Carbohydrate Chemistry: Chemical and Biological Approaches Volume 43 / Edition 1

by Am lia Pilar Rauter, Thisbe Lindhorst, Yves Queneau

Overview

Demonstrating the interdisciplinary nature of modern glycosciences, this volume covers research in the fields of polysaccharides and small carbohydrates from the synthetic and structural viewpoints, with applications ranging from biology to the bioeconomy. Key aspects of the synthesis and properties of imino disaccharides and regioselective glycosylation reactions are reviewed, glycosyltransferase inhibitors are shown to be potential future therapeutic agents, protein-carbohydrate interactions in plant cell-wall biodegradation are targeted by the use of glycan microarrays, biological properties of polysaccharidic microbial surface antigens are discussed with respect to their intimate structure, and contributions on carbohydrate-based hydrogelators, green/blue sugar-based surfactants and carbohydrate-based green solvents illustrate the modern design of tomorrow’s chemicals. With the increase in volume, velocity and variety of information, researchers can find it difficult to keep up to date with the literature in their field and this book remains a valuable addition to any researcher’s library.

Product Details

ISBN-13:	9781788010030
Publisher:	RSC
Publication date:	12/13/2017
Series:	Specialist Periodical Reports - Carbohydrate Chemistry , #43
Pages:	276
Product dimensions:	6.15(w) x 9.20(h) x (d)

About the Author

Dr Yves Queneau, Research Director at CNRS, is Head of the Organic and Bioorganic Chemistry Laboratory at INSA Lyon, Deputy-Director of the “Institut de Chimie et Biochimie Moléculaires et Supramoléculaires” (ICBMS), University of Lyon, France and Honorary Professor at the University of Hull, UK.
After his doctorate on aqueous Diels-Alder reactions involving glycodienes under the supervision of Professor André Lubineau (Orsay, 1988) he was appointed as CNRS fellow and worked on cycloaddition reactions towards complex sugars. He then spent one year in 1992 in Professor Samuel J. Danishefsky’s group in Memorial Sloan Kettering Cancer Center in New York, USA. He later moved to Lyon in a mixed CNRS-industrial research facility dedicated to sucrose chemistry (1995-2003) before joining its present position where he develops his research in organic and biological chemistry with a particular interest for the use of carbohydrates as renewable raw materials.

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CHAPTER 1

Synthesis and biological properties of imino-disaccharides and -oligosaccharides

Alberto Marra and Renaud Zelli

1 Introduction

Iminosugars, in the past erroneously called azasugars, are polyhydroxylated monocyclic (pyrrolidine, piperidine, azepane) and bicyclic (pyrrolizidine, indolizidine, nortropane) nitrogenated compounds that can be considered carbohydrate analogues bearing a basic nitrogen instead of the endocyclic oxygen atom (Fig. 1). These naturally occurring products are strong inhibitors of both glycosidases, the enzymes that catalyse the cleavage of glycosidic bonds in oligosaccharides and glycoconjugates, and glycosyltransferases, the enzymes that catalyse the formation of the glycosidic bond starting from an activated sugar donor. Besides the sterical and stereochemical resemblance to sugars, their inhibition activity arises from the protonated endocyclic nitrogen, at physiological pH, which leads to strong electrostatic interactions with the carboxylate ion located in the active site of the enzyme.

In order to find new treatments for the severe pathologies originated by a malfunction of the above sugar processing enzymes, many synthetic monosaccharidic iminosugar have been prepared over the last four decades. However, also designed and synthetized were less conventional derivatives such as the imminosugar clusters and the imino-disaccharides and -oligosaccharides. While the former class of compound has been extensively reviewed, only two review articles and a book's chapter have been dedicated to the latter family of iminosugars, two dealing exclusively with the carbon-linked disaccharides (imino-C-disaccharides, see section 5), the other focused mainly on the synthesis and biological properties of the imino-O-disaccharides (see section 2). The interest in the di- and oligosaccharidic iminosugar, i.e. carbohydrates constituted of an iminosugar moiety linked to one or more sugar units, resides in their expected stronger and more selective glycosidases inhibition. Indeed, these enzymes are not totally selective for the monosaccharide (e.g. D-glucose, D-mannose, etc.) and the anomeric linkage (α] or β) to be cleaved, and thus also the iminosugar-based inhibitors are poorly selective and scarcely used in therapy. Nevertheless, many glycosidases are endowed with some aglycon specificity, i.e. they selectively recognize the sugar(s) linked to the monosaccharide to be hydrolysed. Therefore, compounds bearing a mimic of the glycon hydrolysis intermediate (the iminosugar) and a natural mono- or oligosaccharide are good candidates for the highly selective glycosidase inhibition.

