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Minireview Recent Developments of Ionic Liquids in Oligosaccharide Synthesis. The Sweet Side of Ionic Liquids M. Carmen Galan, Rachel A. Jones, Anh-Tuan Tran PII: DOI: Reference: To appear in: Received Date: Revised Date: Accepted Date: S0008-6215(13)00139-0 http://dx.doi.org/10.1016/j.carres.2013.04.011 CAR 6454 Carbohydrate Research 21 February 2013 9 April 2013 10 April 2013

Please cite this article as: Carmen Galan, M., Jones, R.A., Tran, A-T., Recent Developments of Ionic Liquids in Oligosaccharide Synthesis. The Sweet Side of Ionic Liquids, Carbohydrate Research (2013), doi: http://dx.doi.org/ 10.1016/j.carres.2013.04.011

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Recent Developments of Ionic Liquids in Oligosaccharide Synthesis. The Sweet
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Side of Ionic Liquids. M. Carmen Galan,a* Rachel A. Jonesa and Anh-Tuan Trana,b
a b

School of Chemistry, University of Bristol, Bristol BS8 1TS, UK Current Address: Institut Parisien de Chimie Moléculaire, Université Pierre et Marie Curie , 75252 Paris Cedex 05

*Corresponding author: Tel: +44(0)1179287654; Fax: +44(0)1179298611; E-mail:M.C.Galan@bristol.ac.uk Keywords: Carbohydrates Oligosaccharide synthesis Glycosylation at room temperature Ionic liquids Supported oligosaccharide synthesis

Abstract The area of ionic liquid (IL) research has seen tremendous growth over the last few decades. The development of novel ILs with new and attractive physical and chemical properties has had a direct impact on organic synthesis. In particular, ILs have had many applications in carbohydrate chemistry including their use as solvents for dissolving high molecular weight carbohydrate polymers such as cellulose and as solvents and catalysts in oligosaccharide synthesis. In this area, ILs have been involved in protecting group manipulation reactions as well as glycosidic couplings leading to new methodologies and enhanced procedures. In addition, ILs have been successfully utilized as solution-phase purification supports. This review focuses on the most recent advances in the application of ILs to oligosaccharide synthesis. This is an emerging area that offers great promise at addressing some of the obstacles that remain on the path towards the automation of oligosaccharide synthesis.

1. Introduction Carbohydrates are one of the most diverse and important classes of biomolecules in nature. Oligosaccharides found on the surface of cells as part of glycoproteins and glycolipids play key roles in the control of various normal and pathological processes 1

4-7 While the methods differ on the nature of their approach. scientists can develop diagnostic tools to identify diseases at an early state when treatment is more likely to be effective. If we are to understand glycan diversity and function. One of the main difficulties in the automation of oligosaccharide synthesis is the requirement for purification after each reaction step. fertilization. Researchers have endeavoured to circumvent the issue by developing one-pot synthetic strategies whereby multiple glycosylation reactions can be performed in a single reaction vessel. masking of immunological epitopes. The nature of cell-surface carbohydrates can differ considerably between sick and normal cells. neural development and cell proliferation and organization into specific tissues. they all share the identical goal of making carbohydrates more accessible to mainstream chemists and biologists. It is not surprising then that much effort has been devoted over the last twenty years towards the development of oligosaccharide methodologies that can be automated. target-oriented lengthy chemical syntheses or enzymatic approaches. reducing the number of purification steps. if unique glycan markers for diseased cells are found. as it has had to rely either on isolated materials. approaches to prepare diverse libraries of complex carbohydrates in a rapid manner are greatly lacking and that has had a detrimental effect on the progress of glycobiology research.8 Supported oligosaccharide syntheses have been developed as a viable alternative to traditional methodologies.1-3 It is the multitude of biological roles carbohydrates and their glycoconjugates play. where purification is simplified by the use of a covalently attached purification label to either the glycoside donor or acceptor and which allows 2 . it is essential to have access to oligosaccharides in sufficient purity and quantity to be able to carry out biological studies. although instrumental to the coding of biological information in intra. develop vaccines or novel drugs that could inhibit the interaction of those glycans with their binding partners. For instance. However.and intercellular recognition processes (Glycocode).in living organisms. bacterial 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 adhesion. makes isolation of pure samples and in sufficient amounts from biological sources extremely difficult. viral infection. embryogenesis. Chemical synthesis offers the advantage of producing pure and structurally defined oligosaccharides for biological investigations. cell-cell communication. which is normally accomplished by chromatography. which has stimulated scientists to devote their efforts to determine the mechanisms of interaction involved in both healthy and disease processes. such as protein folding.4 Glycan heterogeneity.

Solid and soluble polymers supports. R = hydrocarbon residue.4 A) O PO Linker LG OH Activation Linker O OP Deprotection Linker O OH O PO LG Activation RO O O O OP Linker Linker Cleavage O O O OP B) O HO Acceptor 1 OR Activation of 1: IL. fluorous tag. General schematic representation for common oligosaccharide assembly strategies: A) Supported phase oligosaccharide assembly on a polymer resin. DCM LG OH R. fluorinated labels. ILs are a new class of solvents which have attracted growing interest over the past few years due to their unique physical and chemical properties for a broad number of synthetic and enzymatic applications. P = temporary protecting groups. AO O Product Activation of 2: NIS + TMSOTf Solvent evaporation Product extraction and purification IL O AO O O O OR 'Armed' Donor 2 O DO LG O OD 'Disarmed' Donor Figure 1. LG = leaving group. The glycan units are attached by means of a linker to the support and the cycle consists of activation and deprotection steps. The nature 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 of the purification label differs from approach to approach.9-15 ILs consist of poorly coordinating ion pairs with physical and chemical properties that can be tuned by altering the cation or the anion structure. ILs have had many applications 3 .for chromatography-free isolation of the product after each reaction step. NIS. D = disarming protecting group.16 In particular. A = arming protecting group. B) Reactivity-based one-pot glycosylation synthesis.15.T. ionic-liquid-based tag or gold sticks. The last few decades have seen an explosion of research in the field of ILs applied to organic synthesis with some ILs able to act as recyclable catalysts as well as reaction media in organic reactions. Finally the linker is cleaved to procure the desired oligosaccharide. gold platforms and more recently ionic liquids (ILs) have been used within this strategy.

