mainly dedicated to the investigation and utilisation ofcarbohydrate-specific enzymes, the reader will also find enzymology andglycobiology combined with glycochemistry, demonstrating how the inter-disciplinary approaches taken in the glycosciences contribute to theincreasingly important field of glycomics

The first chapter of this book is dedicated to the radical bromination ofsugars, involving a broad range of substrates and their transformations Ithighlights the synthetic utility of this type of reactions and, in particular, theuniqueness of carbohydrates as substrates, leading to a wide variety ofmolecular tools for chemical glycobiology Examples are given of acceptorsubstrate analogues for glycosyltransferases, inhibitors of glycosidases,compounds that inactivate retaining N-acetylglucosaminidases, amongstmany other bioactive compounds that were synthesized via radical-mediated halogenation of carbohydrates While the first chapter is dedi-cated to synthetic organic glycochemistry, the second illustrates theimportance of enzymatic and chemoenzymatic syntheses for the production

of the polysaccharide heparin, marketed as anticoagulant agent Recentdevelopments on synthetic glycolipids as ligands and as inhibitors ofmycobacterial cell wall components, biosynthesis and functions are descri-bed in chapter 3, also focusing on the inhibition of key glycosyltransferases

by glycolipids The next chapters deal with carbohydrate-processingenzymes and their inhibitors, most of them small molecule inhibitors.Design and synthesis of glycosyltransferase and glycosidase inhibitors isreviewed, paying particular attention to imino sugars and to carbohydrateepoxides as synthetic key intermediates of this important class of ther-apeutic targets, with applications in the treatment of influenza infection,cancer, AIDS, and diabetes Also an overview on glycosidase metabolicchanges in diabetes is presented The deficiency in humans of hex-osaminidases causes severe neurodegenerative disorders, including theAlzheimer’s disease Hence a survey of the most efficient and selectiveinhibitors of these glycosidases, required for the research of their physio-logical functions, is given in this volume In recent years binding sites ofcarbohydrate-specific enzymes have been investigated in greater detail, withspecial focus on surface and secondary binding sites (SBS) SBS, playingseveral supporting roles in enzyme function, are binding sites that arelocated on the catalytic domain of a particular enzyme, but separate fromthe enzyme’s main active site Another chapter is devoted to this interestingarea of research that aims to modulate enzymatic behavior without alteringthe enzyme active site, focusing on SBS potential roles, techniques for SBSstudy and applications The last but not the least, X-ray crystallography oflectins is the subject of a chapter, emphasizing the characterization of lectin-carbohydrate complexes with high precision, and revealing in detail theunderlying molecular recognition mechanisms

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

c The Royal Society of Chemistry 2013

Volume 39 contains chapters covering chemical, biochemical and gical approaches that demonstrate, in a meaningful way, how inter-disciplinary approaches in the glycosciences help to advance and appreciateour understanding of the biological processes involving carbohydrates thatmay be controlled to promote health and prevent disease.

biolo-Ame´lia Pilar RauterThisbe K Lindhorst

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Ame´lia Pilar Rauter and Thisbe K Lindhorst

Radical-mediated brominations at ring-positions of carbohydrates –

4 Biological effects of and/or studies with compoundsobtained via the brominated sugars and their ensuingproducts

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

c The Royal Society of Chemistry 2013

Synthetic arabinan, arabinomannan glycolipids and their effects on

mycobacterial growth, sliding motility and biofilm formation

58

Binod K Bharati, Kotari Naresh, Dipankar Chatterji and N Jayaraman

2 Development of synthetic glycolipid inhibitors 61

3 Biological studies of modified arabinose oligosaccharides 63

4 Biological studies of iminosugar-arabinan oligosaccharideconjugates

Shuai Wang and Se´bastien Vidal

3 Inhibitors of O-linked N-acetylglucosamine transferase (OGT) 92

Positive attitude, shape, flexibility, added-value accessories or ‘‘just

being different’’: how to attract a glycosidase

120

Arnold E Stu¨tz and Tanja M Wrodnigg

3 Good shape and flexibility - catering for quite diverserequirements

130

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4 Added-value accessories – addressing and exploitingcooperative binding

Epoxy carbohydrate derivatives and analogues as useful intermediates

in the synthesis of glycosidase inhibitors

150

M Soledad Pino-Gonza´lez, Antonio Romero-Carrasco and Noe´ On˜a

Surface binding sites in carbohydrate active enzymes: an emerging

picture of structural and functional diversity

Structure determination of lectins by x-ray crystallography –

Radical-mediated brominations at

ring-positions of carbohydrates – 35 years later

La´szlo´ Somsa´k* and Katalin Czifra´k

DOI: 10.1039/9781849737173-00001

The unique ability of sugar derivatives to undergo bromination at ring positions by aradical mechanism is surveyed more than three decades after the discovery of thereaction The range of substrates as well as their transformations have been enor-mously extended, and many of the ensuing products have proven valuable tools forchemical glycobiology

1 Introduction

The title reaction, namely the possibility for a direct replacement of ahydrogen atom in a carbohydrate ring by bromine, was first reported byFerrier and Furneaux in 1977.1,2The transformations need to be performedunder irradiaton or in the presence of radical initiators and can thus beunderstood by a radical mechanism (Scheme 1) They are sometimes calledthe ‘‘Ferrier photobromination’’ The resulting products contain the bromineattached to carbons adjacent to the ring oxygen, i.e the bonds formed areeither C-1–Br or C-5–Br/C-4–Br (pyranoid vs furanoid rings); with certaincompounds competitive reactions to give C-1–Br and C-5–Br/C-4–Br deri-vatives can take place Sporadically chlorinations have also been carried out.The reactivity of several carbohydrate derivatives under such conditionswas tested and a comprehensive survey of these studies, including suggestionsfor the rationalization of the observed regio- and stereoselectivities as well astransformations of the primary brominated products, was also published in

1991.3Since then the reaction has been extended to new types of substratesand a broad range of subsequent transformations has led to various carbo-hydrate derivatives demonstrating the synthetic utility of this bromination.The aim of the present article is to survey this type of functionalization ofcarbohydrate derivatives and to update the previous review more than threedecades after finding the transformation New developments in the reaction

Department of Organic Chemistry, University of Debrecen, POB 20, H-4010 Debrecen, Hungary E-mail: somsak.laszlo@science.unideb.hu

H Y

Br –HBr

Br2–Br

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

conditions and protecting groups are summarized first, followed by thebrominations themselves While in the 1991 review these reactions weregrouped somewhat arbitrarily, also considering historical and chronologicalaspects, here the brominations are categorized according to substrate typesclassified by exocyclic bonds of the C-1 centre (e.g C-1–O, C-1–S, etc.) Thenext part deals with the transformations of the brominated sugar derivativesalso outlining further synthetic uses of the obtained compounds A briefsummary of those results covered in the first review introduces each of thesesections The chapter is concluded with a tabular presentation of biologicalactivities and utilization of the synthesized compounds.

