Part I

MONO-, DI-, AND TRI-SACCHARIDES AND THEIR DERIVATIVES

By J. S. Brimacornbe
R. J. Ferrier
J. M. Williams
N. R. Williams

1 Introduction

The general terms of reference remain those set out in the Introduction to Volume 1 (P. 3).

Several novel approaches to the synthesis of O-glycosides are reported in Chapter 3, which also contains details of the latest studies by Angyal's group on the Fischer glycosidation of sugars in the presence of metal cations. The use of imidates for selective activation of the anomeric centre of monosaccharides appears to be very promising for the stereocontrolled synthesis of 1,2-cis-related disaccharides, etc. (Chapter 3). The use of a deuteriated substrate has revealed that the enzyme-catalysed reaction of glycerol (and, most likely, of water) with D-galactal is a trans addition (Chapter 3).

A new procedure for the tritylation of secondary hydroxy-groups, which is based on the use of triphenylmethylium perchlorate or tetrafluoroborate in the presence of a sterically hindered base, should be widely exploitable in carbohydrate chemistry (Chapter 4). So should a new approach to the regioselective acylation of polyhydroxy-compounds through selective enhancement of the nucleophilicity of hydroxy-groups by trialkylstannylation using a limited amount of bis(tributylstannyl) oxide (Chapter 6). Moreover, the reaction of alkyl tributyl-stannyl sulphides with glycosyl halides or acetates in the presence of tin(IV) chloride has provided a mild and efficient route to alkyl 1-thioglyco-pyranosides and -furanosides (Chapter 10). Several new procedures for the specific deoxygenation of sugar derivatives are mentioned in Chapter 11. In the absence of large neighbouring groups, deuteriated Raney nickel in refluxing deuterium oxide causes deuterium-exchange with carbon-bonded hydrogen atoms geminal to the hydroxy-groups in mono- and di-saccharide derivatives, but isomerization, although much slower than deuteriation, is sometimes observed at a centre undergoing deuterium-exchange (Chapter 14). The simple, but elegant, way in which this exchange reaction can be utilized to facilitate the analysis of the 13C n.m.r. spectra of carbohydrates is illustrated in Chapter 20.

Stoddart's group has pursued its interest in the incorporation of carbohydrate residues into the 18-crown-6 framework (Chapter 17). The ability of these chiral cryptands to complex with primary alkylammonium cations indicates their potential to provide the binding requirements of an enzyme analogue. No year would be complete without a crop of newly discovered antibiotics: the structures of new antibiotics are given in Chapter 18, which also indicates the considerable efforts that are being devoted to the synthesis of antibiotics of various types and their analogues. The troublesome problem of assigning the anomeric configuration to nucleosides has been overcome by a method based on 1H n.m.r. spectroscopy of nucleoside 3',5'-phosphates, since the value of J1',2' in these conformation-ally rigid molecules is, without exception, ≤ 1 Hz for 1',2'-transisomers and ≥ 33.5 Hz for 1',2'-cis-isomers (Chapter 19). A more sophisticated, but equally successful, approach based on the spin-lattice relaxation rates of the protons has been used to distinguish between the α- and β-anomers of C-nucleosides (Chapter 19). Both methods are applicable when only one anomer is available. The likelihood that the anomeric proton of the non-reducing residue of disaccharides receives relaxation contributions from the prutons on both sugar rings was noted in last year's Report (Vol. 10, p. 183). The use of specifically deuteriated analogues has enabled Hall and his colleagues to identify and measure the relaxation contribution that the anomeric proton on a sugar ring receives from the protons of an aglycone (Chapter 20). Conformational studies of cell-surface oligosaccharides and aminoglycoside antibiotics by this approach should be of great interest.

Carbohydrates have again been used as chiral precursors for the total synthesis of other natural products, including thromboxane B,, (-)isoavenaciolide, and insect pheromones – but pride of place must be given to a total synthesis of (+)-biotin from D-glucose in which a biomimetic transformation was used in forming the tetrahydrothiophen ring (Chapter 23).