During the last three decades, two series of imino-disaccharides and -oligosaccharides have been synthesized, one featuring the iminosugar (or 1-deoxy-iminosugar) moiety at the reducing end (I, Fig. 2), the other displaying the iminosugar at the non-reducing end (II). Interestingly, in the synthetic disaccharides belonging to the latter series, the polyhydroxy-piperidine (or -pyrrolidine) is linked to the sugar unit through O-, S-, N- and C-(pseudo)glycosidic bonds whereas in the other series, i.e.I, only oxygen- and carbon-linked iminodisaccharides are known. However, many of these imino-C-disaccharides were not genuine isosters, i.e. the interglycosidic oxygen atom of the naturally occurring disaccharides was replaced by various carbon chains instead of a single methylene group. Finally, along with actual N-glycoside derivatives, a few disaccharide analogues that contain endocyclic nitrogen-tethered moieties have been recently synthesized (see section 4.2).

2 Synthesis of imino-O-oligosaccharides

The oxygen-linked glycosides being the first iminodisaccharides reported in the literature, this family of compounds is constituted of a large number of members, mainly prepared by means of conventional glycosylation methods. However, the vast majority of them are di- and oligosaccharides bearing the iminosugar moiety at the reducing end, and only 4 imino-O-disaccharides bearing the sugar unit at the reducing end (described in 3 articles) are known to date.

2.1 Imino-O-oligosaccharides bearing the iminosugar moiety at the reducing end

2.1.1 Enzymatic synthesis of imino-O-oligosaccharides. In 1985, Ezure published the first synthesis of an iminodisaccharide, the 4-O-(α-D-glucopyranosyl)-1-deoxynojirimycin 4 (Scheme 1) obtained in a multigram scale from 1-deoxynojirimycin (1) and α-cyclodextrin (2) by two glycosidase-promoted reactions, namely an O-transglycosylation (catalysed by the Bacillus macerans amylase) followed by hydrolysis of the glycosidic bond between two glucose units (catalysed by the Rhizopus niveus glucoamylase). The disaccharide 4 was then employed to prepare a series of 13 N-alkylated derivatives 5a–m which were submitted to various biological assays (see section 6).

The following year, the iminodisaccharide 4 as well as seven oligosaccharides 3 (n = 1–7) were also prepared by Kainosho and co-workers by transglycosylation of starch with 1-deoxynojirimycin (1) in the presence of bacterial saccharifying amylase (pH 5.5, 37 °C, 16 hours).

More than one decade later, Ezure and co-workers reported on the multikilogram scale synthesis of β-D-galactopyranosyl-1-deoxynojirimycin derivatives catalysed by Bacillus circulans β-galactosidase (Scheme 2). Thus, the incubation at 40 °C for 18 hours of 1-deoxynojirimycin 1 (5 kg) and D-lactose 6 (50 kg) in the presence of the enzyme led mainly to the 1,4-linked imino-O-disaccharide 7. Also isolated and fully characterized were the 1,2- (8), 1,3- (9) and 1,6-linked (10) regioisomers (yields not given).

Another study on the transglycosylation catalysed by glycosidases was published in 1994 by Asano and co-workers. They used an immobilized rice α-glucosidase to promote the reaction between a large excess of maltose (12) and the Cbz-protected 1-deoxynojirimycin 11 which, being a carbamate, did not act as a glycosidase inhibitor (Scheme 3). After 2 hours of incubation at 37 °C, the main product was found to be the α-1,3 disaccharide that, after hydrogenation (yield not given) afforded the deprotected imino-O-disaccharide 13. The transglycosylation gave also the α-1,4 and α-1,2 regioisomeric disaccharides that could be isolated. The native (i.e. not immobilized) enzyme led to similar results. On the other hand, the α-1,2 isomer was the main product when native yeast α-glucosidase was used as the catalyst while the immobilization of this enzyme led to a significant decrease of its activity. The β-D stereoisomers were obtained employing native yeast β-glucosidase and cellobiose (14), in large excess, as the glycosyl donor. After 3 hours at 37 °C the β-1,2 imino-O-disaccharide was isolated in 28% yield and then hydrogenated to give 15 (yield not given). Also isolated was the β-1,4 regioisomer (4%). Upon immobilization, this enzyme was still reactive and the β-1,2 isomer was recovered as the main product. Interestingly, in any case the α- or β-1,6 imino-O-disaccharide was formed, probably due to steric hindrance caused by the Cbz protecting group. The disaccharides 13 and 15 were assayed as glycosidase inhibitors (see section 6).

