Carbohydrate Chemistry Volume 22

Monosaccharides, Disaccharides, and Specific Oligosaccharides

By R. J. Ferrier

The Royal Society of Chemistry

Copyright © 1990 The Royal Society of Chemistry
All rights reserved.
ISBN: 978-0-85186-212-5

Contents

Chapter 1 Introduction and General Aspects, 1,
Chapter 2 Free Sugars, 3,
Chapter 3 Glycosides and Disaccharides, 15,
Chapter 4 Oligosaccharides, 46,
Chapter 5 Ethers and Anhydro-sugars, 56,
Chapter 6 Acetal, 65,
Chapter 7 Esters, 71,
Chapter 8 Halogeno-sugars, 86,
Chapter 9 Amino-sugars, 91,
Chapter 10 Miscellaneous Nitrogen Derivatives, 108,
Chapter 11 Thio-and Seleno-sugars, 120,
Chapter 12 Deoxy-sugars, 126,
Chapter 13 Unsaturated Derivatives, 136,
Chapter 14 Branched-chain Sugars, 145,
Chapter 15 Aldosuloses, Dialdoses, and Diuloses, 156,
Chapter 16 Sugar Acids and Lactones, 159,
Chapter 17 Inorganic Derivatives, 170,
Chapter 18 Alditols and Cyclitols, 177,
Chapter 19 Antibiotics, 192,
Chapter 20 Nucleosides, 205,
Chapter 21 N.M.R. Spectroscopy and Conformational Features, 228,
Chapter 22 Other Physical Methods, 237,
Chapter 23 Separatory and Analytical Methods, 248,
Chapter 24 Synthesis of Enantiomerically Pure Noncarbohydrate Compounds, 258,
Author Index, 271,

CHAPTER 1

Introduction and General Aspects

The field continues to develop on all fronts, and improvements in synthetic methodology are giving access to substantially more complex products. Nowhere is this move apparent than in oligosaccharide and C-glycoside synthesis and in the use of synthetic procedures which are dependent on carbohydrate-derived carbanions and particularly free radicals. The increasing interest shown by “non-carbohydrate chemists” in carbohydrate chemistry is welcomed; their contributions have enlivened the field appreciably as is best illustrated by their descriptions of novel approaches to glycoside synthesis and, of course, many syntheses of enantiomerically pure non-carbohydrates from sugars.

El Khadem has published a book “Carbohydrate Chemistry: Monosaccharides and their Oligomers”, and reviews of general interest have appeared on the chemistry and biochemistry of the sweetness of sugars and on the use of immobilised enzymes in preparative carbohydrate chemistry.

Volume 45 of Advances in Carbohydrate Chemistry and Biochemistry (1987) contains articles on circular dichroism n.m.r. (proton relaxation rate data in structural analysis) and mass spectrometry (FAB methodology). The volume also contains tributes to the lives and work of Professors B. Helferich and F. C. Gonzalez.

The succeeding volume of the series contains reviews on H.p.l.c. of carbohydrates, n.m.r. of fluorinated monosaccharides,” the use of photosensitive protecting groups in carbohydrate synthesis” and high-temperature transformations of monosaccharides in aqueous solution.

Appreciations of the lives and work of Professor K. Onedera and V. Deulofeu are also included in this volume.

CHAPTER 2

Free Sugars

1 Theoretical Aspects

Recent progress in the physical chemistry of small carbohydrate compounds has been reviewed. There is accumulating evidence that solvation plays an important part in determining the solution equilibria and conformational properties of sugars. The standard geometries of both anomers of the eight hexopyranoses in the 4C1 conformation have been calculated and are given in the form of orthogonal co-ordinates. The geometries found for pyranose rings corresponded to the averaged ring structures determined from X-ray diffraction analyses of 161 compounds (see B. Sheldrick and D. Akrigg, Acta Crystallogr., 1980, 836. 1615). A revised CHARMM molecular mechanics potential-energy function has been developed for use in the dynamical simulation of simple carbohydrates in aqueous solution. Application to the molecular dynamics simulation of the motions of α-D-glucopyranose in vacuo in both the 4C1 and 1C4 conformation produced a D-glucose molecule less flexible then had previously been determined. CNDO Force constants for both anomers of D-glucopyranose have been evaluated, and an ab initio investigation of the electronic structure of the α-D-glucose molecule by use of the Hartree-Fock-Roothan method has been carried out. The effective charges agreed with those derived from semi-empirical calculations.

