“… long may this valuable SPR title continue to fulfil the timely needs of all of us interested in that burgeoning topic called carbohydrates.”– “Natural Product Reports, 2001, 18, 228-230”

“A wealth of diverse and valuable carbohydrate chemistry appears within the covers of this book … long may this valuable SPR title continue to fulfil the timely needs of all of us interested in that burgeoning topic called carbohydrates.”– “Journal of the Chemical Society, Perkin Transactions 1, 2001, p 566-567 (Reviewing Vol 31)”

“Well written by the groups of experts, this book provides critical in-depth accounts of progress in carbohydrate chemistry, offering a unique tool for the active research chemists working in the field of science.”– “Revue de Biochimie (Reviewing Vol 21)”

Carbohydrate Chemistry Volume 34

Monosaccharides, Disaccharides, and Specific Oligosaccharides

By R. J. Ferrier

The Royal Society of Chemistry

Copyright © 2003 The Royal Society of Chemistry
All rights reserved.
ISBN: 978-0-85404-238-8

Contents

Chapter 1 Introduction and General Aspects, 1,
Chapter 2 Free Sugars, 4,
Chapter 3 Glycosides and Disaccharides, 14,
Chapter 4 Oligosaccharides, 62,
Chapter 5 Ethers and Anhydro-sugars, 91,
Chapter 6 Acetals, 95,
Chapter 7 Esters, 100,
Chapter 8 Halogeno-sugars, 115,
Chapter 9 Amino-sugars, 118,
Chapter 10 Miscellaneous Nitrogen-containing Derivatives, 136,
Chapter 11 Thio-, Seleno- and Telluro-sugars, 157,
Chapter 12 Deoxy-sugars, 166,
Chapter 13 Unsaturated Derivatives, 169,
Chapter 14 Branched-chain Sugars, 175,
Chapter 15 Aldosuloses and Other Dicarbonyl Compounds, 188,
Chapter 16 Sugar Acids and Lactones, 190,
Chapter 17 Inorganic Derivatives, 200,
Chapter 18 Alditols and Cyclitols, 205,
Chapter 19 Nucleosides, 248,
Chapter 20 Enzymes in Mono-and Oligo-saccharide Chemistry, 303,
Chapter 21 Structural and Quantitative Analytical and Separatory, 322,
Chapter 22 Carbohydrates in Chiral Organic Synthesis, 338,
Author Index, 367,

CHAPTER 1

Introduction and General Aspects

This year saw the publication of a triple issue (numbers 7–9) of Glycoconjugate Journal highlighting ‘Glycobiology at the Millennium, a look back and a glance ahead’. Topics covered range from an appreciation of A. Kabat (Feizi and Lloyd) and affinity enhancement of lectin–carbohydrate interactions (Lee and Lee) to carbohydrates as future anti-adhesion drugs for bacterial disease (Sharon and Ofek). A symposium issue of Journal of Carbohydrate Chemistry features a collection of articles from the First Euroconference on Carbohydrates in Drug Research. A special issue of Chemical Reviews has been published entitled ‘Frontiers in Carbohydrate Research’, and sub-titled by the guest editor (J.K. Bashkin) ‘Carbohydrates – A Hostile Scientific Frontier Becomes Friendlier’. Amongst other topics, many of which are referred to at the beginning of relevant chapters, this issue covers solid-phase oligosaccharide synthesis and combinatorial carbohydrate libraries (Seeberger and Haase), intramolecular O-glycoside formation (Schmidt and co-workers), enzyme-based and programmable one-pot strategies for synthesis of complex carbohydrates and glycoconjugates (Koeller and Wong, who have written a further review on this topic) and theoretical approaches and experimental validation of studies on the structure, conformation and dynamics of bioactive oligosaccharides (Imberty and Perez).