2 Radical-mediated brominations

2.1 General considerations

2.1.1 Reaction conditions The reactions were originally performedunder the classical conditions for Wohl-Ziegler brominations,4,5 i.e inrefluxing CCl4with N-bromosuccinimide (NBS) or bromine as the reagents

in the presence of substoichiometric amounts of radical initiators likedibenzoyl peroxide (Bz2O2) or azobisisobutyronitrile (AIBN) or/and withirradiation The use of ultrasound in place of the previous initiationmethods was reported to give higher yield and purity for the products inslower reactions.6–10Advantageous addition of CBrCl3as a co-solvent wasmentioned in sporadic cases.3 Addition of BaCO3or K2CO3 as acid sca-vangers especially in reactions with Br2could be beneficial

Due to its several hazardous effects (e.g acute toxicity, specific organtoxicity to liver, kidneys, eyes, and heart, carcinogenicity, aquatic toxicity,ozone layer damages) the use of CCl4, being otherwise an ideal solvent forthese transformations, was seriously restricted, practically banned There-fore, some research groups succesfully tried to replace CCl4by Cl3CCH3with NBS,11and CHCl3or CH2Cl2with Br2.12Another study13showed thatbenzotrifluoride (PhCF3, BTF) could be used as solvent in several cases, andthe unconventional bromination reagent system14 KBrO3–Na2S2O4 in

CH2Cl2–water biphasic solvent mixture proved also widely applicable NBSwas also shown to perform well in the latter solvent system For chlorina-tions SO2Cl2in CCl4with AIBN initiator was used.15

2.1.2 Protecting groups Hydroxyl groups of the sugar derivatives aregenerally protected by esters (benzoates preferred to acetates as the lattercan undergo bromination) Recently, the use of 4-bromobenzoate esters16and carbonates17was reported From the ether type protective groups methyland trityl18could be applied, but benzyl ether is sensitive towards bromineradicals The 2- and 4-trifluoromethylbenzyl ethers, which are stable undersome oxidative conditions,19 can, to a certain extent, survive NBS inducedcleavage of benzylidene acetals,20 but have, to the best of our knowledge,never been used in radical-mediated brominations The applicability of silylethers will be illustrated in Section 2.6.1 Benzylidene- and other aldehyde-derived 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 thebromination conditions22 (Section 2.6.1) For the protection of COOHgroups besides methyl also phenacyl23esters were used (Section 2.7.1).

Compounds with primary carboxamide (CONH2) substituents can bebrominated without protection of the NH functionalities (Section 2.6.1).Various data are available on brominations in the presence of secondaryamides (e.g AcNH substituents) which were either masked as Ac2N,phthalimido,24or 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 1991review3an attempt was made to rationalize the observed selectivities of thereactions Since then, no focused studies have been carried out to tackle thesepoints, nevertheless, those rules can be applied to explain new findings, aswell To give a general frame for understanding the outcome of the reactions,the factors determining selectivities are outlined here As an illustration ofthese considerations Table 1 summarizes the substrates studied so far in thebrominations and indicates the main products of the reactions

Regioselectivity of the reactions is influenced by the ease of hydrogenabstraction which is determined by radical stabilities as well as stereochemicaland steric effects C-H bonds adjacent to ring oxygens are prone to homolysis,which is reflected in the preponderant formation of a-bromoether type com-pounds (cf Scheme 1) In addition, radical stability is influenced by the sub-stituents Y and Z; a particularly stable radical is formed and the correspondingsite will be highly reactive if the so-called capto-dative substitution pattern ispresent (Y or Z is an electron withdrawing group, cf Table 1) A numericalestimate 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 beingsignificantly more reactive The steric availability of the hydrogen atom to beabstracted also contributes to the selectivity issues: bulky substituents e.g inplace of Z (cf alkyl and aryl glycosides in Table 1) were shown to direct thereaction to the C-5 centre, while axial substituents can slow down or eventotally 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 modynamic anomeric effects, both in favour of the formation of axiallybrominated compounds Epimeric substrates can give common radicalswhich result in the same product(s) Conformation of the intermediateradicals is another important issue which can exert an effect on the for-mation of diastereomeric products Glycosyl radical conformations andtheir consequences for stereoselectivities cannot be treated here, the reader

ther-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 tection having axial aglycons gave no isolable products With equatorialaglycons C-1-bromination (and subsequent reactions or decomposition)occurred for methyl glucosides, while C-5 bromides were formed fromphenyl b-D-glucosides with increased yield for the 4-nitrophenyl derivative

pro-Carbohydr Chem., 2013, 39, 1–37 | 3

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Table 1 Overview of the brominations with references to the 1991 review 3 and to the sections

of this survey.

Starting compound

H O Y Z

O Y Z

O Y Z H

the 1991 review

this survey

-CH 2 OAcyl NAryl bromination in the aromatic ring - 2.4.1.

H or CH 2 OAcyl Br (of

5-thiopyra-nosyl derivatives)

H O Y

H H

O Y

H Br

O Y

H H Z

O ZH Y

H

Br Y

H

H Y

Br

Brominations of 4-methoxyphenyl- and 2,2,2-trichloroethyl tetrachlorophthalimido-b-D-glucopyranosides were observed to take place

2-deoxy-2-at both reactive centers, however, isol2-deoxy-2-ation in 43% yield of the 5-bromide 1

of the latter substrate was reported only.25Phenyl b-D-xylopyranoside gave

2 (25%), but extended reaction times resulted in brominations of the OAcand the phenyl groups, too.295-Bromides of uronic acid derivatives 3 and 4were isolated in 39%30and 65%31yield, respectively

O AcO

OCH 2 CCl 3

Br AcO

NTCP

O AcO

OPh

Br OAc

O F

Br OAc HOOC

O D AcO OC 6 H 2 Cl 3 (2,4,6)

of b-D-glucuronic acid Both epimers of a formally substituted b-D-xylose tetraacetate gave the same C-5-bromide

5-(2-cyanoethyl)-Bromination of O-per(4-bromobenzoylated) b-D-glucopyranose gave thehigh melting C-5 bromide 5 in 83% yield.16 O-Peracetylated N-acetyl-D-glucosamine was reported to be incompatible with the bromination condi-tions The N,N-diacetyl derivative gave an inseparable mixture of the C-1and C-5 bromides, but tetrachlorophthaloyl (TCP) or phthaloyl (Pht)protection could be applied to give 6 and 7, respectively Interestingly, thesterically more crowded 8 was obtained in higher yield than that of theanomeric 6.25 a-D-Lyxopyranose tetraacetate gave the 5-bromide in 35%yield, the formation of the possible other epimer was not mentioned.32Methyl 1,2,3,4-tetra-O-acetyl-a-D-glucopyranuronate was brominated togive 9 in a yield of 65–70%.33,34

O RO

Br RO

OR

O AcO

OAc Br

AcO

N(TCP or Pht)

O AcO

OAc Br AcO

OAc Br OAc

AcO OAc Br

OAc

O BzO

BzO Br

R

CH2OBz BzO

Bromination of D-ribofuranose tetraacetate was mentioned to give thecorresponding 4-bromide 10 as the only product, however, no experimentaldetails were given.35D-Fructofuranose pentabenzoate could not be bromi-nated 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 galactopyr-anosides brominated at the anomeric centre and ensuing reactions gave iso-lated enone type compounds O-Peracetates reacted similarly, however, thesereactions suffered from overbromination in the OAc protecting groups Thea-D-gluco configured substrates reacted significantly slower to give the sameproduct Bromination of O-peracetylated methyl (phenyl 1-thio-b-D-gluco-pyranoside)uronate took place both at C-1 and C-5 to yield the above enonetype compound and the 5-bromide, respectively O-Peracetylated b-D-gluco-pyranosyl phenyl sulfoxide gave acetobromoglucose on bromination, whilethe corresponding sulfone furnished both C-1-Br and C-5-Br derivatives in analmost equal ratio