changes in the diastereoselectivity of the reactions have been observed when ILs were used as reaction media. facilitating a wide range of chemical transformations.18 Additionally.23 Subsequently. including acetylation. ortho-esterification. carbohydrate scaffolds have been used as a source of ILs and chiral ILs. A greater degree of β-selectivity was achieved when the reaction was 4 . reactions in ILs have kinetic and thermodynamic behaviour different from classical solvents. when [bmim][PF6] was used as the solvent in the presence of catalytic TMSOTf. mainly cellulose. benzylidenation and glycosylation reactions of carbohydrates. 2. in 2011 Afonso and co-workers discussed the application of ILs in carbohydrate dissolution. the group of Poletti reported that the stereoselectivity outcome of reactions with trichloroacetimidate glycoside donors bearing a nonparticipating group at C-2.20-24 The high polarity of ILs can provide strong accelerating effects to reactions involving cationic intermediates and as a result. this review will only describe the most recent developments in this particular area over the last few years. In the context of glycosylation reactions. for further processing17 and as solvents and catalysts in protecting group manipulation reactions as well as glycoside couplings leading to new methodologies and enhanced procedures and also as purification supports to simplify purification. For instance. ILs have been shown to exhibit excellent solubilising properties.25 The use of ILs as solvents for the transformation of carbohydrates was first reviewed by Linhardt in 2005. no anomeric selectivity was observed.19 This review will focus on the most recent advances on the application of ILs in oligosaccharide synthesis.in carbohydrate chemistry including their use as solvents for dissolving high 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 molecular weight oligomers. α-glycosides were favoured. in different ILs as solvents and using catalytic TMSOTf as promoter. Ionic Liquids as solvents in oligosaccharide synthesis. This is an emerging area that offers great promise at addressing some of the obstacles that remain on the path towards the automation of oligosaccharide synthesis. was significantly affected by the reaction media. whereas when [emim][OTf] was used as the solvent in the presence of the Lewis acid. which often leads to improved process performance. the catalyst and by the anomeric configuration of the donor.18 Therefore.26 In their report.

Treatment of peracetylated glycosides with aryldisulfide in the presence of Et3SiH and BF3.28 In the case of unprotected glycosides. This can be rationalized by a mechanism in which the glycosylation occurs via an oxocarbenium ion that can be stabilized by the IL. A range of ILs were screened and [bmim][BF4] was found to be the most suitable IL. When [1-hexyl-3-methyl][NTf2] was used as the solvent then β-glycoside products were favoured. B) Glycosyl phosphites.27 Interestingly. yielded thio-arylglycosides in good to excellent yields (80 – 90%). by formation of a transient α-glycosyl triflate that yields predominantly β-glycoside products (Scheme 1.and β-trichloroacetimidates suggested that triflated-based ILs participate in glycosylation reactions. These results were independent of the anomeric configuration of the glycoside donor (Scheme 1. the α-product was preferred.‟s observations when using glucopyranosyl diethyl phosphite as glycosyl donors in the presence of catalytic amounts of a protic acid when an IL was the solvent. when the same group used glucopyranosyl fluorides as glycoside donors in the presence of [1-hexyl-3-methyl][NTf2] and a protic acid (HNTf2). A). IL effect on the stereoselectivity of the glycosylation reaction: A) Trichloroacetimidate glycoside donors. reactions proceed under thermodynamic conditions. glycosylations in ILs tend to give products with increased α-selectivity.22 A BnO BnO B BnO BnO OBn O OBn C BnO BnO a:b 76 : 24 45 : 55 20 : 80 OBn O OBn OH O CCl3 NH BnO Lewis acid BnO IL. Their 1H NMR studies on protected glucoside α. RT ROH HNTf 2 OP(OEt) 2 [hexmim][NTf ] 2 OBn O OBn IL O [bmim][PF 6] [emim][OTf] [emim][OTf] OBn O OBn Lewis acid TMSOTf TMSOTf none BnO BnO OR b favoured OBn O OBn F ROH HNTf 2 [hexmim][NTf 2] BnO BnO OBn O BnO OR a favoured Scheme 1.24 A recent example on the use of ILs as solvents has come from the lab of Misra et al. The key advantages of the 5 . C) Glycosyl fluorides. thus favouring α-glycoside formation. B and C). 30 who reported the use of ILs as solvents for the facile preparation of thioglycosides (Scheme 2).OEt2 at room temperature in [bmim][BF4].29 At higher temperatures.performed with [emim][OTf] in the absence of the Lewis acid and when the starting 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 trichloroacetimidate was in the β-anomeric configuration. These results are in agreement with Toshima et al.

