Carbohydrate Chemistry Volume 23

Monosaccharides, Disaccharides, and Specific Oligosaccharides

By R. J. Ferrier

The Royal Society of Chemistry

Copyright © 1991 The Royal Society of Chemistry
All rights reserved.
ISBN: 978-0-85186-172-2

Contents

Chapter 1 Introduction and General Aspects, 1,
Chapter 2 Free Sugars, 3,
Chapter 3 Glycosides, 16,
Chapter 4 Oligosaccharides, 51,
Chapter 5 Ethers and Anhydro-sugars, 62,
Chapter 6 Acetals, 69,
Chapter 7 Esters, 74,
Chapter 8 Halogeno-sugars, 90,
Chapter 9 Amino-sugars, 95,
Chapter 10 Miscellaneous Nitrogen Derivatives, 108,
Chapter 11 Thio- and Seleno-sugars, 122,
Chapter 12 Deoxy-sugars, 127,
Chapter 13 Unsaturated Derivatives, 134,
Chapter 14 Branched-chain Sugars, 145,
Chapter 15 Aldosuloses, Dialdoses, and Diuloses, 156,
Chapter 16 Sugar Acids and Lactones, 158,
Chapter 17 Inorganic Derivatives, 171,
Chapter 18 Alditols and Cyclitols, 177,
Chapter 19 Antibiotics, 191,
Chapter 20 Nucleosides, 205,
Chapter 21 N.M.R. Spectroscopy and Conformational Features, 237,
Chapter 22 Other Physical Methods, 246,
Chapter 23 Separatory and Analytical Methods, 254,
Chapter 24 Synthesis of Enantiomerically Pure Non-carbohydrate Compounds, 264,
Author Index, 281,

CHAPTER 1

Introduction and General Aspects

The 1989 literature of mono- and oligo-saccharide chemistry illustrates continuing general advances on all fronts with strong emphasis on the development of synthetic methods and their application to problems with origins in biology. Many examples of this are clearly given in the Sections on oligosaccharides, nucleosides and antibiotics, while the role of carbohydrate chemistry in general organic chemistry is well illustrated by the many complex conversions of sugar derivatives into enantiomerically pure natural substances of a non-carbohydrate nature. Once again, however, biological issues – in this case medicinal – are commonly the driving forces behind the work.

Relevant reviews have appeared on recent developments in modern aspects of synthetic carbohydrate chemistry, stereoselective chemical syntheses of sugar derivatives, syntheses of unusual sugars by combinations of chemical and enzymic methods, and purely enzymic syntheses. Baer has surveyed recent synthetic studies of nitrogen-containing, deoxygenated sugars and related compounds, and more specifically, the use of allylboronates in the synthesis of carbohydrates, and the conversion of 7-oxanorbornenes to sugars and their derivatives have been reviewed. The strategies for bonding sugars to proteins have been covered in a survey of neoglycoproteins, and two Chinese reports have dealt with the applications of carbohydrates in the synthesis of other natural products, and the effects of ultrasound on the reactions of derivatives of β-D-ribofuranose.

CHAPTER 2

Free Sugars

1 Theoretical Aspects

The historic development of the understanding of carbohydrate stereochemistry has been briefly reviewed, and a lecture with four references on the energetics and geometry of furanoid systems has been published. Two complementary descriptions of the conformational behaviour of furanose rings have been presented: (i) by quantum-mechanical energy calculations; and (ii) by a geometrical model of pseudorotation in five-membered rings.

Molecular dynamic simulations of β-D-ribofuranose and 2-deoxy-β-D-erythro-pentofuranose in solution showed that their hydroxy groups are better hydrogen-bond donors, but worse acceptors, than water and that the ring oxygen atoms accept even less hydrogen-bonding. In a similar study with α-D-glucopyranose, solvation was found to have little effect on the preferred conformation of the sugar molecule. According to molecular dynamics simulation experiments both glucitol and mannitol have bent energy minima in vacuo: in aqueous solution mannitol is also bent, but glucitol prefers a planar zig-zag conformation.

A computer program for molecular modelling which is part of the 3D-Molmaster system has been used to carry out computations of the energetics of monosaccharide, polysaccharide and glycoside conformations. By use of the MM2 method a conformational energy map of β-laminarabiose has been constructed which makes allowance for the presence of several inter-converting conformers (“structural relaxation”). The finding that this map differs from one based on a fixed structure indicates the importance of “structural relaxation” within the glucose residue. Newly developed computational methods for describing and understanding molecular motion and flexibility have been employed to describe the “relaxed” potential energy surface of maltose, which was chosen as a prototypical carbohydrate system. Calculations to give solvent-specific “relaxed” energy surfaces have been applied to carbohydrate molecules, in particular to a mannobiose, with the aim of providing new insights into the conformational properties of sugars in solution.