Bromination of O-peracetylated b-D-gluco- and b-D-galactopyranosylmethoxycarbonylethyl sulfones gave moderate yields of both C-1-Br andC-5-Br derivatives 12–15, respectively (Table 2) b-D-Glycopyranosyl sul-fonamides brominated similarly to give 16 and 17 ofD-gluco as well as 18and 19 of D-galacto configuration in low isolated yields together with sig-nificant amounts of the corresponding glycosyl bromides A mechanisticrationale, based on relative radical stabilities and b-fragmentation of sul-fonamidyl radicals, was proposed to explain the regioselectivities and theformation of glycosyl bromides.37

2.3.2 Glycosyl thiohydroximates Antecedents:3none

Under treatment by NBS and irradiation, glycosyl thiohydroximates(Scheme 2, A2) undergo spirocyclization to give mixtures of epimeric oxa-thiazolines D2 and E2.38This spirocyclization can be understood either bythe oxidative formation of biradical B2 to yield the major isomer byrecombination with the known axial preference of glycosyl radicals28or bybromination of A2 to intermediate C2 and subsequent intramolecularnucleophilic substitution The anomeric configuration of A2 had no influ-ence on the reaction as neither the rate nor the stereoselectivity were sig-nificantly different.39

Table 2 Bromination of glycosyl sulfones and sulfonamides.

AcO AcOR

2.4 Substrates with C-1–N bonds

2.4.1 N-Glycosyl compounds and N-glycosylheterocycles Antecedents:31,N-Dibenzoyl-20,30,50-tri-O-benzoyladenosine was brominated in the 40-position

O-Peracetates of some N-aryl-b-D-glucopyranosylamines were reactedwith NBS/Bz2O2, however, only aromatic brominations could be observed.Similarly protected N-acetyl-N-aryl-b-D-glucopyranosylamines remainedintact under these conditions Acetylated N-b-D-cellobiosylpiperidine, as analiphatic N-glycosidic substrate, gave the corresponding a-D-cellobiosylbromide.15

In an attempt to prepare glucitol spiro 1,2,4-oxadiazolines40 (as gues of the spiro-oxathiazolines shown in Scheme 2) O-peracetylated b-D-glucopyranosylamidoximes (Scheme 3, A3) were treated with NBS underirradiation Various proportions of compounds C3–E3 could be isolatedwhose formation can be explained by the oxidative milieu: C3 is a directoxidation product of A3; the expected B3 can be formed by a mechanismsimilar to that depicted in Scheme 2, however, this compound undergoes atautomeric ring opening followed by aromatization of the heterocycle togive D3 which is further oxidized to E3

analo-Bromination of a glucopyranosylpurine gave the 50-bromo product 20,while an unselective reaction was observed with 20,30,50-tri-O-benzoylur-idine.15On the other hand, benzoylated 5-fluorouridine gave the 40-bromide

21, and 40-bromoadenosine 22 could also be isolated.41Failure of attempts

to brominate 20-deoxycitidine was reported.35

O AcO S N R O O

AcO S N R HO H

O AcO S N R HO Br

O AcO O N S

O AcO

O R

AcO

AcO

OAc H

N HO

Ar

O AcO

AcO AcO

AcO

O N

H Ar

OH AcO

AcO AcO

AcO O N

N Ar

O AcO

AcO AcO

AcO O N

N Ar

O AcO

AcO

OAc N N O Ar

O AcO

Br AcO

OAc N N

N N

BzO OBz Br

2.4.2 Glycosyl azides Antecedents:3none

Reactions of variously protected glycosyl azides with NBS under diation or in the presence of Bz2O2 or AIBN (Scheme 4) resulted in therather labile bromoiminolactones 23–31.15,18,42Anomeric configuration ofthe starting azides had a considerable bearing on the rate (but not on theyields) of the reactions:18 competitive experiments showed the relativereaction times for O-peracetylated glycopyranosyl azides of b-D-manno, b-D-gluco, a-D-manno, and a-D-gluco configurations to be B2:3:6:15, respec-tively In furanosyl azides the reactivities of the anomers were practically thesame A detailed mechanistic proposal suggests the formation of ananomeric radical as the initial step, which looses molecular nitrogenand rearranges to an iminyl radical whose reaction with bromine gives thefinal product.18Contrary to bromination, radical-mediated chlorination ofO-peracetylated b-D-glucopyranosyl azide gave the C-5-chloro derivative 32(Scheme 5).15

irra-O

N3

O NBr 23–31

O RO

RO

NBr RO

OR

O AcO AcO

NBr

OOO O

AcO Cl AcO

OAc X O

AcO AcO AcO

OAc X

SO2Cl2, AIBN CCl4, reflux

2.4.3 Glycosyl isothiocyanates Antecedents:3none.

Bromination of O-peracetylated b-D-glucopyranosyl isothiocyanateunder several conditions gave acetobromoglucose and 2,3,4,6-tetra-O-acetyl-D-glucopyranose or an unsaturated lactone in varying yields andratios On the contrary, chlorination resulted in the C-5-chloro product 33(Scheme 5).15

2.5 Substrates with C-1–P bonds

Antecedents:3none

Diethyl 2,3,4,6-tetra-O-acetyl-a- and -b-D-glucopyranosylphosphonateswere brominated to give the same product 34 in 53% and 64% yields,respectively.27 To get the 2-deoxy counterpart 35 (25% isolated by chro-matography as a rather unstable syrup) an anomeric mixture of the corre-sponding phosphonate was used.43 Similarly, a mixture of both anomerswas reacted to furnish the sialic acid analogue bromide 36 in 45% yieldwhereby 15% of the starting material was recovered.27 Possible differentreactivity of the anomers got no mention in these reports

O AcO AcO AcO

AcO

PO 3 Et 2

Br

O AcO

2.6 Substrates with C-1–C bonds

2.6.1 C-Glycosyl formic acid (anhydro-aldonic acid) derivatives.Antecedents:3Several O-peracetylated glycopyranosyl cyanides (2,6-anhy-dro-aldononitriles) were brominated From the hexose-derived compoundsthe b-D-gluco and a- and b-D-galacto configured ones gave the C-1-bromoproducts (38 and 41) in yields above 80% The a-D-manno substrate furn-ished the analogous axial bromide 42 in 49% yield Among pentosederivatives the a- and b-D-arabino compounds gave high yields of the sameC-1-bromide 44, while the b-D-xylo and b-D-ribo derivatives reacted tomixtures of C-1-bromo epimers 43

Since the first investigations a very large array of C-glycosyl formic acidderivatives were studied under bromination conditions Bromides 37–61which were isolated in pure state are collected in Table 3 (for the sake ofcompleteness also including some compounds actually obtained by ionicchemistry, but which could have been prepared by the radical method, too).Table 4 contains non-isolated bromides 62–69 used immediately for furthertransformations Significant difference in reaction times of the a- and b-D-pyranosyl derivatives was observed to show a 10–12 times higher reactivityfor the equatorially substituted substrates leading to e.g 37 and 41, whilethe 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 anosyl)formates (Scheme 6, A6) was observed, namely the primary

C-(2-deoxyglycopyr-Carbohydr Chem., 2013, 39, 1–37 | 9

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Table 3 Isolated bromides of C-glycosyl formic acid derivatives.

