CHAPTER 1
Introduction and General Aspects
As always, an extensive range of reviews and symposia proceedings of general interest in the field has appeared. A novel approach to molecular modelling of carbohydrates uses the averages of intra- and inter-molecular bonding energies and potential energy functions, and apparently allows very efficient computation of the energetics and conformational properties of carbohydrates in aqueous solution. A symposium was held on important characteristics of hydrogen bonding in molecular recognition undertaken by sugars, and an analysis has been undertaken of the effects of stereochemistry on carbohydrate hydration.
Two symposia reports have appeared on issues associated with sweetness, the first dealing with natural and artificial sweetners, which included consideration of theoretical, structural and physical chemical correlations, while the second focused on the sweetness of halogenated sugar derivatives. A lecture on the synthesis of glycothanes as receptors in novel compounds derived from α,α-trehalose has been published.
A review on protective group strategies in carbohydrate synthesis has appeared which included consideration of the preparation of phosphate and sulphate esters of heparin oligosaccharides, and a related article covered the detailed consideration of the binding domains associated with the heparin-antithrombin 3 complex.
A survey of the C-homologenation of sugars involving the use of thiazoles in aldol condensations has appeared, and another covers a diverse range of synthetic methods for synthesizing carbohydrate derivatives from acyclic precursors.
Free radical chemistry continues to be of importance in the field and a survey has been published on polar and enthalpic effects in free radical reactions. A further short review dealt with free radicals, carbenes and nitrenes at the anomeric centre of carbohydrates. A useful survey has appeared of the application of carbohydrate based chiral auxilliaries in stereoselective syntheses which covers a range of reactions, for example cycloaddition processes, reductions and Strecker reactions.
Considerable interest continues to be shown in the application of enzymes in synthesis of carbohydrate compounds, and a review has appeared on the use of aldolases, glycosyl transferases and subtilisin. Other reviews have concentrated on aldolases applied in the synthesis of C-C bonds. Another deals with the synthesis of optically active carbohydrates by biooxidation of chlorinated aromatic compounds using Pseudomonas putida. Enzymes may be also used to affect the hydroxyl groups of carbohydrates, and a review on the protection of such groups and deprotection has appeared.
CHAPTER 2
Free Sugars
1 Theoretical Aspects
The chemical reactivity at different sites in α-D-glucopyranose and β-maltose has been examined by use of AMI molecular orbital calculations with a view towards an understanding of the reactivities of glucans. AM1.PM3 molecular orbital calculations on D-xylopyranose and harmonic dynamics calculations on both anomers of glucose in the crystalline state have been reported. Predictions, by means of UNIFAC, of liquid-solid phase diagrams for aqueous sugar systems, (e.g., sucrose/glucose-, sucrose/fructose-, or xylose/mannose-mixtures) compared favourably with experimental data.
The interactions between the surfaces of some heterogeneous catalysts and monosaccharides, e.g., between gallium(I) and glucose in DMSO, have been described.
2 Synthesis
Transketolase (EC 2.2.1.1), which catalyses condensations between aldehydes and hydroxypyruvic acid with loss of CO2 (see Vol. 25, Chapter 2, Ref. 9) has been produced in relatively large quantities from an over-expressed E. coli transformant carrying the transketolase gene. This enzyme was fairly non-specific with respect to the aldehyde component, although best results were achieved with α-hydroxyaldehydes.
2.1 Trioses to Hexoses.- A kinetic analysis of the formose reaction has led to the conclusion that the carbonyl rearrangement and retro-aldol reaction steps play a substantial role in the autocatalytic process. The condensation of D-glyceraldehyde acetonide with racemic alkyl (alkylthiomethyl) sulfoxides proceeded with high selectivity to produce diastereomeric l-alkylsulfinyl-l-alkylthio-3,4-O-isopropylidene-D-tetroses with a predominance of erythro-products. An example is given in Scheme 1. 4-Deoxy-D-L-glycero-tetrulose (4) has been synthesized from butanone (1) via dibromide 2 and diacetate 3. The acetyl groups were hydrolysed by use of a lipase.