34 More recently.11 The conditions are mild. It was subsequently shown that [bmim][BF4] could be used as a recyclable solvent for the BF3·OEt2 assisted thioglycosylation of peracetylated glycosides using aryl thiols. Misra and colleagues also showed that the optimised conditions were also applicable to the synthesis of selenoglycosides. low temperature and molecular sieves are required. and compatible with a range of hydroxyl protecting groups. Glycosidic bond formation is a crucial step in oligosaccharide synthesis. AcO O RS -SR or RSe -SeR OAc Et 3SiH. Tol.and stereocontrol. acetals. uses of ILs in the area of oligosaccharide synthesis have emerged.31 3. There are currently many applications of ILs as solvents in chemistry. such as acetates.32 ILs offer an interesting alternative to traditional reagents.33. A great deal of research has been devoted to finding improved reagents for performing glycosylations with the best yields and with complete regio.e. reported the first application of [bmim][OTf] as a mild and versatile IL co-solvent and promoter for the room temperature glycosylation of both thiophenyl and trichloroacetimidate glycoside donors (Scheme 3).and selenoglycosides using [bmim][BF4] as the solvent at room temperature. BF 3. Ionic Liquids as co-solvent/promoters in glycosylation reactions. phthalimido 6 .20-22.protocol is that chlorinated solvents such as CH2Cl2 can be avoided and that the IL 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 can be recycled and re-used up to four times without any significant losses in yield and selectivity. benzyl ethers. pNP Scheme 2: One-pot preparation of thio.27.35 Galan et al. to identify reliable glycosylation promoters that can be generally applied to oligosaccharide synthesis and that are applicable to both laboratory and industrial scale preparation. using aryl diselenides in place of aryl disulfides.5 There is still a need however. with some able to act as recyclable catalysts as well as reaction media in organic reactions. Naph. They are also amenable to NH2 masking strategies i.12. typically. Traditional glycosylation reagents tend to suffer from several drawbacks. resulting in the rapid formation of a range of selenoglycosides in good to excellent yield (70 – 90%). The ocurrence of side reactions with by-products resulting from the use of promoters is also another limitation.OEt 2 [bmim][BF 4] AcO O 80-90% SR or AcO O 70-90% SeR R = Ph.

glycosylations with activated thioglycosides bearing non-participating groups at C-2 showed an increase in α-glycoside products in comparison to reactions carried out using TMSOTf at low temperatures (Table 1). while less active (disarmed) donors required the addition of catalytic triflic acid. while modifications at R2 had an effect on the rate of glycosidic bond forming reactions. the ability to recycle the IL promoter is very attractive in terms of green chemistry. and in general the ability of ILs to promote 7 .t. In their examples. LG = OC(NH)CCl3 Recycling IL -OTf O Product OR IL Solvent evaporation Product extraction IL Acceptors (R OH) O R= N N+ Br Ph O O OO Ph O O O SPh NP P=HTroc P=Phth Scheme 3: Glycosylations of thioglycosides and trichloroacetimidate donors using [bmim][OTf] as the co-solvent and glycosylation promoter at room temperature. Initial mechanistic studies suggested that [bmim][OTf] can facilitate glycosylation reactions by the slow release of catalytic amounts of triflic acid and that the IL also protects the newly formed glycosidic linkage from hydrolysis. Furthermore. Interestingly.11 Those experiments further demonstrated the importance of the choice of counter ion when choosing an IL to promote this type of glycosidic bond forming reaction. Studies from the same group explored the scope and limitations of imidazoliumbased ILs by generating a series of substituted imidazolium ILs 1a-n. It was shown that imidazolium based ILs bearing triflate or triflimide counter ions serve as room temperature selective glycosylation promoters for armed thiophenyl glycosyl donors. Galan‟s results also demonstrated that the stereoselectivity of the glycosylation reactions was significantly affected by the IL. For example.11. BnO NIS O BnO ROH LG = SPh BnO O LG OR + Activated Donor IL /CH2Cl 2 TMSOTf Product r.(Phth) and trichloroethoxycarbonyl (Troc).36 Using ILs to promote these type of reactions offers several advantages over other traditional promoters. with differing R1 and R2 groups and a range of counter ions (X-) and testing their effectiveness in glycosylation reactions (Scheme 4 and Table 1). The team also showed that the triflated IL 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 could selectively promote activated (armed) thiophenyl and trichloroacetimidate glycosyl donors. substitutions at R1 of the imidazolium cation did not have an effect on the reactivity or diastereoselectivity of glycosylations with thioglycoside donors.

R2=H. X=OTf R1=Me. R2=H. R2=H. R 2=H. X=HSO3 R1=CH2COOH.)/DCM Room Temp. X=N(Tf)2 R1=Me.and 8 . Galan et al. R2=Ph.67/1 Reaction time.14 showcased the versatility of the IL/NIS promoter in a series of regio. R2=H. X=OTf 1m R1=Me. X=OTf 1n R1=Me. Representative examples of glycosylation reactions with screened ILs OBn O OBn BnO BnO OBn O OBn O SPh + O OH O OO Promoter NIS(2 equiv. X=OTf O RO RO OR O SPh OH O 1k R1= . X=Br R1=Me. R2=H. R2=CH3. R2=H. Glycoside Acceptor RO O LG ROH NIS IL/ DCM room temp. h 3 3 2 1 Having demonstrated that the [bmim][OTf]/NIS system was excellent for activating armed thioglycoside donors in the presence of disarmed thioglycosides. X=OTf 1l R1=Me. X=Cl R1=Me. X=N(Tf)2 Scheme 4: Screening of ILs (1a-1n) as the co-solvent and glycosylation promoter at room temperature in glycosylation reactions with thioglycosides. X=BF4 R1=Me.75/1 0.78/1 0. R2=H. BnO O OR Product Glycosyl Donor Ionic Liquids (ILs) XN + N R1 2 R2 Thioglycoside Donnors OR O SPh OR R=Bn R=Ac OR RO OR R=Bn R=Ac Glycoside Acceptor O O OO 1a 1b 1c 1d 1e 1f 1g 1h 1i 1j R1=Me. X=BF4 R1=CH2COOH. BnO BnO O O O O OO Entry 1 2 3 4 Promoter TMSOTfb 1a 1l 1m Yield % 75 97 90 72 Ratio α/β 0. Table 1. R2=H. R2=H. R 2=H. R2=Ph. X=AlCl4 R1=Me. X=PF6 R1=Me.02/1 0.glycosylation reactions at room temperature is amenable to cost effective automated 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 oligosaccharide synthetic protocols where no strict control of low temperatures will be required.