O PGO

R PGO

R′

Br

a-CN needed 12 times longer reaction time

by hydration of 39) 12

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’’=C 6 Cl 5 , R’=BzO, PG=Bz (89% from b-COOR’’) 22

O OAc

AcO

R ′ Br

60 R’’=C 6 Cl 5 , R’=OAc (77% from b-COOR’’) 22

O AcO

R OAc

R ′

Br

O Br R OAc OAc

AcO

b-CONH 2 ) 52

O AcO

AcO

R AcO Br

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

O Br R OAc OAc AcO

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

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

O

Br R OAc OAc

AcO

O PGO

PGO R ′

R Br

brominated product C6 eliminated HBr to give glycal D6 which, afterbromine addition, furnished the isolated dibromide B6 Compound E6 gaveF6 as the major product with some identified by-products.64

Under usual bromination conditions (Br2/CHCl3-sunlight) O-acetyl-b-D-galactopyranosyl thioformamide gave the corresponding 3,5-bis(glycosyl)-1,2,4-thiadiazole in 80% yield More safely reproducibleresults were achieved by using the non-conventional bromination reagentsystem in Scheme 7 (Gly=Ac4-b-D-Glcp, 77%; Bz4-b-D-Glcp, 86%; Ac4-b-

2,3,4,6-tetra-D-Galp, 80%; Ac3-b-D-Xylp, 62%).65

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

O O

TBSO Br OTBS

6311, 60, 61

Br O

O

6411

6511,62

O TBSO

TBSO

TBSO

CO2Me Br

6611

O

H 3 C TBSO

TBSO

CO2Me Br

6711, 63

O

H 3 C O

CO2Me Br O

O AcO

OAc

CO2Me AcO

Br

O OAc

Br AcO

Br

O AcO

OAc

CO2Me

AcO

O OAc AcO AcO

CO 2 Me

O AcO OAc

CO2Me

Br AcO

Br

O AcO OAc AcO

CCl4

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

Gly-CSNH2 KBrO3-Na2S2O4

CH2Cl2-H2O, rt N

N S

2.6.2 C-Glycosyl homo- and heterocycles Antecedents:3 Some vations on the possible formation of 2,3,4,6-tetra-O-acetyl-1-bromo-D-glucopyranosylbenzene (B8e in Scheme 8) were discussed Brominatons ofO-peracetylated C-glycopyranosyl 1,3,4-oxadiazoles and benzothiazoleswere investigated with the b-D-galacto, b-D-xylo, and a-D-arabino config-urations to give mostly isolable C-1-bromides.

obser-Bromination of glycosylbenzenes (Scheme 8, A8 and C8) in the presence

of water allowed to isolate lactols D8 as products of hydrolysis of the marily formed bromides B8 This finding demonstrated the highly selectiveabstraction of hydrogen from the C-1 position of A8 and C8 A reactivityorder was also established by competitive experiments and the reactiontimes (C8e:C8a:A8=15:40:85 min)66 reflected higher radical stabilization

pri-by the axial 2-OAc substituent.28

2.7 Substrates with C-1–halogen bonds

2.7.1 Glycopyranosyl halides Antecedents:3O-Peracetylated anosyl chlorides of the b-D-gluco and b-D-manno configurations affordedmixtures of separable C-1 and C-5 bromides in very good overall yields and

glycopyr-in aB5-6 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 configuredchloride and bromide yielded a 1,2-dibromide presumably in a HX-elimination–Br2-addition sequence (see also ref 67) Tetra-O-acetyl-b-D-glucopyranosyl fluoride furnished the C-1- and C-5-brominated compoundsfavouring the C-5-Br derivative in a ratio ofB14 to 1 The correspondinga-fluoride produced only the C-5-bromide

It was shown later that the C-1-halogenated products isolated from thebromination mixtures of the b-D-gluco, b-D-galacto, and b-D-manno con-figured glycopyranosyl chlorides also contained the corresponding 1,1-dichlorides (r10%) besides the major 1-bromo-1-chloro compounds.Formation of the minor products can be attributed to a Cl abstraction fromthe solvent (CCl4) These mixtures were inseparable by chromatography,but repeated crystallizations allowed to remove the dichlorides No C-5-bromide could be isolated from the reaction of the b-D-galacto substrate.68O-Peracetylated 2-deoxy-2-fluoro-b-D-glucopyranosyl chloride expectedlygave a mixture of C-1 (71) and C-5 (72) bromo derivatives which provedinseparable.69

O AcO

AcO

OAc AcO

O AcO

AcO AcO

AcO

Br

O AcO

AcO AcO AcO

a e

e a

O AcO

AcO

AcO

OH

e a

D8 C8

Br2/h ν CCl4-H2O 3:2

~95%

~95%

a: α-D-manno e: β-D-manno

a:D-manno e:D-gluco

Scheme 8 Bromination of glycopyranosylbenzenes in the presence of water.

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O AcO

AcO

F AcO

Br

Cl

Br

O AcO

73 in 84% yield, the a-anomer proved to be unreactive.16 O-Peracetylated2-deoxy-2-fluoro-b-D-glycopyranosyl fluoride and 1-fluoro-b-D-glycopyr-anosyl fluoride produced 74 and 75, respectively, and the latter substratewas reported to be extremely unreactive.69b-Fluorides of O-peracetylatedN-acetyl- and N-phthaloyl-D-glucosamines afforded 7626and 77,24respec-tively None of 74–77 was isolated in pure state

Br

O BzO BzO

AcO AcO

F F

Br

O AcO

R

AcO

F

Br O OAc

AcO AcO AcO

F

Br

O AcO AcO

OAc AcO

OAc F PhCOCH2O

O

Br

O AcO AcO

OAc F R

Br

O AcO

AcO F

Tetra-O-acetyl-a-D-galactopyranosyl fluoride gave 52% of 78,70and thea-D-manno derivative 79 was obtained in 53% yield.71 A phenacyl (b-D-glucopyranosyl fluoride)uronate furnished 80 (43%) selectively due to thecapto-dative nature of the C-5 centre.23 Interestingly, the formally alsocapto-datively substituted CH2moiety of the phenacyl protecting group wasnot reported to be reactive, most probably indicating the smaller radicalstabilizing capacity of the O-acyl moiety compared to the O-alkyl one.Bromination of tri-O-acetyl-b-D-xylopyranosyl fluoride allowed to isolatethe 5-bromide 81 (38%) and 5,5-dibromide 82 (19%), while the a-anomerfurnished 83 (20%).72

2.7.2 5-Thiopyranosyl bromides Antecedents:3none

Prolonged bromination of an anomeric mixture of O-peracetylated5-thio-D-glycopyranosyl bromides gave tribromide 84 in 30% yield 5-Thio-b-D-xylopyranosyl bromide afforded 90% of the anomeric dibromide 85 in ashort reaction time, while after longer treatment tribromide 86 alsoappeared among the products (containing further minor polybrominated

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compounds in yields of 4–7%) 5-Thio-a-D-xylopyranosyl bromide reactedmore sluggishly to give a mixture of 85 (45%), 86 (32%), and two otherpolybrominated compounds (B10% for the two) These findings demon-strated that the presence of sulfur in the ring activated both the C-1 and C-5positions towards homolysis, as occurred for the otherwise less reactiveequatorial C-H bonds.73

Br

S AcO

AcO AcO AcO

Br Br

S AcO

AcO AcO Br

Br

Br

S AcO

AcO AcO Br Br

of the corresponding C-5-bromides Monosaccharide derivatives with a en-2-one structural motif were brominated at the C-5 center most probablydue to a more extended delocalization of the formed radical