The preparation of acyclic 3,4:5,6-di-O-isopropylidene-D-glucose from 1,2:3,4:5,6-tri-O-isopropylidene-D-gluconate is referred to in Chapter 6. L-Glucose derivatives have been synthesized from D-glucose via 2,3,4-tri-(9-benzyl-6-O-t-butyldimethylsilyl-D-glucono-1,5-lactone, following a modification of Shiozaki's method (see Vol. 25, Chapter 2, Ref. 15), and from 2,3,5-tri-O-benzyl-L-arabinofuranose by use of phenyldimethylsilylmagnesium chloride in a highly stereoselective Grignard reaction. Methylenation of protected D-ribono- and D-xylono-1,4-lactone 5 and 8, respectively, with Tebbe's reagent was inefficient, but exposure to Cp2TiMe2 gave alkenes 6 and 9 in 95% and 75% yield, respectively. Dihydroxylation with osmium tetroxide/NMO furnished mainly the β-anomers of D-psicofuranose and D-sorbofuranose derivatives 7 and 10. The fragmentation/rearrangement of carbohydrate anomeric alkoxy radicals formed on treatment of free sugars with iodosylbenzene has been investigated, in particular its application to the synthesis of ketoses from precursors with a free hydroxyl group at C-5 and a hydroxymethyl-branch at C-2. An example is shown in Scheme 2.
A new route to monosaccharides employing catalysed asymmetric aldol condensation has been illustrated by the preparation of L-fucose from crotonaldehyde and ketene silyl acetal 11 (Scheme 3) in 4 steps and 49% overall yield. The preparations of D-tagatose 1,6-diphosphate and of (3S/4R)- configurated ketose 1-phosphates by use of aldolases are covered in Chapter 7.
2.2 Chain-extended Compounds.- A review (50 pp., 75 refs.) on aspects of modern higher carbon sugar synthesis has been published. A further report on the preparation of sedoheptulose by spinach transketolase-mediated condensation between D-ribose and hydroxypyruvic acid has appeared (see Vol. 25, Chapter 2, Scheme 1). The hexulose phosphate synthetase-promoted aldol condensation between ribulose 5-phosphate and acetaldehyde gave a mixture of (5R/6S)- and (5R/6R)-7-deoxy-4-heptulose. The (R)-stereochemistry at C-5 was ascertained by extensive n.m.r. analysis, especially n.O.e. experiments. The configurations of two 7,8-dideoxy-4-octuloses prepared previously from ribulose 5-phosphate and propanal (see Vol. 25, Chapter 7, Ref. 45) and originally assigned as (55) have now been corrected to (5R). Condensation of D-ribose with dihydroxyacetone phosphate under catalysis by rabbit muscle aldolase, followed by exposure to phosphatase (see Vol. 20, Chapter 2, Ref. 33), gave octulose 12 in good yield.
