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ISBN-13: 9780854042234
Publisher: Royal Society of Chemistry, The
Publication date: 12/31/2000
Series: Specialist Periodical Reports Series , #31
Pages: 438
Product dimensions: 6.14(w) x 9.21(h) x (d)

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Carbohydrate Chemistry Volume 31

Monosaccharides, Disaccharides, and Specific Oligosaccharides

By R. J. Ferrier

The Royal Society of Chemistry

Copyright © 2000 The Royal Society of Chemistry
All rights reserved.
ISBN: 978-0-85404-223-4


Introduction and General Aspects

The long awaited comprehensive IUPAC/IUBMB paper on Nomenclature of Carbohydrates which covers all aspects of the subject has received wide dissemination.' Although the contents have the formal status of 'Recommendations', they are effectively the 'rules' to be followed. The subject has been revisited, particularly from the Hungarian perspective. Hanessian's multi-authored book 'Preparative Carbohydrate Chemistry' deals with a wide range of practical aspects of modern synthesis. Examples, which include experimental details, cover such topics as oligosaccharide synthesis, the conversion of carbohydrates into carbocyclic compounds, free radical reactions, the use of organotin reagents in the field, selective O-substitution and oxidation reactions applied to carbohydrates. A further book on synthesis consists of 21 chapters written by experts on various aspects of the field including methodology and the synthesis of different carbohydrate-based natural products.

A method for the representation of oligosaccharide structures by graphic theoretical methods has been developed for the purpose of storing and searching relevant information.

Attention is drawn to the plethora of reviews that have appeared on specific features of the subject and which are noted in relevant chapters. An extreme example is Chapter 4 which begins with a catalogue of 39 references to review material relevant to oligosaccharide chemistry and biochemistry.

Reviews of wider interest have appeared on the following topics: protecting groups of value in carbohydrate chemistry; protecting groups revealed in the 1997 literature; the use of phase transfer catalyses in anomeric transformations and glycosylations; the use of sugar derivatives as phase transfer catalysts and combinational synthesis in the field.

Biologically inclined treatments have dealt with preparative biotransforma-tions of carbohydrate derivatives (survey of the 1997 literature); structure-biological activity relationships of natural products; the role of 1-deoxy-D-threo-pentulose as a precursor in thiamine biosynthesis; chemo-enzymic synthesis of oligosaccharides of importance in molecular glycobiology. A brief discussion of molecular recognition events involving carbohydrates and their biological consequences has been written for non-specialists.

A very interesting proposal by A.I. Scott regarding the prebiotic biosynthesis of polyketides, fatty acids and polyprenoids uses ribonucleosides 5'-linked to RNA as templates, the C-C bonding reactions involving monomeric units linked to O-3'.

A survey has been presented on the carbohydrate transformations that can be induced by hypervalent iodine reagents. Such topics as the direct oxidation of tri-O-acetyl-D-glucal to the corresponding 1-en-3-one, C-1, C-2 bond oxidation of derivatives protected at all the hydroxyl groups except the anomeric and H-1 abstraction from C-glycosidic compounds were covered.

A significant development has been made in use of sodium periodate for oxidizing carbohydrate α-diols with the reagent adsorbed on silica; oxidations are carried out in dichloromethane and can be followed by TLC; product isolation requires decanting of the solution and removal of the solvent; yields are very high.

Carbohydrate-containing dendrimers are attracting considerable attention (see Chapter 3) and an overview of the topic by Stoddart and colleagues has appeared.

The subject of dihexulose dianhydrides has been the subject of a thorough review.


Free Sugars

1 Theoretical Aspects

An improved method for partitioning the overall molecular charge distribution into atom-centred monopole charges has been applied to D-glucose and d-fructose. The influence of the exo-anomeric effect on the conformations of D-glucose, as well as simpler tetrahydropyran derivatives, in the gas phase and in aqueous solution has been investigated by use of ab initio calculations.

2 Synthesis

The synthesis and reactions of sugars and nucleosides under conditions pertinent to early evolution have been incorporated in a review on 'prebiotic chemistry'.

2.1 Pentoses – C-3- Modified D-erythro- and D-threo-2-deoxypentofuranose derivatives, such as compounds 1 and 2, useful as precursors of nucleoside analogues, have been synthesized from 2,3-O-cyclohexylidene-D-glyceraldehyde as outlined in Scheme 1; a zinc-mediated allylation was used for extending the carbon-chain. 1-O-Acetyl-2,3,5-tri-O -benzyl-β-L-ribofuranose was obtained from 3,5-O -Tips-protected methyl L-arabinofuranoside viaa 2-O-trifluoromethanesulfonyl-intermediate.