3-For the preparation of 2-oxoglycosyl bromides B9 by tion, the required substrates were obtained on route A9-D9-F9 (Scheme9) A high yielding method was found for the direct transformation of A9

photobromina-to B9 by using NBS in MeOH This ionic reaction replaced the radical route,and bromides B9 and C9 were extensively applied in the syntheses of variousoligosaccharides As this chemistry has been authoritatively reviewed veryrecently, the reader is kindly referred to this excellent survey.74

O O

H 2 NOH

MeCHO/H +

NBS/hν CCl4

NBS/h ν CCl 4

2.9 Substrates with bridged sugar rings

Antecedents:3O-Acetyl or -benzoyl protected 1,6-anhydro-Danoses underwent bromination with exclusive regioselectivity at the C-6centre to give the exo-bromides (e.g 87) as the sole products in the gluco,manno, galacto, ido, and talo configurations Besides exo-monobromides6,6-dibromides could also be formed from the allo, altro, and gulo isomers

-aldohexopyr-on prol-aldohexopyr-onged reacti-aldohexopyr-on times, and relevant stereochemical features allowingthis to happen were assessed The reaction was investigated with maltoseand lactose derivatives having 1,6-anhydro rings, but took a different coursefor the latter that was not brominated in the bicyclic system 1,5-Anhydro-

D-aldopentofuranoses with O-acetal or O-acyl protection gave isolated exo-bromides in each configuration

C-5-O O Br

O

O

O O

Br

O

Ac 2 N AcO

OAc AcO

O OAc AcO

MeOOC

OMe O

Later the reaction was extended to O-peracetylated derivatives to get 88and 89 of D-manno and D-galacto configuration, respectively.75 Isotopelabelled (6S)-1,2,3,4,5,6-2H-1,2,3,4,5,6-13C-1,6-anhydro-2,3,4-tri-O-benzoyl-6-bromo-D-glucopyranose was prepared in the same way.76

Bromination of bicyclicL-fucose mimics gave the less hindered bromides

9077and 91.78Compound 92 was used as an intermediate in the synthesis ofherbicidin glycosides.17

2.10 Halogenation of exocyclic methylene centres

Both pyranosides and furanosides with a phenylthio substituent attached tothe exocyclic methylene unit were chlorinated with NCS in CCl4to give C-6-(or C-5)-chlorides e.g 93 by an unspecified mechanism.79

2.11 Disaccharide substrates

Antecedents:3 Several disaccharide substrates were studied and providednice illustrations for the governing effects of the brominations Thus, 1,6-anhydro-2,3-di-O-benzoyl-4-O-[methyl(2,3,4-tri-O-benzoyl-b-D-glucopyr-anosyl)uronate]-b-D-glucopyranose was preferentially brominated at the

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C-5 of the uronate moiety, but minor amounts of the product with a secondbromine in the anhydro ring could also be isolated b-D-Maltose octaacetategave the C-5 bromide of the reducing part, and the presence of an anhydroring in the same unit of maltose directed the bromination at the C-6 in thatmoiety Disaccharides with 2-benzoyloximino groups, giving the corre-sponding glycosyl-bromides, were mentioned in Section 2.8 and this topichas been comprehensively reviewed.74

As a later example for bromination of an uronic acid containing accharide, compound 94 was isolated (64%) containing the bromide at theexpectedly most reactive capto-dative centre.29 Reaction of cellobiosylpiperidine was notified in Section 2.4.1

dis-3 Transformations of the brominated compounds

C–Br bonds are prone to reactions following both heterolytic andhomolytic pathways These possibilities have been extensively exploitedwith the brominated sugar derivatives The reactions are categorizedaccording to the above mechanistic characteristics Reactions of structurallyrelated anomeric halides of KDO and Neu5Ac derivatives will not behandled here

3.1 Ionic reactions

3.1.1 Nucleophilic substitutions

3.1.1.1 Hydride and deuteride as nucleophiles Antecedents:3The simplestnucleophile, the hydride ion (from LiAlH4) was used for reductive deha-logenations of some 5-brominated D-glucopyranosides The reactionsgave preponderantly the configurationally inverted products thusproviding an access to L-idose derivatives Reduction of 1-bromo-

D-glycopyranosyl cyanides by NaBH4 gave anomeric mixtures of thecorresponding glycosyl cyanides Deuteration of 1,5-anhydro-5-bromo-2,3-O-isopropylidene-b-D-ribose by LiEt3BD took place with very highlyselective inversion

To the best of our knowledge, no further examples of H–/D–substitutionsexist in the literature

3.1.1.2 Halogen nucleophiles Antecedents:3 O-benzoyl-4-bromo-b-D-galactofuranose gave the D-gluco configured4-fluoride with AgF in CH3CN while an epimeric mixture was obtainedwith AgBF4in Et2O Similar observations were made with 1-O-acetyl-2,3,5-tri-O-benzoyl-4-bromo-b-D-ribofuranose to give, as the major product, theinverted 4-fluoride with AgF and the retained one with AgBF4 On treat-ment with AgF, 2,3,4,6-tetra-O-acetyl-1-bromo-b-D-glucopyranosyl chlor-ide gave the corresponding 1-chloro-1-fluoro compound with inversion ofconfiguration and the 1,1-difluoride was produced by using an excess of thereagent Equilibrations of 2,3,4,6-tetra-O-acetyl-1-bromo-b-D-gluco- and -galactopyranosyl cyanides with Bu4NBr in CCl4gave mixtures containingB10% of the a-D-anomers, and this allowed to estimate a rather stronganomeric effect for the CN group

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The general trend of substituting F for Br mainly with inversion by using AgFand mainly with retention by applying AgBF4(sometimes replaced by AgFfollowed by BF3or HF) was widely observed in syntheses of various fluorides.Phenyl 5-fluoro-glucoside 95 was obtained with retention in 58% yieldfrom the corresponding 5-bromide Since the radical bromination of methylglucosides took a different course (preponderant attack at C-1, see Section2.2.1), for the preparation of methyl 5-fluoro-glucosides related to 95 analternative ionic route was also described.16 O-Peracylated 5-fluoro-b-D-glucopyranoses 96–98 with a retained configuration at C-5 were isolated in

61, 85, and 80% yields, respectively (97 was accompanied by a small amount(8%) of the 5-epimer 100) 5-Fluoride ofL-idose peracetate 99 was obtainedwith inversion at the C-5 in 76% yield.16

For D-glucosamine derivatives Br-F exchange at the C-5 could be bestachieved for the b-D-anomeric acetate with N-phthaloyl protection: theinverted 102 was obtained in 52% yield whose epimerization gave 101 (75%).Also studied were the corresponding 2,2,2-trichloroethyl b-D-glucosaminides

as well as both anomeric acetates each with N-tetrachlorophthaloyl tion, however, these gave less satisfactory results.25

protec-Reaction of AgF (1.25 equivs) with O-peracetylated 1-bromo-b-Dgalactopyranosyl chloride gave an inseparable mixture of 103 and 104 (57 :43), while 3.3 equivs gave difluoride 105.68,80

-1,5-Difluorides 106 and 107 of b-D-anomeric configuration were prepared

in 55 and 80% yields, respectively.16The 2-phthalimido compound 108 wasobtained in 16% overall yield for the Br and subsequent F substitution.24O,N-Peracetylated 5-bromo-b-D-glucosaminyl fluoride furnished the inver-ted 109 in a modest 8% overall yield for the bromination-fluorinationsequence.26L-Iduronic acid derivative 111 was obtained by AgF treatmentwith a C-5 inversion of the corresponding bromide which furnished amixture of 110 and 111 (32 and 12%, respectively) on reacting withAgBF4.23 From 5-bromides of a-D-anomeric fluorides with D-gluco and

