“Well written by the groups of experts, this book provides critical in-depth accounts of”

Carbohydrate Chemistry Volume 32

Monosaccharides, Disaccharides, and Specific Oligosaccharides

By R. J. Ferrier

The Royal Society of Chemistry

Copyright © 2001 Royal Society of Chemistry
All rights reserved.
ISBN: 978-0-85404-228-9

Contents

Chapter 1 Introduction and General Aspects, 1,
Chapter 2 Free Sugars, 3,
Chapter 3 Glycosides and Disaccharides, 15,
Chapter 4 Oligosaccharides, 58,
Chapter 5 Ethers and Anhydro-sugars, 85,
Chapter 6 Acetals, 92,
Chapter 7 Esters, 97,
Chapter 8 Halogeno-sugars, 112,
Chapter 9 Amino-sugars, 116,
Chapter 10 Miscellaneous Nitrogen-containing Derivatives, 133,
Chapter 11 Thio- and Seleno-sugars, 153,
Chapter 12 Deoxy-sugars, 161,
Chapter 13 Unsaturated Derivatives, 166,
Chapter 14 Branched-chain Sugars, 174,
Chapter 15 Aldosuloses and Other Dicarbonyl Compounds, 191,
Chapter 16 Sugar Acids and Lactones, 194,
Chapter 17 Inorganic Derivatives, 206,
Chapter 18 Alditols and Cyclitols, 210,
Chapter 19 Antibiotics, 241,
Chapter 20 Nucleosides, 256,
Chapter 21 NMR Spectroscopy and Conformational Features, 312,
Chapter 22 Other Physical Methods, 325,
Chapter 23 Separatory and Analytical Methods, 342,
Chapter 24 Synthesis of Enantiomerically Pure Non-carbohydrate Compounds, 353,
Author Index, 396,

CHAPTER 1

Introduction and General Aspects

Boons has edited a multi-author book ‘Carbohydrate Chemistry’ which deals mainly with many topics of interest to synthetic chemists concerned with mono- and oligo-saccharide chemistry, while David has authored one which serves as a basis for studies of the carbohydrates for chemists, biochemists and biologists.

IUPAC-IUBMB recommended rules for the nomenclature of glycolipids have appeared.

Advances in Carbohydrate Chemistry and Biochemistry, Vol. 53 has chapters dealing with tin-containing intermediates in carbohydrate chemistry, synthesis aspects of selenium-containing sugars and antibodies with specificity for monosaccharide and oligosaccharide units of antigens. It also records appreciations of the work of John E. Hodge, Allene R. Jeanes and Harriet L. Frush.

Reviews of general significance have been written on the transformation of D-fructose, L-sorbose and isomaltulose, i.e. the most accessible ketoses, into starting materials for industrial synthesis, and the use of carbohydrate ‘building blocks’ for the synthesis of Pharmaceuticals. A review of papers covering advances in protecting group chemistry published in 1997 includes sections on the protection of diols, amines, carboxylic acids and phosphates – all with significance for carbohydrate chemists.

Many reviews relevant to the topics covered in the body of the Reports are referred to at the beginning of the chapters; others to have appeared relate to: cyclodextrins (a complete issue of Chemical Reviews has been devoted to them), the chemistry of neutron capture therapy (sugar derivatives having linked carboranes are the significant compounds), biosensing with polymer vesicles having biorecognition molecules on their surfaces (sialic acids, for example) and carbohydrate-selectin interactions (including the identification of the Sia Lex groups which determine the binding).

Two other somewhat general topics to have been reviewed are the production of enantiopure bioactive molecules by biotransformations (e.g. cyclopen-tene and cyclohexa-1,3-diene derivatives), and the use of hypervalent iodine reagents in carbohydrate chemistry (mainly addition and oxidation reactions of glycals).

CHAPTER 2

Free Sugars

1 Theoretical Aspects

The anomeric effects in 2-methoxytetrahydropyran, 2-deoxyribose and glucose have been investigated by use of class II force field calculations, and ab initio quantum mechanical methods including continuum solvation have been employed to study the intrinsic exocyclic hydroxymethyl rotational surface for (β-D-glucopyranose as well as the α/β energy difference for D-glucopyranose.

Mathematical calculations for predicting saccharide–saccharide interactions under vacuum and in aqueous solutions indicated very strong interactions for (β-D-glucopyranose/(β-D-glucopyranose, α-D-glucopyranose/α-D-fucopyranose and sucrose/ (β-D-glucopyranose.

