Synthesis of Fluorinated Carbohydrates

The similarities in bond length and polarization between C-F and C-OH, as well as the altered hydrogen-bonding properties present in carbohydrates bearing a fluorine atom in place of an hydroxyl group can be exploited in place of an hydroxyl group can be exploited in biochemical investigations (enzyme-carbohydrate interactions, Lectin-carbohydrate affinities, antiobody-carbohydrate binding, etc.). ^1–5 In addition, the different chemistries exhibited by the flourinated carbohydrates have made them important reagents in both metabolic studies and disease diagnosis such as the use of 2-deoxy-2-[18f]-D-fluoroglucose in positron emission tomography. 6,7 Becasue of their widespread utlity, the synthesis of fluorinated carbohydrates is of importance. However, the Introduction of fluorine into a carbohydrate moiety can be an arduous task because of (1) the protection and deprotection steps required to set up the desired hydroxyl group for the introduction of fluoride, (2) the low nucleophilicity fo fluoride ion, and (3) fluoride ion catalyzed elimination reactions. 8,9 The search for Milder and more selective methods for the introduction of fluorine into Carbohydrates has continued at a rapid pace and it is appropriate to review som of the recent results.     

Indium(III) Triflate: A Highly Efficient Catalyst for Reactions of Sugars[1]

Indium(III) trifluoromethanesulfonate has been found to be extremely efficient in catalyzing acyl transfer reactions of various carbohydrates and their derivatives. Selective acetolyses of certain benzyl ethers/isopropylidene acetals of sugars have been possible using In(OTf)₃ in Ac₂O (neat). Reaction of the per-O-acetate of 2-deoxy-2-phthalimido-D-glucose with benzyl mercaptan in the presence of In(OTf)₃ led to the formation of the corresponding thioglycoside in high yield. Facile formation and hydrolysis of the isopropylidene and benzylidene acetals of various carbohydrates have also been achieved very efficiently in the presence of In(OTf)₃. The results show great promise for In(OTf)₃ in synthetic carbohydrate chemistry.     

Rare Sugars: Recent Advances and Their Potential Role in Sustainable Crop Protection

Rare sugars are monosaccharides with a limited availability in the nature and almost unknown biological functions. The use of industrial enzymatic and microbial processes greatly reduced their production costs, making research on these molecules more accessible. Since then, the number of studies on their medical/clinical applications grew and rare sugars emerged as potential candidates to replace conventional sugars in human nutrition thanks to their beneficial health effects. More recently, the potential use of rare sugars in agriculture was also highlighted. However, overviews and critical evaluations on this topic are missing. This review aims to provide the current knowledge about the effects of rare sugars on the organisms of the farming ecosystem, with an emphasis on their mode of action and practical use as an innovative tool for sustainable agriculture. Some rare sugars can impact the plant growth and immune responses by affecting metabolic homeostasis and the hormonal signaling pathways. These properties could be used for the development of new herbicides, plant growth regulators and resistance inducers. Other rare sugars also showed antinutritional properties on some phytopathogens and biocidal activity against some plant pests, highlighting their promising potential for the development of new sustainable pesticides. Their low risk for human health also makes them safe and ecofriendly alternatives to agrochemicals.     

Utilisation d'ylides du phosphore en chimie des sucres,X. Synthèse stéréospécifique de l'épimère en C3 du streptose et d'autres sucres ramifiés,dérivés de désoxy-5-pentoses, à groupements gem-hydroxy-formyle ou gem-hydroxy-hydroxyméthyle

The synthesis of branched-chain sugars of the gem-hydroxy-formyl and the gem-hydroxy-hydroxymethyl types is described. A 5-deoxy-1,2-O-isopropylidene-furanos-3-ulose is treated with cyanomethylene-triphenyl-phosphorane, yielding the two geometrical isomers of the corresponding branched-chain unsaturated sugar. Cis-dihydroxylation(KMnO₄) of these cyanomethylenic compounds affords stereoselectively and in high yield the gem-hydroxy-formyl branched chain sugars whose formyl group is on the more hindered face of the furanose ring. The hydroxymethyl analogues of the latter compounds are readily prepared by their borohydride reduction. This method constitutes a new general route to type A branched-chain sugars epimeric at the branching-point with the sugars which would have been obtained by the classical procedure involving Grignard reagents.     

Synthesis and Conformational Analysis of 2′-Deoxy-2′-(3-methoxybenzamido)adenosine,a rational-designed inhibitor of trypanosomal glyceraldehyde phosphate dehydrogenase (GAPDH)

A series of 2′-benzamido-2′-deoxyadenosine analogues were synthesized in an effort to find new lead structures for the treatment of sleeping sickness. The 2′-deoxy-2′-(3-methoxybenzamido)adenosine ( 1h ) was proved to be a selective inhibitor of the parasite glyceraldehyde 3-phosphate dehydrogenase which confirms the modeling studies. The solution-state conformation of 2′-(thiophene-2-carboxamido) analogue 1d demonstrates a 2′-endo conformation, an orientation of the thiophene ring under the ribose moiety, and the base part occupying a ‘syn’/‘anti’ equilibrium.     