A review from Zechel and Withers, entitled ‘Glycosidase Mechanisms: Anatomy of a Finely-tuned Catalyst’, addresses issues of transition state structure, substrate distortion, acid–base catalysis and trapping of covalent intermediates. Winchester and Fleet have reviewed modification of glycosylation of glycoconjugates as a therapeutic strategy; the use of glycosphingolipid synthesis inhibitors as therapy for glycolipid storage disorders has been also reviewed. The glycan repertoire of genetically modified mice has been analysed by nano-NMR spectroscopy – a key step on the way to understanding the role of glycosylation in vivo. At the whole-cell level, synthetic A-glycolylmannosamine pentaacetate has been used to prime A-glycolylneuraminic acid formation in neural cell cultures and hence alter cell phenotype. Synthetic heparin–diazeniumdiolate conjugates have been shown to act as inhibitors of thrombin-induced blood coagulation by virtue of their ability to generate nitric oxide. A comprehensive, and comprehensible, survey of topical issues in glycobiology appears in Essentials of Glycobiology.

The synthesis and biological activity of glycolipids, with a focus on gangliosides and sulfatide, has been reviewed. Extensive studies at the forefront of chemical synthesis, detailing the successful total synthesis of the oligosaccharide antibiotic everninomycin 1, have been reported by Nicolaou and co-workers. The use of olefin metathesis in carbohydrate chemistry has been reviewed.

Combinatorial methods have been used to generate penta- and hexa-peptides with monosaccharide-recognition ability. A number of review articles have appeared concerning solution and solid-phase approaches to the generation of carbohydrate-based combinatorial libraries. The use of anomeric radicals in the synthesis of O- and C-glycosides has been reviewed, as have the conformations of the radicals and their reactions under reductive conditions. An extensive review of iodine and iodine-based reagents in carbohydrate chemisry has appeared.

Last year saw the death of Professor Guy Dutton, well known for his leading work on polysaccharide structural analysis; his obituary has appeared.

CHAPTER 2

Free Sugars

1 Synthesis

1.1 Tetroses and Pentoses. – A new synthesis of 2-O-benzyl-3,4-O-isopropylidene -D-erythrose (2) from 2,3-O-isopropylidene-D-glyceraldehyde involved chain-extension by use of methyl tolyl sulfoxide, followed by benzylation of the new hydroxyl group to give 1. Quantitative transformation of the sulfoxide to a formyl group (1 ->2) was achieved by exposure to lutidine-trifluoroacetic anhydride, then aq. sodium hydrogen carbonate.

Compound 3 was prepared from commercially available (R)-(+)-5 -hydroxymethyl-5H-furan-2-one by O-benzylation and subsequent conjugate addition of (PhMe2Si)2 Cu(CN)Li2, and converted to 2-deoxy-L-ribose (5) via the 2-deoxy-L-ribonolactone derivative 4. 2′-Deoxy-D-ribose 5-phosphates 13C-labelled at C-3 and C-4, and/or at C-5, were prepared in a chemoenzymatic approach by cyclizing appropriately labelled dihydroxyacetone monophosphates with unlabelled acetaldehyde. By use of [13C2]-, [1-13C]- or [2-13C]-acetaldehyde, labels were also introduced at C-1 and/or C-2.

1.2 Hexoses. – The de novo syntheses of enantiopure D- as well as L-hexoses from vinylfuran (see Vol. 33, Chapter 2, Ref. 10) were greatly improved by use of optimal conditions for the required Sharpless catalysed asymmetric dihydroxylation.

Hetero Diels–Alder cycloaddition of α,β-unsaturated carbonyl compounds and dioxygenated alkenes in the presence of a chiral bisoxazoline-Cu(OTf)2 complex as Lewis acid catalyst furnished hexopyranose precursors in good yields and high enantomeric excess. In the synthesis of the precursor 6 of ethyl tetra –O-acetyl-β-D-mannopyranose outlined in Scheme 1, for example, a 69% overall yield and 99% ee were achieved. A new route to hex-2-uloses involving boron-or, preferably, lithium-enolates is exemplified in Scheme 2. Only 3,4-trans- products were formed when the chiral lithium amide 7 was used to generate the enolate, with the D-tagatose derivative 8 as the major (69%) and its D-psicose isomer 9 as the minor (8%) products.