Various aspects of sucrochemistry, general carbohydrate synthesis, and naturally occurring carbohydrates of unusual structure (e.g. antibiotics)," and the use of Lewis acids in carbohydrate chemistry have been reviewed. Several books of interest have appeared during the past year.

The May and August issues of Carbohydrate Research were dedicated to the memory of Professor J. K. N. Jones (1912 — 1977) and Professor Sir Edmund Hirst (1898 — 1975), respectively.

2 Free Sugars

Reviews have appeared on the sugars present in honey and on various aspects of the chemistry of sucrose.

Isolation and Synthesis

Glucose, galactose, and mannose have been identified as the principal monosaccharides in sedimentary rocks aged 200 million years. The oligosaccharides (1) — (3) were among those isolated following deacetylation of the products obtained on partial acetolysis of the extracellular polysaccharide from X antho-monas campestris, while partial acid hydrolysis of the extracellular polysaccharide from the red alga Porphyridium cruentum yielded the hexuronic acid-containing disaccharides 3-O-(α-D -glucopyranosyluronic acid)-L-galactose, 3-O-(2-O-methyl-α -D-glucopyranosyluronic acid)-D-galactose, and 3-O-(2-O-methyl -α-D-glucopyranosyluronic acid)-D-glucose. 3-O-α-D -Glucopyranosyl-L-sorbose has been 'identified as a metabolite of L-sorbose in such plants as alfalfa (Medicago sativa), tomato (Lycopersicon esculentum), and kidney bean (Phaseolus vulgaris). [U-14C] -Labelled maltosaccharides, [U-14C] maltose, and D-[U-14C] glucose have been obtained by selective enzymic hydrolysis of a soluble [U-14C]-labelled glycogen synthesized from CO2 by the blue-green bacterium Anacystis nidulans.

Stereoselective syntheses of 2,3-O-isopropylidene-DL-ribofuranose and methyl β-DL-ribopyranoside from furfuryl alcohol have been described. cis-Hydroxylation of the enones (4) and (5) with silver chlorate–osmium tetroxide gave methyl β-DL-erythro -pentopyranosid-4-ulose and 1-O-benzoyl-β-DL-erythro -pentopyranos-4-ulose, respectively, which were converted into DL-ribose derivatives by reduction of their isopropylidene derivatives. In further work on the total synthesis of monosaccharides, Achmatowicz's group has synthesized methyl α-L- and α-D-glucopyranosides from methyl (R)- and (S)-(2-furyl)glycolates, respectively, by the reactions outlined in Scheme 1 for the D-series. Related approaches were used to synthesize derivatives of L-mannopyranose and 3-amino-3-deoxy-L-glucopyranose (L-kanosamine)(see also Chapter 8). DL-Ribose, DL-arabinose, and DL-xylose have been synthesized from 2-furaldehyde by way of the unstable endialone (6) (Scheme 2); protection of the formyl group against both acidic and basic conditions was achieved by formation of the 4,4,5,5-tetramethyl-1,3-dioxolan derivative from 2-furaldehyde. In the synthesis of 2,3,6-trideoxyhexoses from such lactones as (7), reduction with di-isoamylborane gives ring-expanded products when the aglycone and the side-chain of the intermediate O-dialkylboryl furanosides are cis oriented and the substituents at C-4 and C-5 have the threo configuration. D-glycero-L-gluco-Heptose and D-glycero-L-manno-heptose have been prepared by way of condensation of D-galactose with nitromethane. Epimerization of each heptose in the presence of molybdate gave a 4:1-mixture in which D-glycero-L-gluco-heptose predominated. The nitromethane route has also been used to prepare D-glycero-D-gulo-heptose and D-glycero-D-ido-heptose from D-glucose. D-glycero-D-gulo-Heptose and D-glycero-L-manno-heptose on treatment with nitromethane, etc., gave D-erythro-L-galacto-, D-erythro -L-talo-, D-threo-L-galacto-, and D-threo-L-talo-octoses.