2.2 Hexoses – Trapping of dihydroxyacetone phosphate (prepared from α-L-glycerol phosphate by use of co-immobilized α-L-glycerolphosphate oxidase and catalase under anaerobic conditions) by DL-glyceraldehyde in the presence of an aldolase gave, after enzymic dephosphorylation, a mixture of D-fructose and D-sorbose. 3,4,6-Tri-O -acetyl-2-azido-2-deoxy-D-glucopyranose (3) (or its manno-analogue) underwent fragmentation on exposure to (diacetoxyiodo)-benzene and iodine to give nitrile 6, by way of alkoxyl radical 4 and a-azido-carbinyl radical 5, as shown in Scheme 2.

In a novel isomerization reaction ditosylate 7 was converted to methyl α-D-altropyranoside (8) by treatment with sodium acetate in DMF, followed by aqueous-KOH; a manno-configured epoxide-intermediate has been postulated.

2,3,4,6-Tetra-O-llyl- and -benzyl-D-glucose have been obtained in 77% yield by thiolysis (EtSH/BF3OEt2,) of per-O-allyl- and per-O-benzylsucrose, respectively and hydrolysis of sucrose, maltose, cellobiose or starch by use of commercial, acidic zeolites at 80–150 °C in aqueous media gave D-glucose in >90% yield. D-Fructose was available similarly by hydrolysis of inulin.

2.3 Chain-extended Sugars – Fructose 1,6-diphosphate aldolase-catalysed condensation of 4-benzyloxybutanal with dihydroxyacetone phosphate furnished, after enzymic dephosphorylation, the 5,6-dideoxy-D-threo-hept-2-ulose derivative 9; its use in the synthesis of the natural macrolactone (+)- aspicilin is referred to in Chapter 24. Molybdic acid has been found to catalyse the carbon-skeleton rearrangement of 2-C -hydroxymethyl-D-aldohexoses tto D-hept2-uloses. In agreement with the known mechanism of the molybdate-catalysed epimerization of aldoses, 2-C-hydroxymethyl-D-glucose (10) gave D-manno-heptulose (12), and 2-C-hydroxymethyl -D-mannose (11) gave D- gloco- heptulose (13) preferentially.

2.3.1 Chain-extension at the "on-reducing End' – The epimeric 6-C-methyl-D-glucoses 14 and their 6-C-butyl analogues 15 have been synthesized by action of methyllithium and butyllithium, respectively, on 1,2-O-isopropyl-idene-5-O-Tbdms-α-β-glucurono -3,6-lactone and subsequent reduction and deprotection (see Vol. 30, Chapter 2, ref. 32). Addition of propargyl groups (HC = CCH 2Br/Zn) to various 5-aldehydo-pentofuranose derivatives proceeded with good erythro-selectivity; the addition products were either partially hydrogenated to alkenes, as precursors of 6-deoxyheptoses, or ozonolysed to afford 6-deoxyhepturonates; an example is given in Scheme 3.

An improved procedure for the synthesis of D-glycero-D-manno-heptofurano-side derivative 18 from 5-aldehydopentofuranose derivative 16 by Wittig addition/cis-hydroxylation via Z-alkene 17 has been reported (see Vol. 20, Chapter 2, refs. 25–27); use of formylmethylenetriphenylphosphorane in place of (methoxycarbonylmethy1ene)triphenylphosphorane furnished mainly the E-alkene 19, which on cis-hydroxylation gave the L-glycero-isomer 20 selectively. The D-glycero isomer 18 was also available by one-carbon elongation of the mannose-derived aldehyde 21 with benzyloxymethylmagnesium chloride.

Several protected 1,6-dialdohexopyranoses have been extended by the Wittig reaction/cis-hydroxylation method (22 -> 23, 24 -> 25) or by use of Grignard reagents (26 -> 27, 28 -> 29). Reaction of carbohydrate-derived Wittig reagents with calixarene tetra-aldehyde 30, followed by reduction of the double bonds, produced 'C-calixsugars', for example compound 31.

The nitrile oxide/oxazoline approach to higher sugars (see Vol. 27, Chapter 2, ref. 39) has now been applied to the syntheses of 7-deoxy-nonose and -decose derivatives, as illustrated in Scheme 4.

Radical alkylation of 6-iodide 32 with trimethyl[(2-tributylstannylmethyl)-2-propenyllsilane (34) furnished the branched, unsaturated tetradeoxynonopyranose derivative 33 in 45% yield.

2.3.2 Chain-extension at the 'Reducing End' – A review on transition metal-catalysed functionalization at the anomeric centre of carbohydrates covered Heck-type and Pd-catalysed vinylic coupling reactions of glycals, as well as reactions of glycal-derived π-allyl complexes.