Many of these one-pot convergent approaches are based on the selective activation of one glycosyl donor over another. r. A) or in a strategy where all the components were mixed together in one vessel at the beginning of the synthesis (Scheme 5. The resulting product became the glycosyl acceptor in the following step. Branched and linear trisaccharides 2 and 3 were synthesized following a one-pot glycosylation reaction where partially protected „armed‟ monosaccharide glycoside. whereby the reactivity of the building blocks is tuned by the choice of protecting groups. NIS HO BnO OH O BnO OMe 4 NIS [bmim][OTf] CH 2Cl 2.3/1) Scheme 5. which was reacted directly with less reactive glycoside donor 6 under TMSOTf/NIS catalytic conditions. BnO BnO OBn O O OBn OAc O OAc O BnO 2 29% (0. r. it was demonstrated that the mild IL/NIS promoter system can be used for room temperature reactivity-based one-pot reactions. B). 5 (branched approach) or 8 (linear approach). One-pot synthetic strategies have been developed as an alternative to traditional sequential approaches to oligosaccharide synthesis.t. NIS 3 RT 44% (0.t.3/1) B NIS [bmim][OTf] CH 2Cl 2 7 + 8 + 6 TMSOTf.chemoselective glycosylation reactions at room temperature where both donor and 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 acceptor bear a free OH of distinct reactivity. a concept initally exemplified by Fraser-Reid‟s armed-disarmed methodology (Figure 1. was used firstly as the glycosyl donor with glycosyl acceptor 4 (branched approach) or 7 (linear approach). One-pot reactivity based synthesis of branched and linear trisaccharides 2 and 3. since multiple glycosylation steps can be formed in a single reaction vessel and purification between individual steps can be avoided.45/1) BnO BnO 7 OH O BnO OMe NIS [bmim][OTf] CH 2Cl 2. B). This could be achieved in both a sequential approach (Scheme 5.14 A Branched trisaccharide OBn O 5 OBn OAc O 6 OAc Linear trisaccharide OBn O 8 OH OAc O 6 OAc BnO BnO SPh AcO AcO SPh + TMSOTf.37 In this context. NIS BnO BnO SPh AcO AcO SPh + TMSOTf. AcO AcO BnO OAc BnO O OAc 3 OBn O O O O BnO OMe AcO AcO O BnO OMe BnO BnO 41% (0. 9 .

the yields for the glycosylations using silver carbonate increased by 50 – 60% when an imidazolium halide was added to the reaction mixture. BTEACl. unknown toxicity and environmentally hazardous starting materials. there are issues with the purification of the IL materials and their incompatibility with reactions involving active metals or strong bases due to the acidity of the C-2 proton of the imidazolium ion. In addition.41 Seven different room temperature ILs (RTILs) were screened for the glycosidation of 4-nitrophenol with tetra-O-acetyl-α-D-galactopyranosyl bromide. AcO AcO AcO Br OAc O AcO AcO OAc 87% b only Ag2CO3 ArOH [bmim][BF 4]. B) Mixing of glycosides at the start of the synthesis.45 A key feature of this new class of ionic salts is the use of quaternary ammonium as cations 10 . Interestingly. RT OAc O OAr Scheme 6: In-situ formation of silver NHCs for glycosylation reactions. Although the use of imidazolium based ILs offers many attractive features.42. the same group decided to explore the effects of adding an IL salt. Benzyltriethylammonium chloride (BTEACl) was shown to be the best salt for promoting metathesis in the glycosylations. while the best yields were achieved with either [bmim][BF4] or [bmim][PF6] as the IL source.44.40. there are also some known drawbacks associated with imidazolium salts such as relative expense. a range of aryl alcohols were used including phenols.38 The group of Malhotra have shown that O-glycosylation reactions can be promoted via silver NHC complexes formed in situ in ILs using silver carbonate. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 Imidazolium based ILs can be used as a source to access N-heterocyclic carbenes (NHCs).39 In a subsequent study. They showed that anion metathesis of the ILs with inexpensive alkylammonium halides also resulted in silver NHC formation and subsequent O-glycosidation in the presence of silver carbonate. To test the scope of the reaction. flavones.43 A new class of IL surfactants has been reported recently as an alternative to imidazolium-based systems. steroids and coumarins with the glycosylations proceeding in good to excellent yields (51 – 94%) with exclusive  selectivity in most cases. This was attributed to the increased ability of NHCs to deprotonate phenols relative to silver carbonate (Scheme 6).A) Sequential addition of glycosides.15.