The hydrophobic indices, i.e, the ratios of hydrophobic to hydrophilic surface areas, of seven monosaccharides have been determined. They were found to correlate well with the partition coefficients of the polystyrene-water system for monosaccharides. The concept of hydrophobic indices is important in the consideration of the hydrophobic interactions of flat molecules in aqueous solution. In an effort to establish quantitative structure-activity relationships for carbohydrates, an experimental data-matrix containing the Rf values of sixteen monosaccharides in thirteen solvent systems was subjected to principal component analysis (PCA). Four PC’s (t1-t4) were found to explain 97.8% of the variance, and the first of these (t1), which described 90% of the variance, was tentatively interpreted as a hydrophobicity scale. Ab initio Calculations have shown that D-ribose is energetically stabilised relative to its L-enantiomer by parity-violating weak interaction (see Vol. 20, p. 2, ref. 4). The possible significance of these findings with regard to evolution has been pointed out.

2 Synthesis

A review on the synthesis of complex carbohydrates by a combination of chemical and enzymic methods has been published. A new strategy for the predictable creation of new chiral centres and its application to the synthesis of sugars and macrocycles is presented in a review on the use of double asymmetric induction in the aldol condensation, the Diels Alder cycloaddition, epoxidation and hydrogenation. Two approaches to the construction of appropriately functionalised six-carbon chains are outlined in a review on the dg novo synthesis of carbohydrates from achiral precursors: (i), hetero-Diels Alder reaction with inverse electron demand of functionalised 1-oxa-1, 3-dienes with dienophiles such as enol ethers followed by diastereoselective addition to the new double bond and (ii), Sharpless oxidation of racemic or meso-divinyl glycols, with concomitant kinetic resolution.

Sugars with four, six, and eight carbon atoms were formed from glycolaldehyde in an aqueous suspension of sodium montmorilIonite at 40°C, hexoses being the main products (see Vol. 20, p. 3, ref. 8). The conversion efficiency was 90% and an aldol-type mechanism has been suggested for the reaction. Aldoses are smoothly decarbonylated by chlorotris(triphenyl)rhodium in N-methylpyrrolidin-2-one at 130°C to give the next lower alditols. D-Glucose for example gives D-arabinose and 2-deoxv-D-erYthro-pentose gives 1-deoxyerythritol in 90% yield. Ketoses undergo more complex dehydration-decarbonylation reactions; thus furfuraldehyde was formed in 79% yield from fructose. Experiments with [1-13C]-labelled substrate showed that C-1 was lost during the reaction.

2.1 Pentoses. – On reaction with aqueous Pb(OH)2 3,4-Q-isopropylidene-L-arabinose rearranged to 2-deoxy-L-ribono-1, 4-lactone which was reduced to 2-deoxy-L-erythro-pentofuranose by sodium borohydride. 2,4-Q-Benzylidene-L-xylose has been prepared in high yield by periodate oxidation of 2,4-O-benzylidene-D-glucitol. Iron(III)trifluoroacetate proved to be an efficient catalyst in the preparation of D-[U-14C] arabinose and D-[U-14C] lyxose by Ruff degradation of universally labelled D-glucose and D-galactose, respectively. A new total synthesis of D- or L-ribose derivatives starts from the optically pure, functionalised oxabicycloheptene (1) (esterified with (-) camphanoic acid) or its enantiomer, respectively. The seven step reaction sequence leading to the D-product (2) is shown in Scheme 1.

2.2 Hexoses. – Strontium and calcium chloride have a marked effect on the selectivity of the triose aldose condensation. Under ordinary conditions, i.e.. in the absence of alkaline-earth metal ions, 3.4-threo configurated products, particularly arabino-2-hexulose (fructose) and xylo-2-hexulose(sorbose), prevail. Typically, the product composition is arabino : xylo : ribo : lyxo = 51 : 38 : 7 : 4. This diastereoselectivity is in accordance with a pericyclic reaction mechanism and the intermediacy of the transition state (3). In the presence of high concentrations of Sr2+ or Ca2+, increased proportions of hexuloses with the 3,4-erythro-configuration, especially the lyxo isomer, are formed at the expense of fructose (e.g.. arabino : xylo : ribo : lyxo = 22 : 34 : 12 : 32) indicating α-chelation and attack of the complex (4) by the dihydroxyacetone enolate from the least hindered side.