Partially protected free sugars reacted with arsonium ylids in toluene under neutral conditions ([Ph3AsCH2 CO2Et]+Br-/Zn) to give mainly E-alkenes (e.g.,35->36 in Scheme 5); under basic conditions (Ph3As=CHCO2 Et/BuLi) fused lactones were formed via C-glycofuranosides (e.g.,36->37->38). D-Mannose has been extended by 4, 6, 8 or 10 carbon atoms by reaction of the protected aldehydo-sugar 39 with the appropriate Wittig reagents, followed by hydro-genation. Two of the products 40 were then elaborated into carbon-backbone-elongated GDP-L-fucose derivatives 41.

It has been demonstrated that Reformatzki alkylations of protected hexos-uloses furnish 2-deoxy-4-octulosuronic acid derivatives with considerable diastereoselectivity; the methodology has been applied to the synthesis of oct-4-ulo-4, 7-furanonate 43 from hexos-2-ulofuranose derivative 42. 4-Benzo-phenone-substituted ribofuranose derivative 46 has been prepared as a precursor of novel nucleoside analogues. The key step involved treatment of 2,3-O -isopropylidene-L-erythrose 44 with Grignard reagent 45, as shown in Scheme 6.

Indium-mediated allylation of D-erythrose in aqueous media generated the trideoxyhept-1-enito1 47 which offered convenient access to 3-deoxy-D-arabino-2-heptulose and 3-deoxy-D-arabino-2-heptulosonic acid. 3-Carbon elongation of 2-acetamido-2-deoxy-D-mannose by similar indium-promoted allylation and subsequent ozonolysis of the terminal double bond furnished 4-acetamido-2,4-dideoxy-D-glycero-D-galacto -octose, isolated as the α-peracetate 48. Allylation at the reducing end of sugars has also been effected with tetraallyltin in micellar systems, although with only moderate stereoselectivity; alkenes 49 were obtained from D-arabinose in 82% yield as a 3:7 mixture of the D-gluco-and D-manno-compounds, for example.

Commercial D-glycero-D-gulo-heptono-1,4-lactone (50) served as the starting material in a novel multi-step synthesis of N-acetylneuraminic acid (shown as the protected derivative 54, Scheme 7). The chain-elongation was achieved by alkylation of a 2-alkoxy-2-cyanoacetate anion with the allylic bromide 51. In a further key-step, opening of an epoxide by a neighbouring trichloroacetimidate group was used to introduce the amino function (52[right arrow]53). A stereospecific addition reaction of lithiated tri-Obenzyl-D-glucal to tetra-O-benzyl-D-glucono-1,5-lactone (55) has been used in the synthesis of the C-C-linked analogue 56 of α,α-trehalose (Scheme 8).

Full details on the acid-catalysed Wagner-Meerwein type rearrangements of glycal-derived carbinols [(57 -> 59, 58 -> 60; see Vol. 27, Chapter 3, Scheme 23) have been published. Reaction of the pivaloylated diazirine 61 with dihydro-furan gave the sugar-spirocyclopropane derivative 62 in 70% yield. The benzylated analogue of 61 and alternative enol ethers (dihydropyran, glycals, 1-methoxyoct-1-ene) reacted poorly, however.

3 Physical Measurements

A cost efficient method for determining the free energies of the anomers of free α- (axial) and β- (equatorial) anomers of D-mannose has been Calculated by three different standard methods [i, free energy perturbation (FEP), ii, potential of mean free force (PMF) and iii, the recently described MC(JBW)/SD simulation technique], the last of which performed best.

The solubilities of sucrose in aqueous MeOH, aqueous EtOH and in MeOW EtOH mixtures have been measured at 25, 40 and 60 °C, and three UNIQUAC-based activity coefficient models were evaluated for their ability to describe these new data, as well as older ones taken from the literature. Glass transition temperatures of aqueous glucose solutions calculated by molecular dynamics simulation were in good agreement with experimental data, in contrast to similarly calculated melting temperatures.

The diffusion constants of water in glassy systems of glucose and maltose syrups at various temperatures, water contents and molecular weights have been determined from the rates of desorption under reduced pressure. The activation energy for CAN-catalysed sucrose hydrolysis is referred to in Section 6 (ref. 45).

4 Isomerization

A study on the catalysis of mutarotation of tetramethylglucose by ribonucleo-sides found cytidine the most efficient, achieving a 20 fold rate increase which suggests a bifunctional mechanism.

It has been postulated that the calcium ion-catalysed epimerization of glucose in alkaline solution proceeds via a complex of the cation with O-1, O-2, O-3 and O-4 of the acyclic form of the sugar, and that the reaction, like the Bilik reaction, involves a rearrangement of the carbon skeleton. The glucose-mannose epimerization reaction has been carried out with the chiral nickel complexes (R,R)- and (S,S)-1,2-bis(dimethylamino)-1,2-diphenyl-ethane.