solvent r. Moreover. The scope of the reaction. reactions with armed glycosyl donors 10a and 10b and super-armed donor 10c yielded disaccharides 11a-c in good yields. For disarmed glucosyl donor 10d. while still being able to discern the less active (peracetylated) donor 10d.46 A range of surfactant ILs 9a-d were tested in model glycosylations and it was shown that 9b was the most reactive activator. Interestingly. less reactive 4. Recently. environmentally benign and commercially available starting materials by a simple ion exchange process. which could not be activated by the [bmim][OTf]/NIS combination.T. For instance. Surfactant IL 9b was shown to be a more reactive activator than [bmim][OTf]. however.6-O-benzylidene. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 this new class of ILs are easily prepared from cheap.11 afforded disaccharide 12e in 75% yield as the β-anomer only (Table 2). mild promoters for thioglycosylations (Scheme 5). AOT 9a: R = H 9b: R = Me 9c: R = Et 9d: R = Pr O R N R R R O O O S O O O R2 R3 R1 O R4 10a-e O SPh O 11 OH O OO 9b NIS. R 4 = OAc d R1 = R 2 = R 3 = R 4 = OAc e R1 = R 2 = OCHPh. R 2 = R 3 = R 4 = OBn c R1 = R 2 = R 3 = OBn.and bis(2-ethyl-1-hexyl) sulfosuccinate (AOT) as the anion component. N-trichloroethoxycarbonyl (N-Troc) protected 10e. The stereoselectivity of the product was shown to be influenced by the co-solvent used. could also be used as selective. As expected. changing the reaction solvent from dichloromethane to a participating solvent such as acetonitrile increased the amount of β-anomer in the final product. and afforded a slightly better overall yield. model glycosyl acceptor 11 and IL 9b was subsequently probed (Table 2). that ILs based on surfactant sulfonate anions ([R4N][AOT]) in combination with NIS. catalytic TMSOTf was required to affect the glycosylation thus allowing AOT-based ILs to potentially be used as glycosyl promoters in one-pot reactions. (Table 2) Table 2: Summary of glycosylation reactions with thioglycoside donors 10a-e and model acceptor 11 in the presence of IL 9b/NIS at R. R 3 = OAc R 4 = NHTroc 11 . with glucose based thioglycoside donors 10a-e possessing different reactivity profiles. as expected.t R2 3 R R1 O R4 12a-e O O O O OO a R1 = R 2 = R 3 = R 4 = OBn b R1 = OAc. it has been shown by Galan et al.

76c 75 Product 12a 12a 12b 12b 12c 12d 12d 12e 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 1 2 3 4 5 6 7 8 a c α/β ratioa 1. Despite the initial hurdles with polymer supported strategies. recent advances in the area brought about by the use of new polymers. 0. B) However. linkers and novel synthetic methodology has lead to the synthesis of many complex oligosaccharides51-54 and glycoconjugates. Ionic Liquid Supported Oligosaccharide Synthesis Following the success of solid phase peptide synthesis (SPPS).50 but low loading of the saccharides. In an effort to address some of the inherent problems of performing chemistry on a solid support.62 12 .m. One of the drawbacks of this approach however. = recovered starting material (glycosyl donor) 4. is the requirement for potentially difficult-to-access fluorinated compounds and the decreasing solubility of large oligomers in the fluorinated solvent as the size of the oligomer increases.Entry Donor 10a 10a 10b 10b 10c 10d 10d 10e Solvent CH2Cl2 MeCN CH2Cl2 MeCN CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 Yield (%) 72 80 78b 98 95 s. In the context of oligosaccharide synthesis this means using excesses of expensive and often laborious to prepare orthogonally protected monosaccharide building blocks. solid supported strategies have been typically associated with slow reaction rates and the need for excess reagents to drive reactions to completion.= 0°C. low solubility during the reaction and difficulties with product recovery made this strategy far from ideal. breaction temp.47-49 (Figure 1. s. fluorinated soluble support strategies that show great potential have also been developed.4:1 1:3 3:1 1:4 β only β only β only Determined by NMR spectroscopy (1H and HMQC data).57-61 The methodology is of particular interest since protectinggroup manipulations and glycosylations can be conducted under conditions typically used for solution-phase chemistry. of TMSOTf used.03 eq.55 Another interesting recent development in the area of solid supports is the surface-tethered iterative carbohydrate synthesis (STICS) reported by the groups of Demchenko and Stine 56 whereby functionalized high surface area porous gold is used as an alternative to solid phase technologies to perform cost efficient and simple synthesis of oligosaccharide chains. polymer supported oligosaccharide syntheses were developed.m. Soluble polymer supports were devised to overcome some of the issues mentioned above.

The groups of Chan63 and Huang64 reported almost in parallel the first application of ILs as soluble. IL labeled substrates (I-Tagsubstrates) are soluble in polar solvents such as those used in glycosylations (i. Trichloroacetimidate 21 was used as the glycoside donor in the presence of catalytic TMSOTf to form disaccharide 22. excess reagents. the IL label (I-Tag) was incorporated by acylation of thioglycoside 13. Following this strategy a series of oligosaccharides. This two step procedure was repeated to yield trisaccharide 18 and the final product 19 was accessed by cleaving the I-Tag with cesium carbonate. functional supports in oligosaccharide synthesis. with bromoacetic acid. also as an ester functionality. dichloromethane. acetonitrile).e. A). of the free OH at C6 followed by SN2 halide displacement of 14 with 1-methylimidazole and sodium tetrafluoroborate to give 15. mainly disaccharide structures. in Chan‟s work (Scheme 7. DCC and DMAP. isopropyl ether or hexanes.4. B). chromatography free purification. In the absence of the polar solvent. 13 .tri-O-benzylated thioglycoside donor 15 was oxidized with m-chloroperbenzoic acid to form activated sulfoxide 16 which was used as the glycoside donor in a subsequent glycosylation to yield I-Tagged disaccharide 17. Huang‟s approach involved the incorporation of the IL. I-Tag-linked-2. unreacted material) can be removed from the I-Tag-products by simple biphasic extractions or by precipitation. were prepared.3. at the C-4 position of glycoside acceptor 20 by reacting the free OH with chloroacetyl chloride in pyridine followed by treatment with 1methylimidazole and subsequent reaction with potassium hexafluorophosphate.e. Both approaches rely on the incorporation of an imidazolium cation via an ester linkage through either the C-663 or C-464 position of the glycoside building block.12 The use of ILs as soluble functional supports in oligosaccharide synthesis shows great promise as it combines the features of solution phase chemistry with the added advantage of fast. This means that non-I-Tag-materials (i.The unique and tunable physical and chemical properties of ILs make this class of 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 molecules particularly useful as new vehicles for the immobilisation of reagents. For instance. On the other hand. the I-Tag-products become insoluble in non-polar solvents such as diethyl ether. (Scheme 7.