2.2.1 Chain-extension at the "Non-reducing End".- Sugar aldehyde 13 was one of a range of substrates which were condensed with 2-(chloromethyl)-3-(trimethylsilyl)-1-propene in the presence of boron trifluoride etherate, followed by DBU-promoted cyclization, in order to generate methylenetetrahydrofurans, in this case 14. 1,2:3,4-Di-O-isopropylidene-D-galacto-dialdose (15) has been subjected to a considerable number of chain-extension reactions: a variant of Dodoni's method (see Vol. 23, Chapter 2, Ref. 15) gave thiazoline 16 and its diastereomer in 95:5 ratio and 58% combined yield. Use of a thiazole-based Wittig reagent allowed a two-carbon chain-extension via alkenyl thiazoles 17. Nitro-sugars 18 and 19 were obtained by application of modified, trialkylsilyl chloride-promoted Henry reactions to aldehyde 15. The former product was transformed to the corresponding aminodeoxy-sugar by hydrogenation over Raney nickel, the latter to the unsaturated trideoxy-octose 20 in three steps involving Barton radical chemistry. The reaction of 15 with t-butyl dibenzylaminoacetate and LDA proceeded with little diastereoselectivity to give syn/anti mixtures of glycosyl-α-aminoesters 21. Pure anti-product 22 was, however, obtained by use of reagent 26 and potassium t-butoxide. Similar reactions have been carried out with other dialdose derivatives. Precursors, such as compound 23, of pseudoglycopeptides were produced by condensation of 15 with diethylphosphonates 27 and LDA. A standard Wittig reaction and subsequent osmium tetroxide hydroxylation have been used to convert the known heptodialdose derivative 24 to its nonose analogue 25.
The diastereomeric C12 (Z)-allylic alcohols 30 [(R/S) 1:2] have been obtained by addition of lithiated alkyne 28 to dialdose derivative 29, followed by partial hydrogenation of the triple bond, and the two (E)-isomers 32 [(R/S) 7:3] were formed when the lithiated alkene derived from tributylstannane 31 was used as nucleophile (Scheme 4).
Chain-extension at C-6 of hexodialdose derivative 33 was involved in the synthesis of the linear C-8-C-8-linked dipyranyl dimer 34, and the diastereomeric alcohols 35, obtained by Grignard reaction on the corresponding C-6-aldehyde, were used as glycosyl donors in the preparation of C-6-methylated analogues of disaccharide 36 and of a related trisaccharide.
The dipolar cycloaddition of nitrile oxides to terminal sugar alkenes (see Vol. 23, Chapter 10, Scheme 18; Vol. 25, Chapter 2, Scheme 11) has been applied to the preparation of the [D-glycero-D-galocto-configurated isoxazolines 38 from hept-6-enose 37, and two methods for the chain-extension of primary iodides, both presumed to involve radical mechanisms, have been reported; examples are given in Schemes 5 and 6.
2.2.2 Chain-extension at the Reducing End.- Reaction of the four unprotected D-aldopentoses with the stabilized ylid Ph3P=CHCO2Me, in the presence of copper(II) acetate to suppress cyclization to furanose derivatives, gave (E)-alkenes 39 (isolated as the tetraacetates or diacetonides) in up to 60% yields. (E)-Alkenes, e.g.40, were also formed, in yields around 80%, when pyranoses or furanoses, protected at all except the anomeric positions, were exposed to arsenic ylids. Cyclization to β-C-glycosides (e.g.40 [right arrow] 41) was brought about by heating with zinc bromide in benzene.
Allylation of unprotected aldoses in aqueous media has previously been carried out with allyl bromide and tin (see Vol. 25, Chapter 2, Ref. 31). This method has now been improved by replacement of tin with indium, and extended to substituted allylic bromides. Its usefulness is impressively demonstrated by the conversion of 2-acetamido-2-deoxy-D-mannose to neuraminic acid derivative 42 in 3 steps and 45% overall yield, as shown in Scheme 7.
3,7-Dideoxyheptulosonic ester 46 has been synthesized from glycal 43 by way of lactone 44 and dithiane 45, and KDN has been obtained by condensation of D-mannose with oxalacetic acid under basic conditions. Stereocontrolled synthesis of polyol chains employing 2-acetylthiazole as lactaldehyde equivalent gave 3-deoxyoctose derivatives from 2,3:4,5-di-O-isopropylidene-D-arabinose (47) (Scheme 8). Stereoselective reduction was achieved with tetramethylammonium borohydride or DIBAL to give the D-glycero-D-galacto- 48 or the D-glycero-D-talo-isomer 49, respectively. A stereocontrolled route to 6-deoxyundecoses involved intermolecular nitrone-olefine cycloaddition between two sugar-derived components to give, for example, isoxazoline 50.