By an examination of optical rotation and n.m.r. measurements, a picture has been developed of the potential energy surfaces of cellobiose and maltose in aqueous solution.

2 Synthesis

The enzyme-catalysed synthesis of mono-, oligo- and poly-saccharides has been covered in a major review with 310 references, and a review has appeared on the synthesis of saccharides uniformly labelled with 14C, starting from D-[U-14C]glucose.

The distribution of products of the formose reaction carried out in aqueous DMF has been studied. Considerable control was possible by adjustment of the water content. When, for example, formaldehyde was heated at 75°C for 1 hour with triethylamine and thiamine hydrochloride in 8:1 DMF-H2O, DL-2-C-hydroxymethyl-3-pentulose, characterised as the tetraacetate (1), was produced in 28% yield. In the absence of water, the major products are dihydroxyacetone and DL-glycero-tetrulose (cf Shigemasa et al., Carbohydr. Res., 1987, 162, C1). In the radiation-initiated formose synthesis in aqueous solution, pentaerythritol and ethylene glycol were the main products, their ratio depending on the initial formaldehyde concentration.

An efficient new procedure for the general ascent of the aldose series, which lends itself to repetitive application and gives an all-anti configurated chain, is shown in Scheme 1. The usefulness of this approach is further extended by the epimerisation referred to in Section 4, Scheme 11, of this Chapter. A new multigram method for trapping aldoses in their aldehydo-form is exemplified in Scheme 2. It exploits the discovery that oxime ethers are cleaved by ozone to give the parent aldehydes in high yields.

In a study of the hydrolysis of cellulose to D-glucose by dilute sulphuric acid, the reversion products which represent 10% of the total yield have been analysed. The main components (>50%) were 1,6-anhydro-β-D-gluco-pyranose and -furanose (7:3). Isomaltose and gentiobiose were the major disaccharides, and (1 [right arrow] 2)- and (1 [right arrow] 3)- linked α-disaccharides predominated over their β-anomers.

2.1 Tetroses.- The D- and L-erythrose derivatives (3) and (4), respectively, are available from chlorobenzene by the enantiodivergent route shown in Scheme 3, via the optically pure microbial oxidation product (2). Small but significant asymmetric induction was observed in the aldolisation of the glycolaldehyde derivative (5) bearing an enantiomerically pure acetal-type protecting group (Scheme 4). The L-erythro-. D-erythro-. L-threo- and D-threo-isomers (6), present as a complex mixture of hemiacetals, were formed in a combined yield of 40-60% in the ratio 33:30:21:16. This was determined after reduction to the corresponding tetritols as mentioned in Chapter 18.

2.2 Pentoses.- 3-O-Hexopyranosyl-D-arabinoses, such as compound (7), have been prepared by Zemplén degradation of aldonobiononitrile octabenzoates with (1 [right arrow] 4) glycosidic linkages. The products were obtained as α/β-pyranose/furanose mixtures and were reduced and benzoylated to the corresponding hexopyranosyl-D-arabinitol octabenzoates for easy characterisation by n.m.r. spectroscopy. The conversion of derivatives of aldopentoses (e.g.. arabinose) to stereoisomeric derivatives of pentonolactones (e.g., L-lyxonolactone) is covered in Chapter 16.

2.3 Hexoses.- A convenient procedure for the synthesis of D-[1-11C]gluco- and D-[1-11C]galacto-pvranose from D-arabinose and D-lyxose, respectively, and 11HCN uses diborane as highly effective and time saving reducing agent.

UDP-[6-3H]galactose of high specificity has been obtained by oxidation of the C-6 hydroxymethyl group of UDP-galactose by galactose oxidase and subsequent reduction with NaBT4. Radiolabelled UDP-N-acetylgalactosamine has also been prepared by this method. Economical access to [6-3H]-labelled L-galactose (8) and L-fucose (9) starting from D-galactose is offered by the reaction sequence presented in Scheme S. A new tritiation method has been employed to synthesise [2,6,6′-3H]-2-deoxy-D-glucose from a mixture of protected bromodeoxyglucose derivatives (10).