D-galacto configurations 11216 and 11370 were obtained in 53 and 14%yields, respectively To get D-manno compounds the corresponding5-bromide was reacted with AgF to give 115 (55%) which was epimerized to

114 by BF3(55%).715-Bromo-b-D-xylopyranosyl fluoride gave 116 (28%)and the a-anomer furnished a mixture of 117 (46%) and 118 (30%).72

Trifluoro derivatives 119 (5%) and 120 (3%) were prepared by AgBF4from the 5-bromide of the corresponding 1,1-difluoro glucose in theindicated overall yields for the bromination-fluorination sequence Eachreaction was reported to be very sluggish and to give many side-products,and this bromide did not react with AgF in CH3CN From a bromina-tion mixture containing both 1- and 5-bromides of 2-deoxy-2-fluoro-b-D-glucopyranosyl chlorides only the latter reacted with AgF to give 121 (7%for the two steps) in an overnight reaction The 1-bromo-2-deoxy-2-fluoro-b-D-glucopyranosyl chloride was treated with an excess of AgF for

10 days to give 122 as an impure material 1,2,5-Trifluoride 123 of L-idoconfiguration was obtained in 28% yield in an inversion reaction elicited byAgF.69 1,5,5-Trifluoro derivative of D-xylose 124 was obtained from thecorresponding 5,5-dibromide in 59% yield.72

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O AcO

OR

F RO

O OAc

AcO AcO AcO

O RO RO

AcO

OAc F PhCOCH2O

O

O AcO

OAc

F

F PhCOCH2O O

F

O AcO

AcO AcO

O OAc

AcO AcO AcO

O AcO AcO

OAc AcO

O AcO AcO OAc

AcO

F

F

O AcO

OAc

F

F

O AcO AcO F

115 (AgF)

O AcO AcO AcO F

F

F

O AcO

AcO

AcO

F F

O AcO AcO AcO

F

F AcO

F

O AcO

AcO

F

F

Cl AcO

O AcO AcO

F

AcO

F F

O AcO AcO

OAc F F

Halogen substitutions in 1-bromo-D-glycopyranosyl cyanides were alsostudied (Scheme 10) Under kinetic conditions (18 h, rt) LiCl converted A10(D-galacto configuration) to a mixture of B10 and C10 (70 : 30) whichreached an equilibrium ratio of 15 : 85 in one week.81Treatment of theD-galacto configured A10 with AgF gave, expectedly, the inverted fluorideD10, while its reaction with AgBF4 furnished the retained fluoride E10.Transformation of B10 with AgF needed forcing conditions to give E10.Reactions A10-D10 were also performed with D-gluco, D-xylo, and

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D-arabino configured substrates, and the conformational equilibria of thepentose derivatives were examined.82

From the reaction of O-peracetylated C-(1-bromo-b-Danosyl)formamide with AgF in CH3CN the inverted fluoride 125 was iso-lated inB3% yield The major product of this transformation was formed

-galactopyr-by solvent incorporation, and this will be discussed in Section 3.1.1.5

O OAc

AcO AcO AcO

CONH2F

O BzO

BzO OBz F

5-Acidic hydrolysis of crude bromoiminolactones furnished lactones 127–131 (overall yields for bromination-hydrolysis).83

glycono-O AcO Br CN

A10

O AcO CN Cl

B10

O AcO Cl CN

C10

O AcO CN F

D10

O AcO F CN

E10

+LiCl

Scheme 10 Halogen exchange reactions in 1-bromo-glycosyl cyanides.

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O O

O R

O O O

O

O AcO

AcO

O AcO

AcO

O AcO

pre-O OAc

AcO

R AcO

R 2

AcO AcO

141 R1 = CN, R 2 = OAc (22%)

142 R1 = OAc, R 2 = CN (53%)

O 4-Cl-BzO

4-Cl-BzO

CN O

NO2

143 (70%)

O-Acyl protected C-(1-bromo-D-glycopyranosyl)formamides and mates (Scheme 11, C11 and D11, respectively), were reacted with severalO-nucleophiles using silver(I) salts as promoters in most cases Hydrolysis

-for-of the respective bromides resulted in ulosonamides A11,45,84 and methylulosonates B11.22 Alkyl glycosides E11 were obtained from C11 withalcohols (R=Me, Et, nBu, tBu, Bn),85while for promoting transformationsD11-F11 (R=Me) Hg(CN)2-HgCl2 was used.64 Phenolate salts reactedwithout promoters to give E11 (R=2- and 4-NO2-C6H4),85 or were gen-erated in the reaction mixture by using K2CO3 in acetone to yieldF11 (R=2-NO2-C6H4and 5-MeO-2-NO2-C6H3).53When C11 was reacted

in acetone, the solvent behaved as the nucleophile and incorporated inthe products G11 (o10%) and H11 (W70%) A probably similar incor-poration of DMSO followed by a Pummerer-type rearrangement gavecompounds I11.84

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Hydrolysis of 1-bromo-glycosyl-benzenes was mentioned in Section 2.6.2.Alcoholysis of 5-thio-xylopyranosylidene dibromide gave 144 (R=Me,

Et, allyl) in 70–90% yields.73

2-Acyloximino-glycosyl bromides were extensively used in tions.86–88Details of this chemistry can be found in a very recent compre-hensive review.74

glycosyla-S AcO

AcO OR

O HO

AcO OAc

OAc

O O AcO

OAc OAc

OAc

O AcO

AcO

OAc OAc

O X

AcO

OAc OAc

OH O

147.89 Both hydrolysis and methanolysis of the corresponding bromidesgave the substituted products 148,77 149, and 15078 with retention of theconfiguration The lactol ring of the hydrolysed product 151 opened up tothe aldehyde which was oxidized to the corresponding carboxylic acid used

in the synthesis of herbicidin glycoside.17

3.1.1.4 S-Nucleophiles Antecedents:3 O-Peracetylated 5-bromo-b-Dxylopyranose was transformed to the 5-acetylthio derivative with inversion

-at C-5 1,6-Anhydro-6-bromo-glucopyranose was converted to the inverted6-phenylthio compound 1-Bromo-b-D-glycopyranosyl cyanides gave thio-glycosides with 2-amino-thiophenol and glycosylidene-spiro-perhydro-1,4-thiazine derivatives with 2-amino-ethanethiol

O AcylO Br COX

O AcylO COX OR O

AcylO

OH COX

O AcylO

O O

OCH 2 SCH 3

I11

+

Ag 2 O, H 2 O DMSO

Tetraacetate of 1-bromo-b-D-galactopyranosyl cyanide was reacted withAgSCN or KSCN in refluxing CH3NO2to give a 6 : 4 mixture of 152 and

153 (combined yield 75%),90and the transformation was extended to the

b-D-gluco, b-D-xylo, and a-D-arabino configured substrates, too.91Formation

of isothiocyanates was not observed in these reactions Equilibration in thepresence of Bu4NCS in CCl4resulted in 152 and 153 in 46 : 54 ratio Thisallowed to calculate the anomeric effect of the SCN substituent, which wascorroborated by X-ray crystallographic measurements of the bond lengthsand angles around the anomeric centres.91 Reaction of O-perbenzoylated1-bromo-b-D-ribofuranosyl cyanide and thiourea in refluxing sulfolane-EtOH mixture followed by acidic hydrolysis furnished 37% of 154.56Ana-logous reaction of O-perbenzoylated b-D-glucopyranosyl cyanide could not

be elicited, however, C-(1-bromo-b-D-glucopyranosyl)formamide reactedwith thiourea to give the spiro compound 155 (82%).92The same substrateand thiophenols in acetone in the presence of K2CO3gave thioglycosides 156(R=Ph, 2-pyridyl, 2-benzothiazolyl) in more than 70% yields.85 5-Thio-xylopyranosylidene dibromide gave 157 (91%) with ethanethiol.73