Condensation of 2,3-O-isopropylidene-D-glyceraldehyde with, for example, malonic, acetoacetic, and cyanoacetic acids gave unsaturated products (8) that could be converted into the 2-ulose (9) and the nitrile (10). D-Erythrose has been purified by way of its 4-nitrophenylhydrazone and procedures have been reported for the preparation of D-mannose from doum-palm kernels. D-[5-18O]Glucose, which was required for a study of the biosynthesis of myo-inositol, has been synthesized essentially free from L-idose via reduction (sodium borohydride) of the keto-acid (12) derived from 1,2-O-isopropylidene-α-D-xylo-hexofuranurono-5-ulose-6, 3-lactone (11) (Scheme 3) (see Vol. 9, p. 118).

Derivatives of D-[2-2H]glucose can be conveniently prepared by reduction (sodium borodeuteride) of methyl 3-O-benzoyl-4,6-O -benzylidene-α-D-arabino-hexopyranosid-2-ulose, while stereospecific syntheses of (6R)- and (6S)-D-[6-2H] glucose from the aldehyde (13) (Scheme 4) have been described. The key intermediate is the monodeuteriated alkene (14), which afforded the (6S)-isomer on cis-hydroxylation with osmium tetroxide and removal of the protecting groups or the (6R)-isomer on treatment with 3-chloroperbenzoic acid, separation of the resulting epoxides, and base-catalysed ring-opening of the D-gluco epoxide, etc.,

Physical Measurements

The effect of added electrolytes (sodium and potassium halides of progressively increasing molecular volume) in the concentration range 0.125 — 3 M on the viscosity behaviour of an aqueous sucrose solution (292 mM) between 25 and 40°C has been investigated. Conductance data on the interaction of the sodium salts of several low-carbon aliphatic acids with sucrose in water and in formamide solutions have been reported and interpreted in terms of the effects that hydrocarbon chains have on hydrogen bonding in saturated solutions of sucrose. Conductance data have also been reported for the interaction of sucrose with symmetrical tetra-alkylammonium halides in formamide and in water in the temperature range 25 — 70°C.

The ratio of α- and β-lactose crystallizing from various solvents has been measured by g.l.c. and an image-analysing computer has been used to measure changes in the distribution of the crystal size during growth in lactose solutions of differing supersaturation. The melting point of sucrose has been found to increase with the rate of heating and with the pH of the solution from which the sample crystallized. Single crystals of sucrose growing in the presence of alkali metal ions or alkaline-earth metal ions have reproducible crystal habits. Lattice energies have been calculated for meso-erythritol, α-D-glucopyranose, pentaerythritol, and glycerol, and they are in reasonable agreement with the sublimation energies obtained experimentally. The acid dissociation constants calculated for raffinose and melezitose in sodium perchlorate solution at 25°C are similar, both trisaccharides behaving as very weak triprotic acids.

A study of the rate of mutarotation of α-D-glucopyranose in DMF in the presence of both pyridine and phenols indicated that their catalytic effect is greatest when they are present in equimolar concentrations, suggesting that the catalytic process involves a termolecular complex. Catalysis of the mutarotation of α- or β-D-glucopyranose in water by such salts as iron(III) chloride and nickel(II) chloride and by carboxylate anions in DMF, DMSO, or aqueous DMS0 has also been studied and discussed. The enthalpy for the mutarotation of D-gluco-pyranose in water containing THF and t-butanol exhibited a complex dependence on the composition of the solvent. The effect of the ternary solvent system on the rate of mutarotation differs from that found in water–DMF–DMSO. Benzamidine catalysed the mutarotation of 2,3,4,6-tetra-O-methyl-α-D-glucopyranose more effectively than other compounds of comparable basicity. The efficiency of benzamidine in promoting anti-dehydrohalogenations suggested that the catalytic effect of benzamidine may not be due to a concerted bifunctional mechanism, as depicted in (15), but rather to the formation of a glycosyloxy–benzamidinium ion pair. Differences between the behaviours of benzamidine and other tautomeric catalysts (e.g. 2-pyridone) were discussed. A c.d. study of the mutarotation of D-glucose, D-ribose, and D-fructose is referred to in Chapter 21.