AgClO4.6-linked di-. -78 °C I-Tag O O SPh 16 OBn 97% - BnO BnO X +N N O I-Tag = O O OBn BnO BnO BnO BnO O Cs 2CO3. In their reports. 25. Subsequently. IL-supported synthesis using ester-linked I-Tags.t. 2. mCPBA.tetra. as in previous strategies. 2. Bu 4NBr - Tag-I BzO BzO OBz O 25 F I-Tag = O O PF 6 +N N 26 66% (over two steps) 27 47% (over four steps) 14 . CH 2Cl 2 BnO BnO I-Tag O HO SPh Br BnO BnO DMAP.66 Starting from imidazolium cation-tagged mannosyl fluoride 25 as the glycoside donor and mono-hydroxylated 1-thio-toluene--D-mannoside 24 as the glycoside acceptor. -78 °C 2. MeOH O O OBn SPh OH O O OBn BnO BnO OBn 18 BnO BnO 53% O O OBn BnO 19 BnO quantitative O OBn SPh B) OH O 20 OAc AcO AcO 21 SPh OAc O AcO O CCl3 NH AcO AcO OAc O OAc O AcO Tag-I AcO X= PF 6 O O OAc AcO Tag-I TMSOTf. CH 2Cl 2. HO BzO BzO OBz O O BzO BzO OBz O STol HO BzO BzO repeat steps 1-2 for another 2 rounds OBz O O BzO BzO OBz O 2 O BzO BzO OBz O STol HO BzO BzO OBz O 24 STol 1.6-di-tert -butyl-4methylpyridine.6oligomannans. r. NaHCO 3. using block couplings the authors were able to synthesize a series of linear α-1. the group of Pathak demonstrated that the IL-supported methodology could be successfully applied to the preparation of homolinear α-1. 2. an ester linkage is also used to covalently link the IL component to the glycoside donor at C-6. (Scheme 8 shows the synthesis of tetramannoside 27 using this approach). which was removed after each glycosylation step to allow for the next oligosaccharide coupling to take place. DCC O O O OBn 14 Br SPh N N BnO BnO O O O N SPh X- + N BnO BnO NaBF 4 OBn 15 87% (over 2 steps) X= BF 4 BnO BnO O 13.65. CH 2Cl 2 BnO SPh BnO mCPBA. 13. -40 to 0 °C 22 AcO 92% NaHCO 3. Cp 2HfCl 2.and octamannosides.6-di-tert -butyl-4methylpyridine. AcO AcO Et 2O SPh O O OAc SPh HO AcO 23 93% Scheme 7.A) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 O OH O 13 OBn I-Tag O BnO O 17 OBn 50% 1. tri. Tf2O. Bu 4NBr. Tf2O.

however the use of ester-linked ionic labels is limiting in terms of the protecting group strategies that can be employed.67 The I-Tag was introduced selectively at the C-6 position of thioglycoside 28 in a 4 step process (57% overall yield). IL-supported methodology applied to the synthesis of α-(1→4)-glycosides. I-Tag-thioglycoside 30 was used as the glycoside acceptor by reaction with trichloroacetimidate 31 to form disaccharide 32 in 81% yield. Gouhier and co-workers subsequently reported the synthesis of α-1.4-glycosides on an ionic support (Scheme 9). afforded hydrophobic I-Tag-thioglycoside 30. To that end. Ester-linked I- 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 Tags. a stannylene acetal was formed on partially protected thioglycoside 28 with dibutyltin dimethoxide followed by esterification with 5-bromopentanoyl chloride in the presence of triethylamine. Br(CH 2) 5COCl. Et 3N HO SEt BnO 29 67% BnO BnO - HO BnO 3. Initial reports in the area of IL supported oligosaccharide synthesis were commendable and pioneering. TMSOTf O I-Tag = O 34 85% Scheme 9. KPF 6 HO O BnO SEt OBn 5 I-Tag O OBn BnO BnO 31 SEt OC(NH)CCl3 BnO BnO BnO TMSOTf OBn O BnO O BnO I-Tag O OBn SEt 30 85% 32 81% OBn O OBn O BnO O BnO I-Tag O BnO O BnO OBn O BnO OMe HO BnO PF 6 +N N 5 33 BnO OMe NBS. Ester-linked ITags. firstly as the glycosyl acceptor and then as the glycoside donor by using a set of chemo-selective leaving groups. It is interesting to note the dual use of the I-Tag-building block. Ester functionalities are often used in oligosaccharide synthesis as transient protecting groups and are known to be labile to mild basic conditions (such as those used to cleave the ester- 15 . IL-supported methodology applied to the synthesis of α-1. N-methylimidazole O O 4. In the first instance. The anomeric thioethyl was then activated in the subsequent reaction step using NBS and catalytic TMSOTf to afford -linked trisaccharide 34 upon reaction with 33 in 85% yield.6-oligomannans.Scheme 8. OBn O Br OH O OBn 28 1. Bu 2Sn(OMe) 2 2. Halide displacement from 29 by refluxing in acetonitrile in the presence of methylimidazole followed by anion metathesis using KPF6 as the salt.