A new approach to multiply-protected aminodeoxyhexoses using an Sn(OTf)2-catalysed cross-aldol condensation between lactaldehyde and a tricarbonyliron/α-aminoheptadiene complex is referred to in Chapter 9.

The synthesis of L-sugars has received considerable attention: the furfural-derived, optically active, bicyclic enone 10 served as common precursor of L-galactose, L-gulose and L-idose. Compound 10 was converted in a four step 1,3-enone transposition to its isomer 11, from which the remaining five L-aldohexoses (L-allose, L-altrose, L-glucose, L-mannose and L-talose) were obtained. Several L-hexoses have been synthesized from the appropriate perbenzylated D-hexono-1,5-lactones by exposure to BnONH2-Me3Al to give acyclic intermediates (e.g.12) which ring-closed with inversion at C-5 on treatment with DEAD-TPP. The resulting oximes (e.g.13) were readily hydrolysed and reduced to the perbenzylated free L-sugars.

D-Glucono-1,4-lactone derivative 14 was converted to L-gulose by reductive opening, followed by persilylation and acetal hydrolysis to give diol 15, then primary oxidation and deprotection. Acetal hydrolysis in the presence of silyl groups was achieved by use of BCl3. In another, as yet incompleted synthesis of L-gulose starting from 2,3,4,6-tetra-O-Tbdms-D-gulono-1,5-lactone, use was made of BCI3 in THF for the selective cleavage of the primary Tbdms ether (16 -> 17), to allow the necessary C-6 oxidation (17 ->18). 1,2:5,6-Di –O-isopro-pylidene-β-L-idofuranose, formed on acid treatment of the 1,2:3,5-di-0-acetal (see Chapters 6 and 13 for synthesis), gave the elimination products 19 and 20 on treatment with DAST-pyridine and PDC-Ac2O-pyridine, respectively. The former underwent stereo- and regioselective hydroboration to furnish L-altrose, after acid hydrolysis; the latter was converted to l- mannose by catalytic hydrogenation, then deprotection. An immobilized L-rhamnose isomerase of Pseudomonas sp. was used to produce L-talose from L-tagatose and D-gulose from D-sorbose in 12 and 10% crystalline yield, respectively. A new formal synthesis of 4-deoxy-L-hexoses from (R)-benzylglycidyl ether is covered in Chapter 12.

Asymmetric dihydroxylation experiments with α-D-xylo-hex-5-enofuranose derivatives (21 ->22) under a variety of conditions showed that the C-3 substituent (X) plays an important role. 3-Esters 21 (X = OAc or OBz) and the 3-deoxy compound 21 (X = H) gave D-gluco- and 3-deoxy-L-ido-products, respectively, with good selectivity when ‘Admix a’ was used as the reagent.

1.3 Chain-extended Sugars. – 1.3.1 Chain-extension at the ‘Non-reducing End’. Methyl 2,3,4-tri-O-benzyl-D-erythro-α-D-gluco-oct-1,5-pyranoside and its L- erythro-β-D-gluco-isomer have been synthesized for the first time by cis-hydroxylation of the appropriate 6-C-vinyl-D- and -L-glycero-D-gluco-pyranose derivatives, respectively.

Homologation of protected dialdohexoses 23 with α-D-gluco-, α-D-galacto- and α-D-allo-configurations by use of various (substituted-methyl)magnesium chlorides, has been undertaken. Good L-selectivity was achieved with PhMe2SiCH2MgCl (e.g. 23 ->24). The glycero-D –manno-heptopyranoside-7-phosphate analogues 25 were obtained from a dialdehydo-mannopyranoside precursor by reaction with MePO(OEt)2-n-BuLi, followed by deprotection.