Derivatives (6) and (8) of D-psicofuranose and 1-deoxy-D-psicofuranose, respectively, have been synthesised by new routes from the protected D-ribonolactone derivative (5) as outlined in Scheme 2. Attempts to hydrolyse the dithiane (7) to an aldehyde were unsuccessful.

A simpler and more efficient version of the traditional Kiliani method has been used to prepare [6-13C] -labelled hexoses. K13CN was added to 1.2-O-isopropylidene-α-D-xvlo-pentodialdo-1.4-furanose. Hydrogenation of the adducts and in situ borohydride reduction followed by deprotection gave D-[6-13C]glucose and L-[6-13C]idose, which were separable on a DOWEX 50 x 8 (Ca2+) column. Molybdate epimerisation of these products afforded D-[6-13C]mannose and L-[6-13C]gulose. Procedures suitable for the large scale (50 g) production of 13C-enriched hexoses have been developed. D-[1-13C] glucose and D-[1-13C]mannose were prepared from D-arabinose by Serianni’s modified Kiliani-Fischer reaction in 20 and 39% yield, respectively. Exposure to NaOH and phenylboronic acid converted the D-[1-13C]mannose into a chromatographically separable 1:1:8 mixture of D-mannose, D-glucose, and D-fructose with retention of the label at C-1. D-[x-13C]Fructose (x = 1 or 2) was obtained in 80% yield from D-[x-13C] glucose by use of immobilised glucose isomerase in the presence of sodium germanite to complex the fructose. In addition, [2-13C]dihydroxyacetone was synthesised from [2-13C]fructose by consequential methanolysis, periodate oxidation, borohydride reduction, and acid hydrolysis.

L-Sorbose has been converted to L-fructose via the key-intermediate (9) (Scheme 3), available in >80% yield by acetonation of L-sorbose with dimethoxymethane and SnCl2 in dimethoxyethane. The synthesis of 3,4;5,6-di-O-isopropylidene-D-glucitol and 2.3 ; 4.5-di-O-isopropylidene-aldehvdo-D-arabinose from D-glucono-1,5-lactone is referred to in Chapter. An improved process for the isolation of D-fructose from the acid hydrolysate of sucrose involves formation of a double salt with Ca(OH)2, followed by decalcification and purification.

2.3 Higher Sugars. – Reaction of isopropylidene-D-glyceraldehyde with triphenyl(propionylmethy1ene)phosphorane afforded the isomeric enuloses (10) and (11) which were separated by chromatography. Hydroxylation then gave access to the four diastereomeric 1,2-dideoxy-3-heptulose derivatives (12)-(15) (Scheme 4). A recently developed route to higher sugar allylic alcohols (see Vol. 20, p. 8) has been exploited in connection with the attempted synthesis of desazatunicamine. It involves coupling of two monosaccharide units derived from D-galactose and D-ribose, respectively, via an additional carbon atom, as shown in Scheme 5. The stereoselectivity of the zinc borohydride reduction of compound (16) and similar higher sugar enones implies complexation of the ring and the carbonyl oxygen atoms with zinc ion in accordance with the Cram cyclic model for 1,2-asymmetric induction, and the steric course of the osmylation of higher sugar enones and allylic alcohols such as compounds (16) and (17) is rationalised in terms of Kishi’s rule.

3 Analytical Methods

A colorimetric assay for glucose in the presence of fructose, based on the selective reduction of ketoses by sodium borohydride and CeCl3 has been developed. An analytical method for the determination of fructose and other ketoses in the presence of aldoses, sucrose, and insulin is mentioned in Chapter 22. In h.p.l.c. separations, reducing sugars may be detected fluorometrically after post-column reaction with 2-cyanoacetamide. The fluorescent species derived from glucose have been identified as the pyrrolidine derivative (19) and the pyridine derivative (20) formed, presumably, as indicated in Scheme 6, from the dehydrated Knoevenagel adduct (18) and its 4-deoxy-5-hydroxy-isomer by cyclisation, further dehydration and, in the case of product (20), reduction. The dienamide (18) itself is strongly u.v. absorbing and susceptible to electrochemical oxidation, which might permit additional methods of detection.