5 Oxidation

Two major products, D-arabino-hex-2-ulosonic acid and D-threo-hexo-2,5- diulose, were formed on oxidation of D-fructose with molecular oxygen over WC catalysts. Promotion of the catalyst with bismuth improved the selectivity for the former product, which, however, deactivated the catalyst

A kinetic and mechanistic study of the Pd(II)-catalysed oxidation of maltose and lactose by acidic NBS to give gluconic acid from maltose and both, gluconic and galactonic acid from lactose, has been published.

6 Other Aspects

The activation energy for sucrose hydrolysis by ceric ammonium nitrate at pH 7 was found to be 5.88 kJ/mol, which is much less than that for hydrolysis by 0.18 N HCl (126 kJ/mol) The hydrolysis of various other disaccharides, such as lactose, maltose and cellobiose, with the former reagent was equally efficient.

The degradation of D-ribose in the presence of propylamine in phosphate buffer at pH 7.4 and 70 °C furnished N-propylglycine propylamide, N-propyl-alanine propylamide, glycolic acid propylamide and lactic acid propylamide. Under similar conditions, D-glucose reacted more slowly giving the same products.

The diboronic acid-appended (R)-binaphthyl 63 showed enantiomer discrimination in the complexation of some saccharides; L-xylose, in particular, was favoured 8.7-fold over D-xylose.


Glycosides and Disaccharides

1 O-Glycosides

1.1 Synthesis of Monosaccharide Glycosides – Sinaÿ and Mallet have presented a review on the preparation and use of glycosyl xanthates and end ethers and related derivatives as glycosyl donors, and Voelter and colleagues have written one on the use of sugar epoxides and unsaturated sugars as intermediates in carbohydrate synthesis which contains work relevant to glycosides synthesis A general review (in Chinese) on glycosylation methods has appeared.

1.1.1 Methods of synthesis of glycosides – A new approach to the synthesis of furanosides adopts pentenyl glycofuranosides as donors, these being made from 4-pentenol and glucose, mannose and galactose using FeC13 as catalyst. The acetylated furanosyl products were used in the synthesis of furanosyl disaccharides, successful 1,2-trans -linking being achieved to the 4-position and, separately, to the 4-position of glucose. A novel specific synthesis of furanosides of ADP-ribose uses the corresponding glycofuranosyl nicotinimide as donor with NAD-ase as the catalyst. Reasonable yields were obtained by transfer to simple primary alcohols. A study of the effect of ultrasound on the glucosylation of butanol and octanol using the free sugar as glycosyl source and montmorillonite as catalyst has been reported

As usual peracetylated sugars have been used commonly as glycosyl donors, and in the cases of the peracetates of glucose, mannose, galactose and an N-protected glucosamine compound, the decyl glycosides have been made in good yield in a solvent-free system with ZnCl2 as catalyst and with the aid of microwave activation. Less commonly, O-benzylated α-D-mannopyranosyl trichloroacetate, activated with a hindered pyridine base, has been used, and it gave good yields of α-glycosides including those of a secondary monosaccharide alcohol and of phenols.


Excerpted from Carbohydrate Chemistry Volume 31 by R. J. Ferrier. Copyright © 2000 The 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.
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Table of Contents


Chapter 1 Introduction and General Aspects1, 1,
Chapter 2 Free Sugars, 4,
Chapter 3 Glycosides and Disaccharides, 15,
Chapter 4 Oligosaccharides, 62,
Chapter 5 Ethers and Anhydro-sugars, 92,
Chapter 6 Acetals, 98,
Chapter 7 Esters, 104,
Chapter 8 Halogeno-sugars, 118,
Chapter 9 Amino-sugars, 123,
Chapter 10 Miscellaneous Nitrogen-containing Derivatives, 142,
Chapter 11 Thio- and Seleno- and Telluro-sugars, 158,
Chapter 12 Deoxy-sugars, 166,
Chapter 13 Unsaturated Derivatives, 172,
Chapter 14 Branchedchain Sugars, 183,
Chapter 15 Aldosuloses and Other Dicarbonyl Compounds, 200,
Chapter 16 Sugar Acids and Lactones, 202,
Chapter 17 Inorganic Derivatives, 216,
Chapter 18 Alditols and Cyclitols, 222,
Chapter 19 Antibiotics, 254,
Chapter 20 Nucleosides, 267,
Chapter 21 NMR Spectroscopy and Conformational Features, 312,
Chapter 22 Other Physical Methods, 322,
Chapter 23 Separatory and Analytical Methods, 340,
Chapter 24 Synthesis of Enantiomerically Pure Non-carbohydrate Compounds, 347,
Author Index, 385,

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