The diastereomeric spirooxirans 52 were formed when glycosylideneaziridine 51 was irradiated in the presence of cyclohexanone. Cycloaddition reactions of 1-thionoglyconolactones and the preparation of carboranyl aldoses from protected aldono-1,4- and -1,5-lactones are referred to in Chapters 11 and 17, respectively.
3 Physical Measurements
The glass transition temperatures, fusion temperatures and the heats of fusion of a number of pentoses, hexoses, alditols, and disaccharides have been determined by differential scanning calorimetry. In the course of an investigation aiming at a rigorous description of the thermal events occurring when frozen saccharide glass-ice mixtures are warmed, a supplemented phase diagram has been constructed based on new measurements of the glass transition temperatures for dilute and concentrated aqueous fructose solutions and literature data. In a quantitative study, by FT-IR spectroscopy, of the composition of aqueous fructose solutions a considerable increase in the percentage of keto form with increasing temperature has been observed, whereas the pH dependence was negligible. Vibrational Raman optical activity studies on 15 monosaccharides are referred to in Chapter 22.
The electro-osmotic transport of D-glucose across progesterone membranes has been investigated.
4 Isomerization
The mutarotation of α-D-glucose has been studied in aqueous solutions of boric acid, in ethanol/water under microwave activation, and in DMSO under γ irradiation. A molecular dynamics investigation of the conformational and anomeric equilibria of D-glucose in aqueous solution is referred to in section 1 of this Chapter.
Previous studies on the Ni(II)- and Ca(II)-complex-catalysed C-2 epimerizations of aldoses by use of 13C-enriched substrates have been reviewed (19 refs.). Amphiphilic complexes between Ni(II) and long-chain N-alkyl ethylenediamines gave rise to "metallomicelles" which coordinated with aldoses which then underwent epimerization (see Vol. 25, Chapter 2, Ref. 51); short-chain complexes had little activity. The epimerization of aldoses by Ca2+ in basic aqueous or alcoholic solution, which proceeds by molecular rearrangement (see Vol. 24, Chapter 2, Ref. 47), has now been developed into a preparative method for converting glucose and xylose to mannose and lyxose, respectively.
The molybdate ion-promoted formation of ketoses from aldopentoses and aldotetroses has been investigated, and physicochemical data for both directions of the heptamolybdate ion-catalysed xylose-lyxose epimerization have been published.
D-Ketohexose-3-epimerase, a new enzyme isolated from Pseudomonas sp., catalysed the epimerization between D-tagatose and D-sorbose, D-fructose and D-psicose, D-xylulose and D-ribulose, and between L-xylulose and L-ribulose.
5 Oxidation
Studies on the oxidation of D-glucose on palladium electrodes in alkaline media, on electro-deposited platinum electrodes, and on single-crystal platinum electrodes have been undertaken.
The catalysis of the oxidation of D-glucose by native and by recombinant glucose oxidase, mediated by one-electron redox co-substrates, has been monitored by cyclic voltammetry. A study on the effect of pH on the Pd-catalysed oxidation of D-glucose revealed that in acidic media the product, free D-gluconic acid, reversibly inhibits the oxidation process.
The oxidation of aldoses and sugar phosphates by Cr(VI) has been reviewed (23 refs.). The kinetic behaviour and the relative reactivities of several trioses, tetroses, pentoses and hexoses, amino sugars, and methylated sugars towards potassium permanganate in perchloric acid solution have been examined. Mechanisms have been proposed for the oxidation of arabinose and xylose by iodine in alkaline solution and by alkaline NBS under Ru(VIII)-catalysis. For the oxidation of monosaccharides by sodium N-bromobenzenesulfonamide in alkaline media, reaction via 1,2-enediol intermediates has been postulated. 1:1 Stoichiometry has been observed in the oxidation of D-fructose with PCC.