O OAc

AcO

AcO CN

O OAc

AcO

AcO SCN

O HO

NH S O

O

O BzO

BzO BzO

BzO N S

O

NH

O BzO

SR BzO

BzO CONH 2

S AcO

AcO SEt SEt

3.1.1.5 N-nucleophiles Antecedents:3 Replacement of the bromide intetra-O-acetyl-5-bromo-b-D-xylopyranose was achieved by azide ion and apurine derivative

Sporadic reports can be found on direct substitution by amines in thebrominated compounds Thus, by treatment with an excess of aniline, therespective O-peracylated C-(1-bromo-b-D-glycopyranosyl)formamides gave

158 (55%) and 159 (75%) with an inversion of the C-1 configuration.85Reaction of the corresponding bridged bromo derivative with anilines,followed by removal of the O-acetyl protecting groups, furnished amines

160 (R=H 93%, 4-MeO 67%, 4-NO2 29%) with a retention of uration.78 In many cases amines were obtained by reduction of azides asindicated in the next paragraphs

HO

OH OH

NHC 6 H 4 R

H 3 C

O

N3AcO

Azide substitution of the bromo derivatives (generally by NaN3 orsometimes with LiN3in DMF or DMSO at rt) was studied very extensively,and took place almost always with inversion of the configuration of therespective reaction centre Phenyl 5-bromo-b-D-xylopyranoside triacetategave 161 (45%) which was then oxidized to the corresponding nitroderivative.29

Azide replacements in O-acyl protected 1-bromo-D-glycopyranosyl nides,81 (Scheme 12, A12, configurations: b-D-gluco, b-D-galacto, a-D-arabino), gave the inverted products C12 in very short reaction times It wasshown (with the b-D-galacto substrate) that in prolonged reactionscycloaddition of the azide ion to the nitrile moiety also occurred providingtetrazole D12 with the same configuration as that of C12 In case of the b-D-mannosubstrate no defined product could be isolated, but the formation of

cya-a 5-(1-bromoglycosyl)tetrcya-azole wcya-as mcya-ade likely In the recya-action of the b-Dxylo substrate, parallel formation of the epimeric C12 and E12 wasobserved, and mechanistic studies were carried out to explain this finding.Due to the generally inverting nature of the azide substitution, compoundsE12 could be obtained from chlorides B12 Longer reaction times led to thecorresponding tetrazoles D12 in these cases, too The azido nitriles gaveoxazepine derivatives in photochemical ring enlargement reactions,93,94andwere studied together with several other glycosyl azides by CD spectroscopyfor their conformational peculiarities.95

-From O-peracylated C-(1-bromoglycopyranosyl)formamides azides 162–

165 (primary amides also with theD-arabino configuration51) were produced(Table 5)

A large array of azides was prepared from anosyl)formates (e.g 166–171 in Table 5) Compound 170, on treatment byZn/N-methylimidazole to remove the trichloroethyl protection,96 gave ananomeric a-azido acid derivative, while with Zn/AcOH furnished a con-figurationally labile anomeric a-amino acid.22 Azides 172–178 wereobtained from the non isolated bromides listed in Table 4, and were used forthe syntheses of anomeric spirocycles and oligopeptides incorporatinganomeric a-amino acids Anomeric a-azido acid azide 179 was prepared bybromination and subsequent azide substitution of the correspondinganhydro-aldonoyl chloride, and used further to get dipeptides

C-(1-bromo-glycopyr-O AcylO Br CN

A12

O AcylO CN Cl

B12

O AcylO CN

N 3

C12

O AcylO

N 3

CN

E12

LiCl DMSO, rt

NaN3DMSO

NaN 3

DMSO

O AcylO

N3

D12

N N

NH N

Scheme 12 Azide substitution in 1-bromoglycopyranosyl cyanides.

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O-Acetyl protected 1-bromo-b-D-glycopyranosyl chlorides gave zido derivatives 180 by using the usual reagents or in higher yields (D-gluco:82%, D-galacto: 65%,D-manno: 36%) under phase transfer catalytic con-ditions.97 These compounds facilitated among others anomeric carbenegeneration98,99 and synthesis of unusual 6,7-dihydropyrano[3,4-d]-1,2,3-triazoles.100

1,1-dia-The corresponding bridged bromo derivatives gave azides 18177 (94%)and 18278(56%) 181 was reduced to the corresponding amine which wasfurther acylated by some acid chlorides.77

O AcO

OAc

N3AcO

O X

AcO

OAc OAc

Table 5 Selected examples of isolated C-(1-azido-glycopyranosyl)formic acid derivatives.

TBSO

CO2Me OTBS

17259 (65%)∗

O OTBS

OTBS

CO2Me

N3

O O

17311,60,61 (71%)∗

O N3

CO2Me O

O

17411 (55%)∗

O TBSO

TBSO

TBSO

CO2Me N

CO2Me

N3O

H3C HO

17922 (60%)∗

O OAc

AcO

N3AcO

* Overall yield for bromination and azide substitution.

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products of these reactions had inverted configuration at the reactioncentre Mechanistic studies were carried out to explain these findings.45Hydantoins (D-gluco,45,102 D-galacto,51 D-arabino,51 and D-xylo45) andthiohydantoins (D-gluco,12,45,46,102 D-galacto,51 D-arabino,51 D-xylo,45 and

L-rhamno52) were prepared in the indicated configurations

Silylated thymine was reacted, as an N-nucleophile, with the sponding bromo compounds to give derivatives 18357 (56%) and 18455(69% for the mixture, the epimers could be separated), which were con-verted further to functionally modified oligonucleotides.55

corre-O BzO

BzO OBz N H

CN

O 4-Cl-BzO

4-Cl-BzO

CN N

O AcylO

D13

N H

O AcylO

O

O O O

O AcylO

C13

N H

O

S

O AcylO Br CONH2

AcO AcO AcO

Br

OAc

AcO AcO AcO

NR 1

R 2

O OAc

AcO AcO AcO

NHCOR 2

CN

O OAc

AcO AcO AcO

amides A14 (R1=H) were transformed, probably via intermediate B14undergoing a tautomeric ring opening and a further tautomerization, intoC14 Compounds of type C14 were obtained in D-gluco and D-arabinoconfigurations, as well (R2=CH3, CH3CH2, CH2=CH, CH2=CHCH2,(CH3)3C, CH3OCH2).103 Reactions of substituted amides A14 (R16¼H)stopped at B14 which could be isolated and opened by a mild acidichydrolysis to give peptides D14 incorporating anomeric a-amino acids (e.g.