2,3,4,6-Tetra-O-benzyl-D-glucopyranose (11) was converted to 1,3,4,5-tetra-O-benzyl-L-sorbose (12) in 94% yield in the presence of bromomagnesium salts of certain phenols and alcohols in dichloromethane. This reaction for which there is no precedent involves, at least formally, a hydride transfer from C-5 to C-1 of the starting material, a possible mechanism being indicated in Scheme 6. A selectively protected fucose derivative (14), suitable for use in oligosaccharide synthesis, has been prepared from the known D-altrose derivative (13) in ten conventional steps and 33% overall yield. 3,4,5,6-Di-O-isopropylidene-2-O-methyl-quebrachitol (15) served as the starting material for a multi-step synthesis of the peracetylated D- and L-galactofuranosides (18) and (19), respectively, as outlined in Scheme 7. The key step was the high yielding (>94%) Baeyer-Villiger oxidation of ketone (16) to the hemiacetal-lactone (17).

In a newly patented process L-rhamnose has been produced from rhamnan sulphate by treatment with strong acid resin, followed by heating.

The enantiomerically pure oxabicycloheptane derivative (20) and its antipode, previously used in a total synthesis of D- and L-ribose (see Vol. 22, Chapter 2, Scheme 1), were the starting compounds for new total syntheses of L-hexoses. Scheme 8 shows the steps leading from ketone (20) via the silyl enol ether (21) to L-allose. By a slightly different reaction sequence the enantiomer of compound (20) was converted to L-talose.

2.4 Higher Sugars.- L-glycero-D-manno-Heptopyranose (L-D-Hepp) (23) was the main product of the hydroxymethylation of the mannose-derived aldehyde (22) with (isopropoxydimethylsilyl) methylmagnesium chloride, followed by deprotection, the high stereoselectivity being consistent with the Cram cyclic model for 1,2-asymmetric induction. Further use was made of the 7-oxabomane silyl enol ether (21) of Scheme 8 in the crossaldolisation with 2,3-O-isopropylidene-D-glyceraldehyde to give octoses as shown in Scheme 9. Under catalysis by TiCI4 the condensation product (24) was formed exclusively. This was transformed, by methods similar to those depicted above in Scheme 8, to the octofuranose derivative (25) and hence in seven steps to a mixture (26) of D-erythro-D-talo- and D-erythro-L-allo-octose derivatives. The enantiomer of silyl enol ether (21) gave analogously the D-threo-L-talo- and D-threo-D-allo-isomers (27).

In accordance with Kishi’s rule osmylation of the carbohydrate derived unsaturated ester (28) gave the D- and L-threo-D-gluco-configurated products (29) and (30) in the ratio 9:1 (Scheme 10), and similar selectivity was observed in the osmylation of the manno analogue of alkene (28). In breach of Kishi’s rule, however, methyl 3,5-O-benzylidene-6, 7-dideoxy-1,2-O-isopropylidene-α-D-gluco-6-octenofuranuronate (31) afforded the β-L and α-D-threo-derivatives (32) and (33) in the ratio 1:2. The X-ray structure of the new compound (32) is referred to in Chapter 22. The selectivities of the osmylations represented in Scheme 10 and of two similar examples were greatly enhanced on addition of the “matching” Sharpless chiral auxiliary, either dihydroquinine p-chlorobenzoate or dihydroquinidine p-chlorobenzoate [e.g., (29):(30) = 20.5:1].

3 Physical Measurements

As part of a study of the stability of enzymes in aqueous sugar solutions the solute-solvent interactions and water activities of small carbohydrates (D-glucose, D-galactose, D-fructose, D-glucitol, D-mannitol, sucrose and maltose) have been examined. D-Fructose was found to provoke the most noticeable perturbation of water structure, to cause denaturation (e.g., of lysozyme), and to lower the storage stability of enzymes (e.g., YADH). Based on the finding that the relative increments of the sound velocities in aqueous sugar solutions (ribose, sucrose, raffinose and six others) correlate with the number of equatorial hydroxy groups in the solute molecules, the suggestion was made that molecules with a large proportion of equatorial hydroxy groups are particularly effective in stabilising the structure of water.

The enthalpies of dilution at 25°C of binary and tertiary aqueous solutions containing the isomeric disaccharides cellobiose, maltose, and trehalose, were investigated, and an empirical relationship between saccharide solvation and solute – solute interactions was deduced. The thermochemical properties of aqueous solutions of small carbohydrates as glasses and rubbers at sub-zero temperatures have been measured by differential scanning calorimetry (DSC), and the thermodynamic properties of alcohols and monosaccharides in aqueous biuret solution at 25°C have been determined by flow microcalorimetry. By use of DTG and DSC-DTA techniques endothennic and exothermic reaction temperatures and enthalpies between 25 and 700°C have been recorded for 24 typical sugars. These data yield important information pertaining to the relation between molecular structure and thermal behaviour.

