CHAPTER 1
Introduction and General Aspects
The very unusual absence of a new volume of Advances in Carbohydrate Chemistry and Biochemistry limits the number of quality reviews to have been published this year, and those that have appeared tend to be referred to at the beginnings of relevant chapters. This chapter is therefore unusually brief.
Danishefsky and Roberge have summarized the Sloan-Kettering work on the use of glycals as glycosyl donors and acceptors in the synthesis of oligosaccharides of glycoconjugates. The use of enzymically derived cis-dihydroxylated aromatics as starting materials for the iterative preparation of oligo- nor-saccharides, -inositols and pseudo-sugars has been surveyed.
In the field of origin of life studies Eschenmoser and Kisakürek have discussed the potential biogenic relationship between hexose- and pentose-based nucleic acids, and a paper has appeared from the same group on the base pairing between oligonucleotides comprising pentopyranosyl D- and L-nucleotides.
CHAPTER 2
Free Sugars
1 Theoretical Aspects
Molecular dynamics simulation calculations aimed at providing better understanding of the relative sweetness of β-D-glucopyranose, β-D-galactopyranose, and α- and β-D-mannopyranose failed to verify the hydrophobic G site hypothesis proposed by Tinti and Nofre (ACS Symp. Ser., 1991, 450, Chapter 15).
2 Synthesis
A comprehensive review (260 refs.) on the synthesis of carbohydrates from non-carbohydrate sources covers the use of benzene-derived diols and products of Sharpless asymmetric oxidation as starting materials, Dodoni's thiazole and Vogel's 'naked sugar' approaches, as well as the application of enzyme-catalysed aldol condensations. The preparation of monosaccharides by enzyme-catalysed aldol condensations is also discussed in a review on recent advances in the chemoenzymic synthesis of carbohydrates and carbohydrate mimetics, in parts of reviews on the formation of carbon-carbon bonds by enzymic asymmetric synthesis and on carbohydrate-mediated biochemical recognition processes as potential targets for drug development, as well as in connection with the introduction of three 'Aldol Reaction Kits' that provide dihydroxyacetone phosphate-dependent aldolases (27 refs.). A further review deals with the synthesis of carbohydrates by application of the nitrile oxide 1,3-dipolar cycloaddition (13 refs.).
A newly discovered NAD-dependent hydrogenase from celery oxidizes D-mannitol to D-mannose; several other pentitols and hexitols, especially those with the same absolute configuration at C-2 as that of D-mannitol, are oxidized to the corresponding aldoses at a slower rate.
2.1 Tetroses and Pentoses – 4-O-t -Butyldimethylsilyl-2,3-O-isopropylidene-D-threose (1) has been prepared in seven efficient steps from D-xylose. 3,4-O-Isopropylidene-D-eythrulose (4) has been synthesized from the known tetritol derivative 2 by primary protection as the silyl ether 3, followed by Dess-Martin oxidation and desilylation. Compound 2 was derived from D-isoascorbic acid (see Vol. 22, p. 178, refs. 9,10). In a similar reaction sequence, the enantiomer 5 has been obtained from L-ascorbic acid. The dehomologation of several di-O-isopropylidenehexofuranoses (e.g.,6 [right arrow] 7) has been carried out in two steps without intermediate purification, by successive treatment with periodic acid in ethyl acetate, followed by sodium borohydride in ethanol. Selective reduction of 3-deoxy-D-glycero-pentos-2-ulose (8) to 3-deoxy-D-glycero-pent-2-ose (9) has been achieved enzymically with aldose reductase and NADPH. 4-Isopropyl-2-oxazolin-5-one (10) is a masked formaldehyde equivalent that is easily converted to an anion and demasked by mild acid hydrolysis. One of the three examples of its use in the synthesis of monosaccharides is shown in Scheme 1.