On the other hand, Paek and co-worker found in 1998 that the α-galactosidase from green coffee beans was able to promote the transglycosylation from p-nitrophenyl α-D-galactopyranoside (16) to the 6-OH of 1-deoxynojirimycin 1 leading to the corresponding 1,6-linked imino-O-disaccharide 17 (Scheme 4) as the main product (5.6%).

Various di- and oligosaccharides containing three different iminosugar moieties were prepared from α-cyclodextrin (2) by Uchida and coworkers taking advantage of two enzymatic reactions. The first was catalysed by Bacillus macerans CGTase (cyclodextrin glycosyltransferase or cyclodextrin glucanotransferase), which is a glycosidase despite the misleading name, whereas the second was promoted by a β-amylase, which catalyses the hydrolysis of the second α-1,4 glucosidic bond releasing β-maltose. Using these two enzymes, the di- (19), tri- (20) and tetra-saccharides (21) were isolated and characterized starting from the known D-xylo configured 1-deoxy-iminosugar 18 (Scheme 5).

When the same enzymatic reactions were carried out using 6-azido-6-deoxy-D-glucose (22, Scheme 6) as the glycosyl acceptor, the four compounds 23–26 were isolated. Catalytic hydrogenation of each of the latter products led to reductive aminocyclisation affording the glucosyl-azepine derivatives 31–34 in good yield. On the other hand, oxidation of 23–26 with bromine in the presence of barium carbonate gave the corresponding aldonic acid intermediates 35–38 which were directly submitted to oxidative decarboxylation (H2O2, Fe2(SO4)3) to produce the 5-azido-5-deoxy-arabinofuranose derivatives 39–42. These products were individually hydrogenated to afford the disaccharide 43 andthe three oligosaccharides 44–46 bearing a D-arabino configured 1-deoxy-iminosugar unit at the reducing end. Most of these compounds were found to be inhibitors of amylases (see section 6).

The CGTase enzyme (from Bacillus circulans) was also exploited by Whiters and co-workers to prepare the trisaccharide 49 (Scheme 7), containing a hydroximolactam unit at the reducing end, as a new a-amylase inhibitor (see section 6). Incubation of the 40-O-methyl-α-D-maltosyl fluoride 48 (1.6 mg), obtained in 7 steps from D-maltose, with the known hydroximolactam 47 (1.0 mg) gave, after column chromatography, 49 in 70% yield (1.7 mg).

In a recent paper, Usui, Fukamizo and their co-workers described the synthesis of 4-O-(2-acetamido-2-deoxy-β-D-glucopyranosyl)-1-deoxynojirimycin (51, Scheme 8) via transglycosylation of the commercially available tetra-N-acetyl-chitotetraose 50 with 1-deoxynojirimycin (1) catalysed by hen egg white lysozyme (HEWL). Although the iminodisaccharide 51 was the main reaction product, the corresponding tri- (52) and tetrasaccharide (53) were also isolated and characterized.

The only example of use of glycosyltransferases, instead of glycosidases, for the synthesis of imino-O-disaccharides was reported by Gautheron-Le Narvor and Wong in 1991 (Scheme 9). The coupling of uridine diphosphate D-galactose (UDP-Gal, 54) with 1-deoxynojirimycin (1) in the presence of β-1,4-galactosyltransferase (EC 2.4.1.22) afforded, after 4 days, the disaccharide 7 in 20–40% yield.

2.1.2 Chemical synthesis of imino-O-disaccharides. The first non-enzymatically synthesized imino-O-disaccharide was prepared by Liu in 1987 by direct glycosylation of the iminoheptitol 56, obtained from the tetra-O-benzyl-D-glucopyranose 55 (7 steps, 26% overall yield), with the glucopyranosyl bromide 57 (Scheme 10). The presence of a participating group at the C-2 position of the glycosyl donor insured the totally stereoselective synthesis of the protected disaccharide 58 from which the desired imino-O-disaccharide 59 was obtained as hydrochloride salt after standard deprotection reactions. The latter compound was found to be a potent inhibitor of various glycosidases (see section 6).

Two years later, the same Author developed another synthesis of the imino-O-disaccharide 59 starting from the known 1-deoxynojirimycin1-sulfonic acid 60 (Scheme 11). The glycosyl acceptor 62 was prepared through a rather long reaction sequence based on the key iminosugar nitrile intermediate 61. Then, the glycosylation of 62 by the trichloroacetimidate 63 was fully stereoselective affording the b-D disaccharide 64 in 84% yield. Finally, hydrogenation and transesterification gave the imino-O-disaccharide 59 in 93% total yield.