Dibromide 27, required for the preparation of doubly homologated analogues of adenosine (see Chapter 19), was obtained by oxidation of 5-deoxy-α-D-allofuranose derivative 26 to the corresponding 6-aldehyde, treatment with Br2C=PPh3 and replacement of the silyl by a benzoyl group. The synthesis of the bridged α,β-unsaturated lactone 30 involved Wittig-extension of the dispiroketal-protected 6-aldehydo-D-mannopyranoside 28 to furnish 29, followed by debenzylation with concomitant cyclization by use of FeCl3 in dry dichloromethane.

C-Alkylation of mannofuranoside 5,6-cyclic sulfate 31 with n-alkylated lithium dithianes gave chain-extended 7-osulose precursors 32, accompanied by by-products 33 in increasing amounts (0-42%) with increasing alkyl chain length (n = 0–12). Cyclic sulfate 34 was opened with lithium trimethylsilyl -dithiane to furnish ketone 35 after dethioacetalation. Further processing gave the 3-trimethylsilyl-5-(threos-4-yl)-pyrazole derivatives 36, as shown in Scheme 3.

3-O-Benzyl-6-deoxy-1,2-O-isopropylidene-α-D-xylo-hexofuranos-5-ulose (37) on treatment with carbon disulfide and methyl iodide under basic conditions afforded α-oxoketene dithioacetal 38, which was transformed to pyrazole derivative 39 by exposure to hydrazine hydrate. A 3-deoxy-3,4-unsaturated analogue was similarly prepared. Conversion of ketone 37 to the Knoevenagel product 40 prior to treatment with CS2-MeI-NaH led to the formation of the sugar ‘push-pull-butadiene’ 41.

In the presence of chloramine T, the non-reducing end oxime 42 underwent 1,3-polar cycloadditions with terminal alkynes to give 3-glycosyl-5-substituted isoxazoles 43 in moderate yields. Reductive alkylation of pyrroline derivative 44 with methyl 2,3,4-tri-O-benzyl-6-deoxy-6-iodo-α-D-glucopyranoside gave, after ester reduction, osmylation and acetylation-deacetylation, the novel poly-hydroxypyrrolidine 45, containing a methyl glucoside moiety.

Chain-extension has been brought about intramolecularly by ring-closing metathesis of glycoside dienes. The 3-0-allyl-hex-5-enofuranose derivative 46, for example, afforded the 3,7-anhydroheptofuranose 47.

Crossed-aldol condensations between 1-deoxy-3,4:5,6-di-O-isopropylidene-L -fructose and various protected aldehydo-pentoses afforded C-11 sugars, mostly as diastreomeric mixtures, in modest yields. Higher analogues of sucrose were obtained by oxidation and one-carbon Wittig extension at C-6 of an appropriately protected starting compound and subsequent cis-dihydroxylation of the 6,7-double bond. Radical addition reactions furnishing D-galactofuranosyl-containing C-disaccharides are covered in Chapter 3.

1.3.2 Chain-extension at the ‘Reducing End’. Mercuricyclization of hept-dienitol 48 and subsequent reductive demercuration in the presence of oxygen afforded a 3:1 mixture of 1,2-unsaturated hept-3-ulofuranosides 49. Reaction of 5,6-O -isopropylidene-2,3-di-O-Tbdms-D-allono-1,4-lactone with allyl magnesium chloride, followed by acetylation, then ozonolysis or epoxidation gave octo s-3-ulose derivative 50 and non-4-ulose derivatives 51, respectively.

The differentially protected F-ring moiety 53 of the altohyrtin group of anticancer macrolides has been prepared using intramolecular opening of epoxide 52 to form the pyranose ring. Compound 52 was obtained by epoxidation of the corresponding unsaturated octitol, which in turn was constructed from small molecules in a multistep asymmetric synthesis.