2 Synthesis

Mixtures containing up to 30% aldopentoses were obtained when formaldehyde and catalytic amounts of known intermediates of the prebiotic pathway were incubated with lead salts.

A section on the preparation of ketosugars via ketosugar phosphates was included in a review on the use of aldolases in synthesis. A kinetic study on the aldolase-catalysed condensation of various electrophilic aldehydes with pyruvate (1 -> 2) showed that there is no advantage in the use of preformed phosphates (compounds 1, R = PO32-).

The mechanism of the condensation of sugar-aldehydes and -ketones with Dondoni’s reagent [2-(trimethyl)thiazole] has been examined with particular attention to the fact that the reactions of ketosugars are accelerated by addition of equimolar quantities of a free aldose or a non-sugar aldehyde.

Efficient hydrolysis (yields 80–90%) of ethyl thioglycosides has been achieved with BU4NIO4 and 70%> aqueous triflic acid in acetonitrile.

2.1 Tetroses to Hexoses. – L-Threose derivative 3 has been synthesized from l-tartaric acid in four standard steps, as a useful precursor of homochiral, functionalized, long-chain alcohols 4. Further tetrose derivatives suitable for chain-extension, such as 5, have been obtained by radical cleavage of the C-1–C-2 bond in pentofuranose derivatives on exposure to (diacetoxyiodo)benzene and iodine (see Vol. 31, Chapter 2, ref. 7). The syntheses of d- and L-threose- and -erythrose-derivatives modified at the 2-position from D-isoascorbic and L-ascorbic acid via intermediate 6 and its enantiomer, respectively, are referred to in Chapters 5 and 12.

Pentodialdose derivatives 7, obtained from D-glucose by conventional methods, were converted to 5-monodeuterated pentose derivatives 8 with S/R-ratios from 4:1 to 1:7.4 by reduction with UAID4 in the presence of various ligands. The use of these compounds in the preparation of 5′-monodeuterated nucleosides is covered in Chapter 20.

The key operation in the preparation of L-xylose from xylitol was the lipase-mediated enantioselective deacetylation of the racemic cyclic acetal 9 to give the L-enantiomer 10, whereas preparation of the L-fucose precursor 12 involved controlled, lipase-mediated mono-acetylation of the galactitol-derived cyclic acetal 11. Addition of nitromethane to D-xylose by an improved procedure and exposure of the 1-deoxy-1-nitroalditol thus formed to Nef conditions (aq. NaOH, then aq. H2SO4) gave simple access to D-idose. 11C-Labelled aldononitriles, obtained from D-arabinose by chain-elongation with NH411CN on a solid support, furnished D-[1-11C] glucose on reductive hydrolysis with Raney nickel/formic acid (radiochemical yield >95%).

The biosynthesis of apiose is referred to in Chapter 18.

A new method for epimerizing free sugars via 1,2-O-stannylene derivatives has been exploited in a practical synthesis of D-talose from D-galactose. The process is equilibrium driven and favours the structure with an axial OH-group at C-2.

Stereocontrolled, Lewis acid-promoted addition of Danishefsky’s diene (E-1-methoxy-3-trimethylsilyloxy-1 ,3-butadiene) to syn-2-formyl-2-methyl-1,3-dithiane-1-oxide furnished compound 13 which is amenable to functionalization of the enone grouping and may thus serve as intermediate in the synthesis of unusual deoxy- and deoxyhalosugars, e.g.14. The preparation of a 2-deoxy-D-xylo-hexose derivative from cycloheptatriene is referred to in Chapter 12.

The hydrogen atoms a to the unprotected anomeric centres in certain sugars are readily exchanged on heating in dioxane-THF -Et3N-D2O (4:4:2:3), often with considerable stereoselectivity as demonstrated by the deuteration 15 ->16 which proceeded almost quantitatively. The direct conversion of aldohexoses to hex-2-uloses in the presence of samarium iodide and oxygen (see Vol. 30, p. 5, ref. 23) has been improved by replacing THF as solvent with THP. The yield of the transformation 17 ->18, for example, increased from 44 to 88%.

The introduction of 17O at C-2, C-4 and C-6 of D-glucose has been effected by irreversible, stereo selective benzoylation of appropriately protected precursors either by displacement of a triflate group with 17O-labelled sodium benzoate or by reaction of a free hydroxyl group with 17O-labelled benzoic acid under Mitsunobu conditions, then debenzoylation.