Transitions observed by differential thermal analysis at and above the melting points of various mono-, di-, and poly-saccharides have been associated with the breaking of inter- and intra-molecular hydrogen bonds, respectively. The thermal stabilities of a series of mono-O-methyl-D-glucoses and methyl D-glucopyranosides varied appreciably, depending on the position of the substituent: methyl β- and α-D-glucopyranosides are more stable than other monomethylated derivatives, among which 4-O-methyl-D-glucopyranose is the least thermally stable. The partial molar volumes of a number of mono-, di-, tri-, oligo-, and poly-saccharides have been determined in water at 25 °C. Measurements of the enthalpy of dilution of one- and two-solute aqueous mixtures of ethylene glycol, pentaerythritol, D-glucose, sucrose, and various amides have been used to calculate the pairwise enthalpy of interaction of each compound with the others. The diffusion of amino-acids, D-glucose, maltose, and maltotriose in solutions of dextran and derivatized dextrans (e.g. DEAE-dextran) has been examined as an aid to the preparation of immobilized enzymes and to an understanding of enzyme kinetics.

The α-furanose (0.6%) and β-furanose (0.3%) forms of D-mannose and the β-furanose form (0.14%) of D-glucose have been detected in aqueous solutions by taking advantage of the high resolving power of 13C n.m.r. spectroscopy. The tautomeric forms adopted by ketoses and their biologically important phosphoric esters at equilibrium have also been discussed. The proportion of carbonyl form present in the equilibrium mixture of each of 23 aldoses and 10 ketoses has been estimated from the c.d. spectrum obtained with a highly sensitive circular dichrometer. An attempt to calculate the probable specific rotations of α- and β-D-fructofuranose is mentioned in Chapter 21.

Reactions

Affinity columns that could be used in the purification of lectins have been prepared by reductive amination of disaccharides (e.g. lactose, melibiose, maltose, and di-N-acetylchitobiose) with sodium cyanoborohydride in the presence of amino-ethylated polyacrylamide gels at pH 9. An L-asparaginase from E. coli was similarly glycosylated by reductive coupling with lactose or N-acetylneuraminyl-lactose. The amounts of D-mannose, D-fructose, and D-gluco-oligosaccharides formed in the acid-catalysed reversion of D-glucose depended on the acid used. The highest yields of di- and oligo-saccharides (isomaltose, maltose, gentiobiose, cellobiose, isomalto-tetraose, -pentaose, and heptaose) were obtained with 10% solutions of D-glucose in 0.01 — 0.5 M-HCl. 5-Hydroxymethyl-2-furaldehyde and 1,6-anhydro-β-D-glucopyranose, as well as D-glucobioses, were among the acid-reversion products obtained from D-glucose in alcoholic solvents, and 1.6-anhydro-β-D-glucopyranose appeared to be one of the first products formed when D-glucose reacted with acids in 1:1-mixtures of water and an alcohol. The ratio (0.60 — 0.74) of (1 -> 4)- and (1 -> 6) -linked disaccharides formed by acid-catalysed reversion of D-glucose in water was found to be virtually independent of the acid used and of the concentrations of the acid and D-glucose. The dehydration of d-fructose has been studied in depth. Analytical procedures for the determination of D-fructose and its dehydration products, viz. 5-hydroxymethyl-2-furaldehyde, levulinic acid (formed by rehydration of 5-hydroxymethyl-2-furaldehyde), and 'humin', were developed and applied in studies of the influence of the initial and catalyst concentrations on the dehydration of D-fructose at 95°C in 0.5–2M-HCl. The influence of the amount of water in the reaction mixture and of pH on the rates of formation and the yields of products in the acid-catalysed dehydration Of D-fructose were also examined. These studies culminated in the development of a continuous process for the manufacture of 5-hydroxymethyl-2-furaldehyde from D-fructose in yields of 65 — 85%. The Maillard reaction of D-glucose and methylamine in slightly acidic, aqueous solution yielded D-fructose and diverse furans, pyrroles, phenols, and enols, including (16) — (22).