A D-glucose-sensitive electrode has been constructed by coating of a platinum electjrode with a cross-linked poly(vinylalcohol) layer containing immobilised D-glucose oxidase and ferrocene.

Physical Measurements

The solubilities of D-xylose and D-mannose in aqueous ethanol (0-100%) at 25°C have been measured by use of refractometry and h.p.l.c., and some physical properties (m.p., solubilities) of crystalline anhydrous α-lactose, α,β-lactose, and β-lactose have been reported. The excess Gibbs free energies of aqueous solutions of carbohydrates and other polyols at 25°C have been determined and correlated with the sugar configurations. The standard enthalpy of formation (1263.4 [+ or -] 1.2 kJmol-1) of α-D-mannose at 298.15 K has been calculated from the corresponding standard energy of combustion (-15.6123 [+ or -] 0.0065 kJg-1) which was measured by use of precision static oxygen bomb calorimetry.

The catalytic activity of hydrated metal sulphates in the mutarotation of D-glucose has been examined, and the relations between logKa, ΔH, and ΔS of the reaction and the parameters of the metal ions, were discussed.

The apparent molal volumes and molal compressibilities of several monosaccharides, disaccharides and methyl pyranosides in dilute aqueous solution have been studied at 5, 15, and 25°C. The results were discussed in the light of solute-solvent interactions and a model for the hydration of galactose and lactose was proposed. The molal volumes of small carbohydrate molecules have been measured in an attempt at elucidating the relationship between molecular properties and sweetness. Molal volumes reflect fine differences in structure e.g.. axial or equatorial disposition of particular hydroxy groups) which are in turn related to differences in taste. In order to interpret differences in sweetness the viscosimetric constants and the heats of dilution of three monosaccharides, three disaccharides and the very sweet chlorinated sugar (21) have been determined, and their i.r. and Raman spectra have been recorded. The osmotic pressures of aqueous glucose, sucrose, and raffinose solutions have been calculated from their freezing point depressions. To obtain the apparent volumes of the hydrated species (0.1865, 0.3525, and 0.5105 nm3, respectively) their partial molal volumes were determined together with the partial molal volumes of the water of their solutions.

The u.v. and i.r. spectra of oligomeric acid products from the alkaline degradation of fructose and glucose have been evaluated. E.s.r. measurements on γ-irradiated crystals of α- and β-D-glucose hydrate confirmed that the structures of the primary paramagnetic centres derived from the hydrated species differ from those from the anhydrous analogues. The existence of several novel free radicals is reported. 13C-n.m.r. spectroscopy has been used to determine the anomeric configuration and the ring-size of D-fructose obtained from sucrose by the action of yeast and Candida utilis invertases. The hydrolysis was complete within 5 min yielding initially β-fructofuranose almost exclusively. After 60 min a mixture containing 74% β-fructopyranose, 22% β-furanose and 3.8% α-furanose had formed.

Isomerisation

The epimerisation of aldoses by metal complexes of alkylenediamines with long N-alkyl substituents has been reported. In a study involving various ligands, N,N’-dialkylethylenediamines showed the highest activity for épimérisation of glucose at C-2, equilibrium being reached within a few minutes under mild conditions. The equilibrium was shifted towards glucose by the more hydrophobic ligands with longer M-alkyl chains. Molybdate ions in aqueous solution at 90-125°C catalysed the isomerisation of D-glucose to a 3:1 mixture of D-glucose and D-mannose. At 120-150°C a mixture of D-glucose, D-mannose, D-allose, and D-altrose was obtained from which the first two sugars were removed by yeast fermentation leaving D-allose and D-altrose (3:2) in 14-17% yield. Several epimerisation reactions are mentioned in Section 2 of this Chapter.

The Ca(OH)2 promoted anomerisation of D-glucose has been studied by 13C-n.m.r. spectroscopy. The degree of anomerisation was found to vary with the Ca(OH) 2 concentration and it is thought that Ca2+ ions bind to O-1 and O-3 of the α-pyranose anomer, whereas in the β-anomer O-1 and O-2 are involved in complexation.

(Continues…)Excerpted from Carbohydrate Chemistry Volume 22 by R. J. Ferrier. Copyright © 1990 The Royal Society of Chemistry. Excerpted by permission of The Royal Society of Chemistry.
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