The trichloroacetimidate-based glycosylation was also employed by Ganem and co-workers to synthesize di-, tri- and tetrasaccharides (70–72, Scheme 12) containing a 1,6-dideoxy-nojirimycin moiety. The suitably protected iminosugar alcohol derivative 68 was obtained from the 6-bromo-glucoside 65 through reductive ring opening followed by in situ reductive amination to give the aminoalkene 66. The latter was submitted to aminomercuration to afford the iminosugar 67 that gave the desired glycosyl acceptor 68 upon carefully optimized reductive oxygenation. The coupling of 68 with the glucosyl imidate 63 afforded the protected imino-O-disaccharide 69 from which the target compound 70 was obtained by standard deprotection reactions in 50% total yield (3 steps). Moreover, glycosylation of the iminosugar 68 with cellobiosyl and cellotriosyl trichloroacetimidates allowed, after O- and N-deprotection, to recover the trisaccharide 71 and the tetrasaccharide 72, respectively, in satisfactory yield (Scheme 12). Compounds 71–72 proved to be efficient glycosidases inhibitors (see section 6).

Another use of trichloroacetimidate derivatives as glycosyl donors was described by Moss and Vallance who prepared the iminosugar analogues (79 and 80, Scheme 13) of the repeating disaccharide unit found in peptidoglycan, i.e. the N-acetylglucosamine-β-1,4-N-acetylmuramic acid. The 3-OH of the commercially available diacetoneglucose 73 was first protected as p-methoxybenzyl ether, then a selective hydrolysis of the 5,6-O-isopropylidene group allowed to activate the primary alcohol as tosylate which was replaced by an azido function. Benzylation, followed by methanolysis of the isopropylidene and treatment with triflic anhydride gave the methyl glycoside 74 as an anomeric mixture. Reduction of the azide led to intramolecular cyclisation and, after protection of the amino group, hydrolysis of the acetal and reduction of the aldehyde, to the Cbz-protected 1-deoxymannojirimycin 75. Silylation of the primary alcohol and installation of the lactate moiety at the 3-OH gave, after removal of the p-methoxybenzyl group, to the glycosyl acceptor 76. Coupling of the latter with the 2-phthalimido-glucosyl trichloroacetimidate 77 in the presence of boron trifluoride afforded the corresponding disaccharide in 50% yield. Selective deprotection of this compound gave the free acid 78 which was coupled with a di- and a tri-peptide under standard conditions to afford, after hydrogenolysis and basic treatment, the peptidyl imino-O-disaccharides 79 and 80, respectively. In a following paper, Moss and Southgate reported the preparation of the 2-epi-acetamido analogues of 79 and 80, i.e. disaccharides bearing a 2-acetamido-1,2-dideoxynojirimycin instead of 1-deoxymannojirimycin unit, using the same synthetic approach. Unfortunately, all compounds did not show antibacterial activity neither were inhibitors of translocases 1 and 2, and transglycosylase, the enzymes involved in peptidoglycan biosynthesis.

The synthesis of six imino-O-disaccharides was described by Hasegawa and co-workers. They prepared a series of suitably protected 1-deoxynojirimycin glycosyl acceptors having a free OH group at the position 4 (81 and 82, Fig. 3) or 3 (83–85) that were allowed to react with thioglycoside or glycosyl bromide donors belonging to the D-galacto (86 and 87, Fig. 3) and D-gluco series (88 and 57). The Authors proved by NMR analysis that the iminosugar adopts, in both mono- and disaccharide derivatives, a 1C4 conformation only when the endocyclic nitrogen is protected as carbamate (Boc or Cbz) and the 4,6-benzylidene protecting group is not present (see Fig. 3).

(Continues…)

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Table of Contents

Synthesis and Biological Properties of Imino-disaccharides and -oligosaccharides;
Bacterial Polysaccharides as Major Surface Antigens: Interest in O-acetyl Substitutions;
Regioselective glycosylation: What’s new?;
Glycosyltransferase Inhibitors: A Promising Strategy to Pave a Path from Laboratory to Therapy;
Targeting Protein-Carbohydrate Interactions in Plant Cell Wall Biodegradation: the power of carbohydrate microarrays;
Low Melting Carbohydrate Mixtures and Aqueous Carbohydrates – an effective green medium for organic synthesis;
Surfactants Based on Green/Blue Sugars: towards new functionalities in formulations;
Low Molecular Weight Carbohydrate-based Hydrogelators