2.2 Chain-extended Sugars.– A facile synthesis of D-gluco-hept-2-ulose from D-mannose is referred to in Part 4 of this chapter (ref. 50).

2.3.1 Chain-extension at the ‘Non-reducing End’. Suitably protected methyl α-D-mannnopyranosides 19 were oxidized (Swern) and chain-extended with benzyloxymethylmagnesium chloride to give the C-5 epimers 20, as well as small quantities of the C-5 epimers 21. Conversion of these heptosides to monophosphates is covered in Chapter 7. One-carbon extensions have also been achieved by indium trichloride-catalysed, asymmetric aldol condensations with formaldehyde; the D-glucose-derived silyl enol ether 22, for example, furnished heptos-5-ulose derivative 23.

Addition of fluorinated-alkyl organometallics to carbohydrate aldehyde 24 gave access to higher deoxyfluoro-sugars 25, and the related compounds 27 have been prepared by addition of fluorinated-alkyl halides to terminal alkene 26 in the presence of dithionite as initiator.

The branched chain-extension in the synthesis of compound 31, a D-glucose-based potential mimetic of the bioactive cyclic dipeptide hapalosin, from benzyl 3-O-heptyl-α -D-glucopyranoside (28) has been accomplished by Wittig reaction of aldehyde 29 to give 30, as indicated in Scheme 1.

Treatment of pentodialdose derivative 32 with vinylmagnesium bromide or allyltrimethylsilane, followed by acryloyl chloride, gave the di-ω-unsaturated higher sugar esters 33, which underwent ring-closing metathesis in the presence of Grubbs’ catalyst [bis(tricyclohexylphosphine)benzylidene ruthenium] and titanium tetraisopropoxide to afford αβ-unsaturated γ- or δ-lactones 34 (Scheme 2). A similar approach was used to produce the unsaturated macrocyclic lactones 35.

A multi-step synthesis of compound 40, a model for the lower periphery of the macrocycle antibiotic maytansine, involved alkylation of an allylic sulfide anion by 6-iodide 36 (obtained in five steps from D-glucal) for introduction of a branched four-carbon extension (Scheme 3). Oxidation to sulfoxide 37 with concomitant 2,3-sigmatropic rearrangement and thiophilic trapping of the resulting sulfenate ester 38 furnished allylic alcohol 39. Grignard methodology was used in the further elaboration to target 40.

Wittig condensations of various sugar dialdehyde derivatives with sugar derived phosphoranes or phosphonates gave higher sugar dialdoses. Condensation of the C12-dialdehyde 41 with the C9-phosphorane 42, for example, produced the C21-dialdose 44 (Scheme 4). This reaction had to be conducted at 13 kB, whereas the more nucleophilic phosphonate 43 reacted at atmospheric pressure, giving rise, however, to elimination by-products. A series of C12- or C13-dialdoses, e.g.46, were prepared by similar condensations between C5- or C6-sugar dialdehyde derivatives and three different C7-phosphoranes or phos-phonates to give enones, in this case 45, followed by highly stereoselective reduction of the carbonyl group (ZnBH4) and osmylation.

2.3.2 Chain-extension at the ‘Reducing End’. The stereoselective osmylation of L-xylo-oct-2-ene-4-ulofuranonate (47) proceeded with high selectivity in favour of diol 48, which was isopropylidenated, then reduced with LAH to give, after deprotection, L-glycero-D-galacto-oct-4-ulose(49).

Alkyl ketosides 53 were available by opening of the mixed spiroepoxides 52 with alcohols in the presence of ZnCl2 (only α-anomers were produced). The isomeric mixture 52 was obtained by oxidation of the known exo-glycal 51 with dimethyldioxirane, and a considerable improvement in the synthesis of 51 from lactone 50 by use of a Peterson olefination instead of reaction with Tebbe reagent has been reported.

Saturated spiroketals 55 have been prepared by acid-promoted cyclization of substituted exo-glycals 54 (the synthesis of 54 and similar substituted exo-glycals by use of a Ramberg–Bäcklund rearrangement is covered in Chapter 13). Unsaturated spiroketals with [5,7]-, [5,6]-, [5,5]- and [5,4]-ring systems, e.g. compounds 58, have been synthesized by ring-closing metathesis in the presence of Grubbs’ catalyst, as illustrated in Scheme 5. The required di-ω-unsaturated compounds 57 were obtained by addition of vinyl- or allyl-magnesium chloride to perbenzylated D-gluconolactone, then use of the products 56 in the glycosylation of terminally unsaturated alcohols.