The synthesis of [5-13C]D-ribose from D-ribose involved diol cleavage of the original C-4-C-5 bond and formation of a new C-4-C-5 bond using a 13C-enriched Wittig reagent. 3,4,5,5-d14 -DL-Ribose (12) has been obtained from dg-glycerol (11), as outlined in Scheme 2.
2.2 Hexoses – The synthesis of hexoseptanose derivatives by ring expansion of uloses, Baeyer Villiger oxidation of inositols, or Baeyer-Fischer reaction of sugar dialdehydes has been reviewed.
The methyl β-L-idoseptanoside derivative 14 was produced by oxidation/reduction (Ru2O-NaIO4/NaBH4) of the corresponding methyl β-D-glucoseptanoside 13. On transmetalation with InCl3, δ-oxygenated allylic stannanes undergo in situ addition to aldehydes furnishing predominantly anti products. This method has been applied to the synthesis of D-altrose as shown in Scheme 3. A similar route to α-L-daunosamine hydrochloride is covered in Chapter 9. The chemoenzymic synthesis of 6-substituted D-fructose analogues by use of epoxide 15 is referred to in Chapters 7, 8, 9 and 10, and that of 6-deoxy-L-sorbose in Chapter 12.
The best conditions for producing glucose with close to 100% H-isotope labelling at C-1, with negligible formation of labelled by-products, by exchange with deuterium or tritium gas in aqueous solution have been determined. Various 2H-labelled D-mannoses, as well as 2,3,4,5,6-d5- and 1,1,2,3,4,5,6,6-d8-D -mannitol, were obtained by ozonolysis/sodium borohydride reduction of the functionalized cyclohexene 16, which was obtained in enantiomerically pure form from 2H5-chlorobenzene following biological hydroxylation.
D-Tagatose 3-epimerase immobilized on Chitopearl beads effected the isomerization of L-sorbose and L-psicose to L-tagatose and L-fructose in 20 and 65% yield, respectively. Sequential use of pyranose 2-oxidase and hydrogen over palladium permitted the one-pot chemoenzymatic conversion of D-galactose to D-tagatose in 30% yield, whereas sodium borohydride reduction followed by microbial oxidation furnished D-sorbose from D-gulonolactone with high efficiency. A remarkable, concurrent oxidation at C-5 and reduction at C-1 in 2,3,4,6-tetra-O-benzyl-D-galactose and -glucose on exposure to samarium(II) iodide, preoxidized with dry air in THF, offers entry into the L-sorbose and L-tagatose series. As a possible mechanism, Meerwein-Oppenauer-like oxidation/reduction via a transition state 17 has been proposed.
On treatment with 5% sodium hydrogen carbonate for 1.5 h, ascorbigen (18) formed the unstable product 19 and, after longer exposure times, the 6-deoxy-L-tagatose derivative 20.
2.3 Chain-extended Sugars – The application of indium- and tin-mediated Barbier-Grignard reactions in aqueous solutions to the chain-extension of unprotected sugars has been included in two general reviews of these reactions. The two main approaches to the synthesis of the undecose system of tunicamycin, namely tail-to-tail coupling of two readily available sugar units and elongation at the non-reducing end of either D-ribose or D-galactosamine, have been reviewed (52 refs.). The synthesis of a variety of higher carbon sugars by tail-to-tail coupling of simple monosaccharides is dealt with in a further review (44 refs.).
The enzyme-catalyzed aldol condensation of ω-functionalized C5- and C6- aldehydes with Dhap (dihydroxacetone phosphate) has been used to synthesize unusual C8- and C9-sugars. An example is given in Scheme 4. Coupling of carbohydrate carboxylic acids such as 21 and 23 with alkanoic acids by mixed Kolbe electrolysis allowed chain-elongation at the 'reducing' or at the 'non-reducing' end, to give products such as 22 and 24, respectively. Chain-extension at the reducing as well as at the non-reducing end has also been brought about by free radical allylation of glycosyl bromides and primary bromo-deoxy sugars, respectively, with allylic sulfides or sulfones. C-Glycoside 25 and the branched trideoxynonuronic acid derivative 26 are typical products of this procedure.