carbohydrate release Oligosaccharide elongation Scheme 10. respectively. Cleavage of I-Tag1 could be achieved by acidic hydrolysis or by methanolysis to yield either the hemiacetal or the methyl glycoside. in a typical glycosylation reaction. the product can be released as a hemiacetal or a glycoside in a form suitable for further oligosaccharide elaboration (Scheme 10). More importantly. The presence of the I-Tag on the glycosyl donor could potentially lead to mixtures of I-Tagged compounds on the more challenging glycosylation steps. H. I-Tag2 was introduced by the same 2 step process described previously. Benzyl derived I-Tag2 was devised as a more versatile alternative to I-Tag1 as it is compatible with most protecting group strategies. glycosylation of 36 with 4-(chloromethyl)benzyl alcohol 16 .68 Furthermore. Two types of I-Tags with different release mechanisms were developed for orthogonal attachment to saccharides.linked-ILs) or even strong acidic media. The ITags were introduced at the start of the synthesis by glycosylation to the corresponding halide containing alcohol and once the desired oligosaccharide sequence has been constructed. Alkyl I-Tag1 was prepared by a two step process entailing glycosylation of glycosyl donors 35 or 36 to 3-bromo-1-propanol followed by alkyl halide displacement with N-methylimidazole to give 38. OC(NH)CCl3 P and P'= orthogonal protecting groups ITagging R= N N chemoselective protecting group manipulations and carbohydrate elongation PO O O R= Me. the glycosyl donor is required in slight excess to drive reactions to completion and unwanted hydrolysis of the glycoside donor is often a side product. More recently. General “Ionic Catch and Release Oligosaccharide Synthesis” (ICROS) methodology. Galan et al. C(NH)CCl3 OR PO O LG PO O Linker cleavage PO O O PO O OI-Tag I-Tag cleavage . addressed these issues by introducing the IL labels at the anomeric position of the reducing end of the saccharide as alkyl functionalities.69 I-Tag incorporation Linker PO OP' O R Linker incorporation via anomeric LG glycosylation OH PO OP' O O R= Br + Linker -X R PO OP' O OI-Tag LG = SPh. having the I-Tag on the 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 glycoside donor increases the linearity of the approach since the I-Tag is introduced in each building block and then removed to allow the next glycosylation step to take place.

Glycosylation of 41 with trichloroacetimidate 36. in this instance. Their approach also involved covalently attaching the linker at the anomeric position of the glycoside acceptor. However. by catalytic hydrogenolysis to afford the hemiacetal.6 and β-1.and tetrasaccharides using trichloracetimidate and thioglycoside glycosyl donors. I-Tag incorporation at the anomeric position. which was prepared in 3 steps from αα‟dibromo-p-xylene (Scheme 13). exclusively as the βanomer.2-linked di-. Product release can be 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 achieved. (Scheme 11) Scheme 11. in the presence of TMSOTf afforded disaccharide 42 in 98% yield. it differs in that I-Tag2. A typical reaction sequence is shown in Scheme 12. 17 .followed by halide displacement to form ionically labeled 40. which was then converted to trichloroacetimidate 44 in 83% by reaction with acetonitrile and DBU. IL supported synthesis using I-Tag2 as the IL support. The versatility of this strategy was demonstrated with the synthesis of biologically relevant -1. is installed by direct coupling of orthogonally protected mannose trichloroacetimidate 45 with a benzyl-type IL-linker containing a free OH. Selective cleavage of the ionic component (I-Tag2) in the presence of H2 and Pd black afforded hemiacetal 43. selective 6-OH unmasking from I-Tag2 labelled compound 40 by O-TIPS removal using a mixture of HCl in MeOH provided acceptor 41 after a simple extraction in 95% yield. Scheme 12. The methodology was subsequently further demonstrated by the Li et al. tri.70 with the synthesis of an α-linked nonamannoside 47 using the same benzyl-type linker (ITag2).

NaOMe 2. in a matter of days. They showed that HPLC in combination with MALDI-TOF and NMR can be used to efficiently monitor reaction progress in situ and that several I-Tag-species can be prepared at once in one reaction vessel. demonstrated that the “Ionic Catch and Release Oligosaccharide Synthesis” (ICROS) is ideally suited for the combinatorial synthesis of small libraries of oligosaccharides. The mixture of oligomers can then be deconvoluted by size exclusion chromatography to yield the individual components (Scheme 14).71 The team has developed a combinatorial ionic-liquid-supported “catch-and-release” strategy for oligosaccharide synthesis (combi-ICROS) where all the oligosaccharide targets are prepared in one pot. This year. IL supported synthesis using I-Tag2 applied to the synthesis of an α-linked nonamannoside. 18 . TMSOTf repeat 8 times BnO BnO BnO BnO BnO BnO N PF 6 +N N Scheme 13.1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 PF 6 +N BnO BnO BnO BnO BnO BnO 46 OAc O O PF 6 +N OAc O O O 7 O O 47 O HO BnO BnO BnO OAc O 45 OC(NH)CCl3 TMSOTf N 1.6-glucan oligosaccharides 51. The strategy was exemplified in the preparation of a series of β-1. Galan et al. without the use of silica gel chromatography purification in between steps. 53 and 55 in one pot. 45.

