Three methods for the generation of pyranosyl nitrile oxide have been utilised: firstly isocyanate-induced dehydration of pyranosylnitromethanes (the Mukaiyama approach); secondly hypochlorite-mediated oxidation of pyranosyl aldoximes, and finally base-catalysed dehydrohalogenation of pyranosyl hydroxyimoyl chlorides. The pyranosyl aldoximes derived from D-mannose, D-glucose, D-xylose and L-fucose were synthesised via stannate (II) mediated reduction of the corresponding pyranosylnitromethane (80-90%), whilst direct chlorination of the aldoximes gave the hydroxyimoyl chlorides (80-95%). The efficiency of nitrile oxide generation by all three methods was illustrated by the high levels of 3,4-(dipyranosyl)-1,2,5-oxadiazole-2-oxides (furoxans) obtained by dimerisation on generation in the absence of a dipolarophile. For example, 3,4-(2,3,4,6-tetra-<i>O-</i>acetyl-β-D-mannopyranosyl)-1,2,5-oxadiazole-2-oxide was prepared from 2,3,4,6-tetra-<i>O</i>-acetyl-β-D-mannopyranosylnitromethane in a 90% yield. The D-glucose, D-xylose and L-fucose derived analogues were synthesised in high yields (79-96%) utilising all three methods. Where compatible, the Mukaiyama approach gave cycloadducts in good yields (>75%) (e.g. on reaction with methylenecyclohexane and styrene). However for low boiling or thermally unstable dipolarophiles or for dipolarophiles with functional groups incompatible groups incompatible with the isocyanate dehydrating agent (e.g. dimethyl acetylenedicarboxylate, allyl alcohol), cycloadditions were carried out successfully using pyranosyl aldoximes and pyranosyl hydroximoyl chlorides as precursors. The cycloaddition reactions with achiral alkenes proceeded with low levels of diastereoselectivity (d.e. < 10%), in contrast to the cycloaddition of chiral alkenes where significant p-facial selectivity was observed (d.e. 40-80%). The chemistry of the dipyranosyl furoxans has also been investigated. Hydrogenation of 3,4-(2,3,4-tri-<i>O</i>-acetyl-β-D-xylopyranosyl)-furoxan in the presence of Raney nickel yielded the corresponding dipyranosyl-1,2-dioxime in 77% yield. Preliminary studies of the chemistry of this class of dioxime have been carried out, for example dehydration to the 1,2,5-oxadiazole (furazan) and re-oxidation to the dipyranosyl furoxan. Attempts at complexation of these novel chiral ligands with nickel show promising results.

The sugar-derived alkenes were prepared using three methods; in the first hex-5-enofuranoses were generated in good yields from the corresponding 5,6-dimesylates using Tipson-Cohen conditions; the second employed an aprotic Bamford-Stevens reaction to give the 1-methylene sugar from the analogous pyranosyl tosylhydrazone. The final approach gave a series of 1-methylene sugars in moderate to good yields (50-82%) by the methylation of sugar lactones with dimethyl titanocene (Petasis Reagent).

Novel linker <i>N</i>-({[4-(3-aminopropylcarbamoyl)phenyl]ethysulphanyl}methyl)-2-phenylacetamide 87 has been developed which is compatible with a range of reactions (e.g. base oxidation, alkylation), can be cleaved under mild conditions and has the ability to release alcohols and amines. An efficient synthesis of the linker has been devised and attachment to a variety of solid supports (Tentagel, polystyrene) has been achieved. (Fig. 9966A). As a general building block 2-acetamido-3, 4-di-<i>O</i>-acetyl-2-deoxy-<i>N</i>-(fluoren-9-yl-methoxycarbonyl)-b-D-glucopyranosylamine 106 was synthesised in gram quantities from <i>N</i>-acetylglucosamine in 8 steps. The saccharide was linked through the 6-hydroxyl group onto carboxy-Tentagel <i>via </i>linker 87 in excellent yield and extension of the glycoside amino group provides a route towards the synthesis of glycopeptides. (Fig. 9966B). As an alternative, sugar building block 2-acetamido-2-deoxy-<i>N</i>-(benzyloxycarbonyl)-b-D-glucopyranosylamine 129 was synthesised from <i>N</i>-acetylglucosamine in 5 steps. The saccharide was attached onto carboxy-Tentagel <i>via </i>linker 87 and has been used in initial studies into the esterification reactions to generate a small library of compounds. (Fig. 9966C).

No description available.