Radical allylation of peracetylated 1-bromo-β-D-glycopyranosyl chlorides 54 (β-D-gluco-, β-D-manno- or β-D-galacto-configuration) with allyltributyl tin under photolytic conditions gave 4-ulopyranosyl chlorides 55 in moderate to excellent yields. Radical dechlorination then furnished the expected 3-(β -D-glycopyranosyl)-1-propenes 56. Alternatively, base-induced dehydrochlorination led to the new glycopyranosylidene dienes 57. Insertion of glycosylidene carbene derived from 58 into boron-alkyl bonds of trialkylborons or B-alkyl-9-oxo-10-borabicyclo[3.3.2]decanes gave the base-stable glycosyl boranes 59 and glycosyl borinates 60, respectively, with low stereoselectivity. Oxidation of 59 and 60 (H2O2-NaOH) afforded exclusively hemiketals 61 and 61a, respectively, with axial OH.

α-Bromoacetals 63, available by 1,4-addition of allyl alcohol to the D-mannono-1,4-lactone-derived enol ester 62 in the presence of NBS, underwent radical cyclization on treatment with BmSnH to afford spiroacetal 64. The spiroketal moieties of spirophostins 66, conformationally restricted analogues of the adenophostin-type nucleoside antibiotics, were formed by acid-promoted cyclizations of precursor non-4-uloses 65. On exposure to DIBAL, the known spiroketal mesylate 67 rearranged to give the hydroxylated, cis-fused 1,6-diox -adecalin 68. Formation of a cyclic intermediate 67a by participation of the C-3 benzyloxy group in the displacement is proposed, the sulfonate being displaced intramolecularly by the tetrahydrofuranyl oxygen atom.

2 Reactions

A short summary of the Bilik reaction (molybdic acid-catalysed epimeric interconversion of aldoses with skeletal rearrangement) has been published. The the corresponding 2-C-(hydroxymethyl)-D-tetroses is covered in Chapter 14. molybdic acid-catalysed isomerizations of D-erythro– and D-threo-pentulose to molybdic acid-catalysed isomerizations of D-erythro– and D-threo-pentulose to the corresponding 2-C-(hydroxymethyl)-D-tetroses is covered in Chapter 14.

The platinum-catalysed oxidation and carboxy-alkylation of free sugars has been reviewed (11 pp., 44 refs.). A kinetic study on the oxidation of aldopentoses in aq. sulfuric acid by electrolytically generated manganese dioxide has been undertaken. The iridium(III)-catalysed oxidation of maltose and lactose by NBS in perchloric acid has been investigated, with particular attention to the effects of various additives, such as acetamide, acetic acid, KCl and Hg(OAc)2 on the reaction rates. In order to locate the reaction sites in starch oxidation processes, the characteristics of the reactions of the model compounds methyl α-D-glucopyranoside and 1,2-O-isopropylidene-α-D-glucofuranose with oxygen in alkaline solution in the presence of copper phenanthroline have been studied.

The highly efficient catalytic activity of lanthanide(III) ions in the thermal degradation of the most common monosaccharides as well as several fructose-containing di- and tri-saccharides in organic solvents, especially in DMSO, with formation of 5-hydroxymethylfurfural has been investigated.

Addition of glycine during the conversion of D-glucose by aqueous alkali greatly increased the rate of formation of carbonyl and dicarbonyl degradation intermediates, whereas their subsequent transformation to carboxylic products was inhibited. In the presence of thiols, browning was accelerated, but when both glycine and a thiol were added, it was slowed down. The effects of constant reaction pH on sucrose degradation has been assessed by use of simulated industrial model systems. It was shown that minimum sucrose degradation occurred between pH 6.45 and 8.50.

3 Other Aspects

The relative proportions of the acyclic aldehydic forms of eight hexoses, four pentoses and three deoxyaldoses has been estimated from the rate constants for their reactions with urazole. The absolute values were obtained by correlation with literature NMR measurements.

(Continues…)Excerpted from Carbohydrate Chemistry Volume 34 by R. J. Ferrier. Copyright © 2003 The Royal Society of Chemistry. Excerpted by permission of The Royal Society of Chemistry.
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