R1=CH2CO2Me, R2=CH2NHCO2Bn).104

3.1.1.6 C-nucleophiles Antecedents:3none

O O R

OAc

OAc OAc

185

6-Bromo-1,6-anhydro-D-mannose triacetate was reacted with methylsilylated carbon nucleophiles in the presence of AgOTf in CH2Cl2togive 185 (R=allyl, phenylethynyl, hept-1-ynyl, allenyl) in 47–63% yields Intoluene 185 (R=4-Me-C6H4) was obtained while with other aromatic reac-tion partners iPrCN proved the best solvent to yield 66–76% of 185(R=2-MeO-5-Me-C6H3, 2,5-di-MeO-C6H3, 2-furyl).105

tri-3.1.2 Eliminations Antecedents:3 The O-peracetylated bromosugarderivatives were prone to HBr eliminations elicited by bases (generallyDBU) or to reductive eliminations induced by a metal (almost exclusively Zn

in AcOH) Thus, 5-bromo-uronates and 5-bromo-b-D-xylose gave the responding 4-acetoxy- or 4-deoxy-hex-4-enopyranuronate and 4-acetoxy- or4-deoxy-pent-4-enopyranose derivatives, respectively In the case of 5-bromo-hexopyranoses the elimination may form endo- and exocyclic double bonds.Thus, from 5-bromo-b-D-glucopyranose esters, HBr elimination gave theendo-alkene, while Zn/AcOH led to the exo-methylene derivative as the mainproducts Interestingly, with the same substrate, endo elimination of HBrtook place instead of substitution with NaCN, NaOBz, or CsF, however,NaSAc or NaI furnished the unsaturated products in exo sense Followingthese lines a 5-exo-methylene derivative could be obtained from the reducing-end 5-bromide of octa-O-acetyl-maltose by Zn/AcOH In b-D-gluco- or -galactofuranose peresters 3,4-endo double bonds were formed by DBU, andreductive elimination furnished the 4-exo-alkenes Acetylated 1-bromogly-cosyl cyanides gave 1-cyano-2-acetoxy-glycals with DBU, but cleaner trans-formations were induced by Hg(CN)2/AgOTf, and aldonolactones wereisolated on treatment by Hg(OAc)2 in DMSO Reductive elimination wasperfomed with Zn in refluxing benzene in the presence of Et3N or pyridine toyield 1-cyano-glycals Reaction of O-peracetylated 1-bromo-b-D-glucopyr-anosyl chloride with DBU or DABCO gave the 1-chloro-2-acetoxy-glucal.Unsaturated uronate 186 was obtained by DBU from the corresponding5-bromide.31 Formation of unsaturated phosphonic esters 187 (76%) and

cor-188 (72%) was brought about by Zn/Cu in EtOH.27The Zn/N-base method

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for reductive elimination was extended to prepare anosyl)formamides (e.g 18950 70% by Zn/N-methylimidazole in refluxingEtOAc) and -heterocycles (e.g 19010638% by Zn/Py in refluxing benzene).Based on these experiences, a general method107 was elaborated for thepreparation of glycals108 from the corresponding O-peracylated glycosylbromides that can be regarded as the aprotic variant of the classical Fischer-Zach synthesis of glycals Mechanistic studies were also disclosed.109

C-(hex-1-enopyr-DBU induced elimination of HCl from 3-(1-chloro-b-Danosyl)propenes produced glycosylidene-butadienes 191 (D-gluco 42%,

-glycopyr-D-galacto 46%,D-manno 45%).110Elimination of HBr from 1-bromo-b-Dgalactopyranosyl chloride by DABCO gave 192 in 33% yield Attemptedreductive elimination to get a 1-chloro-glycal failed under several condi-tions: the only isolable product was tri-O-acetyl-D-galactal.68 From thecorresponding 1,1-dibromide 1,5-anhydro-1-bromo-5-thio-D-threo-pent-1-enitol triacetate (193, 96%) was obtained by DBU.73 Unsaturateddisaccharide 194 was obtained by DBU in DMF in 75% yield.29 Exo-methylene derivative 195 (72%) was prepared from 4-bromo-D-fructofur-anose pentabenzoate by the Zn/N-methylimidazole method in refluxingEtOAc, and used further for polymerization studies.36

-O OAc AcO OC6 H2Cl3(2,4,6)

D

MeOOC

O AcO

AcO AcO

PO 3 Et 2 AcO

O AcHN

CONH 2

O OAc AcO AcO

S N

O AcO

AcO

OAc

AcO

O OAc AcO AcO

Cl OAc

S AcO

AcO

Br OAc

O

Ac2N AcO

OAc AcO

O OAc

Tributyltin-Carbohydr Chem., 2013, 39, 1–37 | 27

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isomers of the corresponding uronic acid derivatives with isolated yields inthe range of 44–64% and 28-38%, respectively With a 4-deoxy derivative,theD-gluco compound was formed almost quantitatively, and retention ofthe C-5 configuration was also very high starting with aD-galacto substrate.Under similar conditions 1-bromo-b-D-glycopyranosyl cyanides gave mostlya/b mixtures (D-galacto 4 : 6,D-arabino 2 : 8,D-manno b only) of the corre-sponding glycosyl cyanides These findings indicated the outstandingimportance of the neighbouring substituent in governing the reductions 1,5-Anhydro-5-bromo-pentofuranose and 1,6-anhydro-6-bromo-hexopyranosederivatives including disaccharides were deuterated in this way at C-5 andC-6, respectively, with very high (often exclusive) stereoselectivities Thisallowed to establish conformational preferences around the C-5–C-6 bond ofpyranoid compounds by NMR spectroscopy Reduction of 5-bromo-5-cyanoethyl-b-D-xylopyranose gave theD-gluco configured product.

Phenyl 2,3-di-O-acetyl-5-bromo-4-deoxy-4-fluoro-b-Duronic acid was deuterated by Bu3SnD to give a B1 : 1 mixture of the

-glucopyranosid-D-gluco and L-ido epimers from which 196 could be isolated in only 5%yield.30Contrary to that of the b-anomer, reduction of methyl 1,2,3,4-tetra-O-acetyl-a-D-glucopyranuronate with Bu3SnH gave the D-gluco and L-idoisomers in 1 : 3 ratio and 197 was prepared in 67% yield.33,34Deuteration of4-bromo-D-ribofuranose tetraacetates gave 1 : 4 mixtures of 198.35Reduction

of non-isolated 1-(2-cyano- or 2-phosphonoethyl)-1-chloro-Danosyl derivatives gave 199 and 200, respectively, thereby providing access tob-D-configured C-glucopyranosyl alkane type compounds.111Reaction of 3-(1-chloro-b-D-glycopyranosyl)propenes with Bu3SnH resulted in the for-mation of C-allyl glycosides 201 (D-gluco 50%, D-galacto 51%, D-manno57%).1101,5-Anhydro-L-rhamnulose 202 was prepared by reduction of thecorresponding ulosyl bromide in 71% yield.112 Isotope labelled (6R)-1,2,3,4,5,6-2H-1,2,3,4,5,6-13C-1,6-anhydro-2,3,4-tri-O-benzoyl-D-glucopyr-anose was prepared by Bu3SnH treatment of the corresponding 6-bromide.76

-glucopyr-O F

D OAc

HOOC

O MeOOC OAc OAc

OAc OAc

O OAc AcO

AcO OAc D

O AcO

AcO AcO

AcO

AcO AcO

OAc

AcO

O

H 3 C BzO

to brominated sugars are illustrated in Scheme 15 Thus, as shown in route

a, radicals Rdmay add to alkenes (C-1 or C-4/5 sugar radicals are renderednucleophilic by the ring oxygen, therefore, ideal partners are electron defi-cient olefines with X=electron withdrawing group) and subsequenthydrogen abstraction gives the alkylated product Route b shows reactions

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