2.3.1. Chain-extension at the 'Non-reducing End' – Both epimers of 6-C-phenylglucose 28 have been synthesized from D-glucuronolactone via intermediates 27. Introduction of a cyclopentadiene moiety at C-6 of diacetonegalactose was effected by reaction of triflate 29 with cyclopentadienyl lithium in DMF to give 30.
Three papers describing chain-extensions by use of C-6-aldehydes have been published: the diacetonegalactose-derived dialdose 31 was extended by two carbons to give the acetamido-dideoxy-octosulose derivative 33via intermediate 32 by consecutive treatment with potassium cyanide in the presence of ammonia acetic anhydride in pyridine, and methylmagnesium iodide; five different benzyl tetra-O-benzyl-L-glycero-α-D-manno-heptopyranosides with one free hydroxyl group were prepared by oxidation of suitably protected benzyl α-D-mannopyranosides at C-6 (e.g.,34 [right arrow] 35), followed by reaction with benzyloxymethylmagnesium chloride and regiospecific protection/deprotection (e.g.,35 [right arrow] 36). Their conversion to monophosphates is covered in Chapter 7; condensation of dialdose 31 with the 5'-diazoriboside 37 gave the C-linked disaccharide ketose 38 as the sole product in 60% yield.
2.3.2 Chain-extension at the Reducing End – Catalytic osmylation of the D-fructose-derived (E)- and (Z)-alkenes 39 gave, after reduction with LAH, a mixture of D-glycero-D-galacto -(40) and D-glycero-D-ido-oct-4-ulose (41), and D-glycero-D-manno-oct-4-ulose (42), respectively, as precursors for polyhydroxyindolizidines. The synthesis of 2-(β-D-glycopyranosyl)-nitroethenes and -nitroethanes from 2,6-anhydro-1-deoxy-1-nitroalditols is covered in Chapter 3, and that of 7-deoxyheptose derivatives as rhamnose mimics, using Kiliani ascent from 2,3-O-isopropylidene-L-rhamnose as the first step, in Chapter 16. The synthesis of octono-1,4-lactones from heptoses by Kiliani ascent is referred to in Chapter 6.
Preparations of various spiro-ketals have been reported: photolysis in the presence of diacetoxyiodobenzene and iodine converted ω-hydroxyalkyl C-glycosides into [6.5]-, [5.5]-, [5.4]-, and [4.4]-ring systems (e.g.,43 [right arrrow] 44). Intramolecular Friedle-Craft reaction of 6-O-acetyl-3,4-di-O-benzoyl-2-O-benzyl-α-D-glucopyranosyl chloride, followed by oxidation of the benzylic methylene group of the cyclic ether moiety and Zemplen deacylation gave lactone 45, which in aqueous solution exists mainly as the hydroxy acid 46.
The key-steps in the synthesis of a part structure of the antifungal papula-candin are shown in Scheme 5.
3 Physical Measurements
A 21 page review on sugar-protein recognition and sugar binding in water and non-polar solvents has appeared.
The melting of a β-D-glucopyranose crystal and the vitrification of the melt-fluid have been simulated by use of a molecular mechanics technique. The interactions between some carbohydrates (lactose, trehalose, cellobiose) and water have been investigated by molecular mechanics and molecular dynamics methods. Molecular mechanics simulations of aqueous trehalose have been carried out to investigate the role played by this sugar as protecting agent against water stress in biological systems.
Reports on the crystallization of sucrose (41 pp.), on the solubility of sucrose in pure water, sugar-containing water and some other solvents (24 pp.) and on the rheological properties of pure and impure sucrose solutions and suspensions(28 pp.) have been published.