The dehydration of xylose in aqueous solution catalysed by a Cp2TiCl2-protoporphyrin complex immobilised in a polyacrylamide gel has been studied, and rate constants activation parameters for this process have been determined, and a thermodynamic investigation of the hydrolysis of sucrose by microcalorimetry and h.p.l.c. has been reported.

In an investigation of the kinetics of isotope exchange between [1-3H]saccharides and hydrogen on Pd catalysts it was found that the compounds examined could be arranged in a sequence of decreasing hydrogen-exchange rate which agreed with the order of decreasing relative mobility coefficients for the 1-H atoms. Widely different polystyrene affinities are displayed by methyl glycopyranosides, deoxysugars and glucooligosaccharides as was demonstrated by measuring the coefficients Kav for partition between polystyrene gel and aqueous solvent systems for these three groups of carbohydrates. In combination with the accessible surface data of sugar molecules, the Kav values collected suggest that the hydrophobicity of sugars is determined, inter alia, by their surface area, the hydration effect of the hydroxy groups and molecular planarity and rigidity.

The non-isothermal kinetic parameters for the kinetically possible thermal decomposition steps of hydrated iron(III) and holmium(III) gluconates were evaluated. The values obtained for the Fe(HI) derivative were sensitive to the rate of heating. The association constants for the interaction of CaCl2 and KC1 with a number of standard monosaccharides are referred to in Chapter 17, and three kinetic studies of the anomerisation of D-glucose are covered in the next Section of this Chapter.

4 Isomerisation

A full report has been published on the newly discovered C-2 epimerisation of aldoses promoted by Ni(II) diamine complexes. The intermediate Ni(II) complex containing both diamine and sugar was investigated by use of C-enriched D-glucose and by extended X-ray absorption fine structure (EXAFS) methods. A procedure has been described for the epimerisation and rearrangement of D-[1-13C]glucose to give a ca 1:1 mixture of starting material and D-[2-13C]mannose. The isomerisation of epimeric pairs of aldohexoses and the related ketohexose by aqueous KOH has been examined in detail. It is proposed that structures with the hydroxy groups at C-1, -2 and -3 in ax/eq/ax or eq/ax/eq arrangements form particularly stable hydrogen-bonded ions or complexes, and that this influences the aldose – ketose equilibrium.

Inversion α to the masked carbonyl group of sugar thiazoles by oxidation – reduction, as exemplified in Scheme 11, promises to be a very useful extension of the thiazole method of ascent in the aldose series which is described in Section 2 of this Chapter (see Scheme 1). The synthesis of 6-deoxy-L-arabino-hexulose by isomerisation of L-rhamnose is covered in Chapter 12.

The “Glukometer GKM 01”, an analytical tool based on a β-D-glucose-specific oxidase, has been used to measure the effects of pH, water content, water activity, and temperature on the mutarotation equilibrium of D-glucose. The equilibration rate showed a minimum value at pH 3 and increased with increasing water-content and -activity. The temperature dependence could be described by the Arrhenius equation, and an activation activity of 66.2 kJ mol-1 was calculated. Similar experiments are reported in a Japanese publication. The mutarotation of α to β-D-glucose in DMSO over an alumina catalyst at 40°C has been investigated under various pressures in the range 0.1-90 MPa and with initial α-D-glucose concentrations of 2.8-12.0 x 10-2 mol dm-3. The kinetic parameters (adsorption coefficients, rate constants for the surface reactions) were evaluated as a function of pressure. In sharp contrast to the negative adsorption volumes observed under homogeneous catalysis, fairly large positive activation volumes were found for the surface reactions, for which a formyl rotation step is thought to be responsible.

An n.m.r. study of the kinetics of anomerisation of D-talose is covered in Chapter 21.

5 Oxidation

The mechanism of oxidation of D-glucose in alkaline media at gold electrodes has been investigated. Experiments using cyclic voltammetry at a rotating disc electrode indicated that the mass-transport-limited reaction proceeds via an enediol intermediate hydrogen-bonded to catalytic hydrous gold oxide. The enediol is cleaved oxidatively and the primary hydroxy group is oxidised at the same time.

(Continues…)Excerpted from Carbohydrate Chemistry Volume 23 by R. J. Ferrier. Copyright © 1991 The Royal Society of Chemistry. Excerpted by permission of The Royal Society of Chemistry.
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