Two-carbon chain-extensions of protected free sugars by reaction with amide-stabilized sulfur ylides and of unprotected aldoses by reaction with a in situ-generated phosphorus ylide, furnishing acyclic products, are referred to in Chapter 16. Also covered in Chapter 16 are the related chain-extensions, (i) of 1,2-anhydro-3,4:5,6-di-O -isopropylidene-D-mannitol by use of a lithiated disilylthioacetal leading to KDO; (ii) of a D-glucopyranosyl oxocarbonium ion, formed from the corresponding glycosyl fluoride by use of 2-(trimethylsilyl-oxy)furan, leading to a dec-2-enonic acid γ-lactone derivative; (iii) of hexonic acid chlorides by use of anions of dialkyl malonate leading to branched-chain 2-deoxyoctulosonic acid derivatives.

A new strategy for the synthesis of C-glycosides of phenols and the synthesis of C-glycoside 59, representing a nine-carbon segment of the marine natural product okadoic acid, from small, non-carbohydrate molecules are referred to in Chapter 3. The synthesis of 6-thio-N-acetylneuraminic acid from a mannose precursor involving a three-carbon chain-elongation by condensation with oxalacetic acid, followed by decarboxylation, is covered in Chapter 11, and a stereocontrolled, Lewis acid-catalysed aza-Cope rearrangement of N-glycosyl homoallylamines to afford chain-extended aminosugars in Chapter 18.

3 Physical Measurements

The pKa values of aldohexoses have been determined by capillary electrophoresis. Aqueous solutions of glucose, fructose, sucrose and trehalose, respectively, at concentrations from 0.2 to 70% have been investigated by modulated differential scanning calorimetry to measure the apparent heats of melting and freezing as well as the melting and freezing point depressions as functions of concentration. The interaction of D-glucose with sodium monoborate has been studied by use of the isomolar solution method.

The kinetics of the decomposition of sucrose in impure sugar solutions have been studied in acid media over a range of temperatures. Whereas the rate constant was affected by both temperature and pH, the presence of non-sugar contaminants appeared to have no effect.

4 Isomerization

In a kinetic study on the non-enzymic glucose-fructose isomerization new measurements of the thermodynamic equilibrium constant at different temperatures were compared to literature data; an enthalpy value of 8.5 kJ mol-1 has been derived.

The Ca(OH)2-promoted epimerization of chito-oligosaccharides to produce ManpNVAc-containing derivatives is covered in Chapter 9.

D-Glucose has long been known to isomerize to D-mannose under the influence of [Ni (H2O)2 (tmen)2] Cl2 in methanol with an interchange in the positions of C-1 and C-2 (see L. London, J. Chem. Soc, 1987, 61; Vol. 21, pp. 4/5, ref. 23), and it has now been shown that 5-azido-5-deoxy -D-glucose undergoes a similar epimerization with skeletal rearrangement, furnishing 5-azido-5-deoxy-D-mannose when exposed to Ni(Me4en) 2Cl2 in methanol. Analogous rearrangements have been observed in the case of D-fructose and the C-6-modified D-fructose derivatives 60, which gave 63; the C-5-modified D-fructoses 61, on the other hand, were degraded to the D-arabinonic acid derivatives 64, and the C-5/C-6 modified compounds 63 gave complex reaction mixtures.

The molybdate-mediated Bilik rearrangement of 2-C-hydroxymethyl -D-mannose (65) to D-gluco-hept-2-ulose (66), which results in a 2:23 equilibrium mixture, has been exploited in a facile synthesis of the latter compound from D-mannose (Scheme 6).

An improved procedure for the direct isomerization of hexoses to hex-2-uloses by use of SmI2/O2 is referred to in Part 2.1 of this chapter (ref. 18).

(Continues…)Excerpted from Carbohydrate Chemistry Volume 32 by R. J. Ferrier. Copyright © 2001 Royal Society of Chemistry. Excerpted by permission of The Royal Society of Chemistry.
All rights reserved. No part of this excerpt may be reproduced or reprinted without permission in writing from the publisher.
Excerpts are provided by Dial-A-Book Inc. solely for the personal use of visitors to this web site.