Measurements of the enthalpies of solution of several crown ethers in aqueous D-glucose indicated that the interactions between D-glucose and the crown ethers are weak. Association constants between a number of monosaccharides and pyrene have been calculated from the solubility of pyrene in aqueous solutions of these sugars at various concentrations, and the hydrophobicity of the saccharide solutions was estimated from the fluorescence spectra of the dissolved pyrene; the two properties were found to be unrelated. The effects of solvent systems such as aqueous DMSO, aqueous acetonitrile or aqueous methanol, on the relative stabilities of complexes between sugars (e.g., D-ribose, D-arabinose, D-glucitol) and lanthanide cations have been studied by thin layer ligand exchange chromatography.
4 Isomerizatioo
Some methods of metal ion-catalyzed chemical and enzymic isomerization (Lobry de Bruyn-Alberda van Ekenstein rearrangement, epimerization at C-2 of aldoses, action of isomerases) of free sugars have been reviewed (136 refs.).
A comparative study on the epimerization of D-glucose and D-mannose catalyzed by water-soluble organometallic complexes with nitrogen ligands showed that strong coordination of the ligand to the metal lowers the catalytic activity. Thus, none of the complexes examined was as active as ammonium heptamolybate. The mutarotation of D-fructose in aqueous ethanol (1:3 - 1:9) has been investigated at temperatures between 24 and 50°C. Increased ethanol content has been shown to favour the furanose tautomers and to retard the mutarotation of the furanose forms to β-D-fructopyranose. The GlcNAc residue at the reducing end of tetrasaccharide 48, isolated from the lyase-catalyzed degradation of heparin, epimerized to a D-mannose unit on standing in 0.25% aqueous ammonia and also under the conditions of isolation of the tetramer.
5 Oxidation
Platinum catalysts supported on activated charcoal, with or without promoters such as bismuth or gold, have been examined for selectivity in the air oxidation of aqueous D-glucose and D-gluconate to glucarate. Palladium (II) has been found to inhibit the oxidation of aldoses by alkaline Fe(CN6), and by Ce(IV).
Exposure of methyl α-D-glucopyranoside in aqueous solution at 50 - 75°C to oxygen at 15 - 20 bar in the presence of bismuth-rich ruthenium pyrochlore oxide caused glycol cleavage; oxidation of the primary hydroxyl groups occurred only to a minor extent and at a much slower rate. β-Cyclodextrin, on the other hand, reacted non-selectively, and this catalyst was therefore declared unsuitable for the controlled oxidation of starch to dicarboxylic acids. Suspended nickel oxide is believed to be the reactive species in the NiS04-catalysed oxidation of sugars such as methyl α-D-glucopyranoside and β-cyclodextrin with sodium hypochlorite at pH 10. Glycol cleavage was the main reaction, accompanied to ca. 20% by primary oxidation.
Kinetic and/or mechanistic studies on the following processes have been reported: the oxidation of several free sugars by diperiodatoargentate(III) in alkaline media; the oxidation of D-glucose, D-mannose, D-fructose and L-sorbose by Mn(III) in sulfuric acid; the hexacyanoferrate-catalysed oxidation of D-glucose with ammonium persulfate; the 1,10-phenanthroline-catalysed oxidation of epidemic aldo- and keto-hexoses by Fe(III); the oxidation of D-glucose by HOBr; and the oxidation of several sugars (e.g., methyl and octyl β-D-glucopyranoside, decyl β-maltoside) by catalytic [Ru(azpy)2(H2O)2]2+ and NaBrO3.
6 Other Aspects
A review (58 refs.) on the homogeneous catalytic hydrogenation of aldehydes and aldoses in water and in organic solvents has been published. The homogeneous hydrogenation of D-glucose and D-mannose by hydrogen transfer from triethyl-amine/formic acid under catalysis by {Ru[tri(m-sulfophenyl) phosphine]} complex (RuTppts) has been compared with the heterogeneous hydrogenation by H2 over a solid catalyst. Both methods were equally effective.