A route to carbon-linked disaccharides (two monosaccharide units linked by a carbon bridge rather than a glycosidic oxygen) employing nitrile oxide/isoxazoline chemistry has been investigated. This convergent approach is based on cycloaddition of sugar-derived alkene and nitrile oxide fragments, followed by ring cleavage and functional group manipulation of the resulting 2-isoxazoline. Careful selection of the nitrile oxide and alkene fragments defines much of the stereochemistry of the products. Two ω-unsaturated hexofuranoses were chosen for study: 3-<i>O</i>-benzyl-5,6-dideoxy-1,2-<i>O</i>-isopropylidene-α-D-<i>xylo</i>-hex-5-enofuranose (<i>37</i>) derived from D-glucose and methyl 5,6-dideoxy-2,3-<i>O</i>-isopropylidene-α-D-<i>lyxo</i>-hex-5-enofuranoside (<i>137</i>), which has the opposite configuration to (<i>37</i>) at C_2, derived from D-mannose. Four nitrile oxides were employed in cycloadditions to these alkenes: ethoxycarbonylformonitrile oxide (<i>36</i>) was used as a model 1,3-dipole to probe the π-facial selectivity of cycloadditions to alkene (<i>137</i>), and three pyranose 1-nitrile oxides (<i>122</i>), (<i>146</i>) and (<i>150</i>), derived from D-xylose, D-arabinose and D-galactose respectively. Additions to alkene (<i>37</i>) proceeded with a high degree of π-facial selectivity (56-82% d.e.) in favour of the 2-isoxazoline with <i>erythro</i> configuration. Similar selectivity was noted in additions to alkene (<i>137</i>). This selectivity can be explained in terms of the 'inside alkoxy effect' proposed by Houk and modified to include the 'homoallylic effect' put forward by De Micheli. Reductive hydrolytic cleavage of the 2-isoxazolines to release the latent β-hydroxy ketone functionality was carried out by both Pd/C and Ra-Ni catalysed hydrogenolysis. In the Pd/C case significant loss of the 3-<i>O</i>-benzyl protecting group was noted, however, Ra-Ni hydrogenolysis afforded the required β-hydroxy ketones (1→6)-carbonyl-linked <i>C</i>-disaccharides) in moderate yield (43-56%) along with a minor product identified as an epimeric mixture of the corresponding γ-amino alcohols ((1→6)-aminomethylene-linked <i>C</i>-disaccharides). Finally, reduction of the β-hydroxy ketone functionality and subsequent removal of the isopropylidene protecting groups afforded the dipyranose (1→6)-hydroxymethylene-linked <i>C</i>-disaccharides.

No description available.

No description available.

No description available.

This t~esis is concerned with the synthesis of phosphonate analogues of carbohydrates as stable lsosteres of the corresponding phosphates. Analogues of glucose-6-phosphate (Part A) and mannose-6-phosphate (Part B) were prepared. Part A Glucose-6-phosphatase plays a central role in the homeostatic regulation of blood glucose, by catalysing the conversion of glucose-6-phosphate to glucose in the terminal steps of both gluconeogenesis and glycogenolysis. Abnormally high glucose-6- phosphatase activity has been noted in some cases of diabetes mellitus. Phosphonate analogues of glucose-6-phosphate (which contain a P-C linkage in place of the P-O-C moiety of the corresponding phosphate) are potential inhibitors of glucose-6-phosphatase and therefore could have an application in the treatment of diabetes. Here, the syntheses of three phosphonate analogues of glucose-6-phosphate are described. A non-isosteric phosphonate analogue (in which the phosphate bridging oxygen of glucose-6-phosphate has been removed) was prepared in seven steps from D-glucose, the key step being an Arbuzov reaction between triethyl phosphite and a benzyl protected glucose-6-bromide. Isosteric and isoelectronic phosphonate analogues (in which the bridging oxygen of glucose-6-phosphate has been replaced by a methylene [CH2] and a difluoromethylene [CF2] group, respectively) were also synthesised in seven steps from D-glucose, the key step being the nucleophilic attack of anion (EtO)2P(O)CX2- (X = H, F) on the C-6 triflate of a benzyl protected glucose derivative. PartB Transforming growth factor-~l (TGF-~l) is one of several cytokines implicated in scarring during adult wound healing. TGF-~l is stored in an inert form and activation is due, in part, to the binding of mannose-6-phosphate residues on latent TGF-~l to the mannose-6-phosphate/insulin-like growth factor-II (M-6-PIIGF-II) receptor. Phosphonate analogues of mannose-6-phosphate could inhibit TGF-~l activation by competitive inhibition of binding of latent TGF-~l to the M-6-PIIGF-II receptor and therefore have antiscarring potential. A non-isosteric phosphonate analogue of mannose-6-phosphate was prepared in eight steps from D-mannose utilising Arbuzov chemistry. Initial evaluation in a rat model indicated an anti-scarring effect. An a-hydroxy phosphonate analogue of mannose-6-phosphate was prepared utilising a Pudovic reaction between the anion of dibenzyl phosphite and the C-6 aldehyde of a benzyl protected mannose derivative. The Pudovic reaction proceeded with a diastereoisomeric excess of -80 % and various attempts were made to determine the absolute configuration of the major diastereoisomer. Several esterified derivatives were prepared in an attempt to obtain crystals suitable for X-ray analysis, however only oils or fine powders were formed. Reactions designed to synthesise conformationally restricted analogues in order to determine the conformation by NOE NMR spectroscopy are also described, however these were not successful. Phosphorylated a-I,2-linked mannobiosides are known to bind strongly to the M- 6-P/IGF-II receptor, and therefore an a-I,2-linked mannose disaccharide with a nonisosteric phosphonate at the non-reducing terminus was prepared. The coupling of a thioglycoside donor bearing a 6-phosphonate with the 1,3,4,6-tetra-O-acetyl-~-Dmannopyranoside acceptor was achieved with the use of the mild activator, Niodosuccinimide. Finally, methodology towards the synthesis of a bidentate ligand incorporating two mannose-6-phosphate groups, together with. the a-I ,2-mannosi~ic linkage is described. A cyclohexane-I,2-diacetal protected a-I ,2-hnked mannose dlsacchande _ beanng a 6- phosphonate moiety at the non-reducing terminus was prepared from protected monosaccharides, again using a mild activation procedure.

No description available.