for the development of an inexpensive and versatile IL-based chemical label (I-Tag) for fast and sensitive enzyme monitoring by MS as an alternative to using expensive radioactive or fluorescence labelled carbohydrates. Ionic liquid tags in enzyme reactions. Pd/C 51 P= I-Tag2 52 P= H 90% (over 2 steps) HO HO HO H2. TMSOTf b) Et2O/Hexanes wash c) TIPS deprotection with HCl/MeOH 42 repeat steps a-c x2 HO BzO BzO O BzO BzO BzO O HO BzO BzO O BzO BzO 49 BzO O O OBz OI-Tag2 O BzO BzO BzO O O O BzO BzO BzO O BzO BzO 50 BzO O O OBz OI-Tag2 H2. A trifunctional cross-linker was developed for this purpose. that enabled orthogonal attachment to substrates (I-Tag3. Scheme 15). ILs are also ideal as mass spectroscopy (MS) probes for fast analysis due to their greater spectral peak intensities and lower limits of detection. the ionic component for MS analysis and a disulfide bond for mild product 19 . Pd/C 53 P= I-Tag2 54 P= H O OH HO HO O O OH OP Global deprotection with: Et3N in MeOH/H2O Size exclusion LH-20 sephadex 95% (over 2 steps) HO HO HO O OH HO HO O O O O OH OP 48 (10%) 49 (30%) 50 (14%) H2. Pd/C 55 P= I-Tag2 56 P= H OH HO HO 85% (over 2 steps) HO HO HO O O OH HO HO O O OH HO HO O OH O HO HO O OH OP Scheme 14. The linker contained an alkyne group for facile coupling to azide-containing sugar moieties. IL supported synthesis using I-Tag2 applied to the synthesis of an -linked nonamannoside.73 The authors demonstrated the potential of using IL-labelled-glycans for the biological screening of glycosyltransferases in enzymatic reactions with bovine milk β-1.4-GalT).4galactosyltransferase (β-1.72 This has been exploited recently by Galan et al. 5.1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 HO BzO BzO O O BzO BzO BzO O 48 OI-Tag2 OBz 41 a) 36.

4-Galactosyltransferase (β-1.74 The new I-Tag was chemically more stable and simpler to prepare than the previously reported disulfide-based I-Tag3 (Scheme 16). This demonstrates that the new I-Tag4 was compatible with the glycosyltransferases used in the study. 20 . were prepared enzymatically. A threestep procedure consisting of conjugation chloride with of commercially the available 4- (bromomethyl)benzenesulfonyl corresponding protected aminopropyl N-acetylglucosamine 56 under basic conditions was followed by halide displacement with methyl imidazole and KBF4. oligosaccharides of significant biological relevance. The apparent kinetic parameters for the enzyme catalysed transformations with β-1. the applicability and versatility of using I-Tags for monitoring enzymatic oligosaccharide transformations and as purification handles was further demonstrated with the development of a new N-benzenesulfonyl-based ionic-liquid label (I-Tag4). I-Tag2-LacNAc (Galβ(1-4)GlcNAc) 60 and I-Tag2LewisX (Galβ(1-4)[Fucα(1-3)]GlcNAc) 61.release. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 Subtrate H N O N N N Subtrate O I-Tag3 H N N3 O S S N H R MichaelisMenten V [m/z] + I-Tag facilitates reaction monitong O S S N H N N [C] BF 4LC-MS qualitative and quantitative analysis Scheme 15.4-GalT) and Fucosyltransferase VI (FucT VI) were determined by LC-MS. From 59. In a more recent report. thus opening the door for applications of these new types of IL-labels with other glycosyltransferases and potentially other enzymes outside the area of oligosaccharide synthesis. IL-based MS labels for enzyme monitoring. Subsequent unmasking of the OH groups yielded I-Tag4-labelled N-acetylglucosamine (GlcNAc) 59 ready to be used in enzymatic reactions.

chromatography free purification and in situ reaction monitoring by MS. The challenges chemists face associated with carbohydrate synthesis include laborious protecting group manipulations. the high polarity of ILs can provide strong accelerating affects to reactions involving cationic intermediates and. K2CO3. MeOH 59 R=H 99% 97% b-1.3-FucT VI. This shows great promise as it combines the features of solution-phase chemistry with the added advantage of fast. Conclusions The preparation of complex structures that can be used in biological studies is key to understanding glycan diversity and function.and stereoselective glycosylation reactions and facile purification of products such as those already available for other less complex biomolecules i. or nucleotide sequences. Despite the many advances in the area of carbohydrate chemistry over the last three decades. ILs have been used as soluble functional supports in the chemical and enzymatic synthesis of oligosaccharide. the need for high yielding regio. mild glycosylation promoters that are amenable to one-pot reactivitybased glycosylation protocols. Finally. This has led to the use of ILs as solvents for the solubilisation of carbohydrate polymers. RO RO O S O OR O O NH AcO AcO O O NHAc 57 90% NHAc 58 R= Ac Et3N. Enzymatic synthesis of I-Tag4-LacNAc 48 and I-Tag2 LewisX 49 6.e. UDP-Gal HO HO OH O HO OH O OH OO OH OH O a-1. as a result. ILs have been used as recyclable.OAc NH2 Br 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 AcO AcO O NHAc 56 ClSO2PhCH2Br. 21 . peptides. Furthermore. CH2Cl2 80% over 2 steps OAc O -BF4 + N N I-Tag4 O S O NH N N KBF4. the field of oligosaccharide synthesis still remains a difficult quest. ILs have been used successfully as reaction media in carbohydrate synthesis. HO GDP-Fuc 90% HO O-ITag4 NHAc OH O O HO OH O 61 OH 60 O-ITag4 NHAc Scheme 16.4-GalT. The unique and tunable physical and chemical properties of ILs make this class of reagents particularly useful in the field of oligosaccharide synthesis.

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Bristol BS8 1TS UK.t. University of Bristol.Recent Developments of Ionic Liquids in Oligosaccharide Synthesis. M. Institut Parisien De Chimie Moléculaire. 75252 Paris Cedex 05 Graphical Abstract Solvents and Promoters in Oligosaccharide Synthesis BnO Ionic Liquids (IL) -X N+ O OR PO O Product N LG ROH IL/CH2Cl2 r.a* Rachel A. Université Pierre et Marie Curie . Carmen Galan. Recycling IL Ionic Liquid Supported Oligosaccharide Synthesis I-Tag + CLEAVABLE LINKER N N Carbohydrate Elongation + CLEAVABLE LINKER N N Product RELEASE Reaction Monitoring LC-MS [m/z] 1 . The Sweet Side of Ionic Liquids. Jonesa and Anh-Tuan Tranb a b School of Chemistry.

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