A method for 13C‐labeling of metabolic carbohydrates within French bean leaves (Phaseolus vulgaris L.) for decomposition studies in soils

The molecular composition of plant residues is suspected to largely govern the fate of their constitutive carbon (C) in soils. Labile compounds, such as metabolic carbohydrates, are affected differently from recalcitrant and structural compounds by soil‐C stabilisation mechanisms. Producing ¹³C‐enriched plant residues with specifically labeled fractions would help us to investigate the fate in soils of the constitutive C of these compounds. The objective of the present research was to test ¹³C pulse chase labeling as a method for specifically enriching the metabolic carbohydrate components of plant residues, i.e. soluble sugars and starch. Bean plants were exposed to a ¹³CO₂‐enriched atmosphere for 0.5, 1, 2, 3 and 21 h. The major soluble sugars were then determined on water‐soluble extracts, and starch on HCl‐hydrolysable extracts. The results show a quick differential labeling between water‐soluble and water‐insoluble compounds. For both groups, ¹³C‐labeling increased linearly with time. The difference in δ¹³C signature between water‐soluble and insoluble fractions was 7‰ after 0.5 h and 70‰ after 21 h. However, this clear isotopic contrast masked a substantial labeling variability within each fraction. By contrast, metabolic carbohydrates on the one hand (i.e. soluble sugars + starch) and other fractions (essentially cell wall components) on the other hand displayed quite homogeneous signatures within fractions, and a significant difference in labeling between fractions: δ¹³C = 414 ± 3.7‰ and 56 ± 5.5‰, respectively. Thus, the technique generates labeled plant residues displaying contrasting ¹³C‐isotopic signatures between metabolic carbohydrates and other compounds, with homogenous signatures within each group. Metabolic carbohydrates being labile compounds, our findings suggest that the technique is particularly appropriate for investigating the effect of compound lability on the long‐term storage of their constitutive C in soils. Copyright © 2009 John Wiley & Sons, Ltd.     

Highly Effective Recognition of Carbohydrates by Phenanthroline‐Based Receptors: α‐ versus β‐Anomer Binding Preference

¹H NMR spectroscopic titrations in competitive and non‐competitive media, as well as binding studies in two‐phase systems, such as phase transfer of sugars from aqueous into organic solvents and dissolution of solid carbohydrates in apolar media revealed both highly effective recognition of neutral carbohydrates and interesting binding preferences of an acyclic phenanthroline‐based receptor 1 . Compared to the previously described acyclic receptors, compound 1 displays significantly higher binding affinities, the rare capability to extract sugars from water into non‐polar organic solutions and α‐ versus β‐anomer binding preference in the recognition of glycosides, which differs from those observed for other receptor systems. X‐ray crystallographic investigations revealed the presence of water molecules in the binding pocket of 1 that are engaged in the formation of hydrogen‐bonding motifs similar to those suggested by molecular modelling for the sugar OH groups in the receptor–sugar complexes. The molecular modelling calculations, synthesis, crystal structure and binding properties of 1 are described and compared with those of the previously described receptors.     

Four new andrographolide metabolites in rats

Four new sulfonate metabolites of andrographolide, 14-deoxy-12(R)-sulfo andrographolide (Metabolite 1), 14-deoxy-12(S)-sulfo andrographolide (Metabolite 2), 14-deoxy-12(R)-sulfo-9(S)-andrographolide (Metabolite 3) and 14-sulfo isoandrographolide (Metabolite 4), were isolated from urine and feces in rats. Their structures were elucidated by chemical and spectroscopic analyses. These four metabolites were formed through a rare metabolic reaction and were all new compounds.     

Metabolomic Markers for Predicting Preeclampsia in the First Trimester of Pregnancy: A Retrospective Study

We sought to identify the characteristic metabolite profile of blood plasma samples obtained from patients with preeclampsia. Direct high-resolution mass spectrometry was used to analyze samples from 79 pregnant women, 34 of whom had preeclampsia. We performed a comparative analysis of the metabolite profiles and found that they differed between pregnant women with and without preeclampsia. Lipids and sugars were identified as components of the metabolite profile that are likely to be associated with the development of preeclampsia. While PE was established only in the third trimester, a set of metabolites specific for the third trimester, including 2-(acetylamino)-1,5-anhydro-2-deoxy-4-O-b-D-galactopyranosyl-D-arabino-Hex-1-enitol, N-Acetyl-D-glucosaminyldiphosphodolichol, Cer(d18:0/20:0), and allolithocholic acid, was already traced in the first trimester. These components are also likely involved in lipid metabolism disorders and the development of oxidative stress.     

Synthesis of stable and cell-type selective analogues of cyclic ADP-ribose, a Ca(2+)-mobilizing second messenger. Structure--activity relationship of the N1-ribose moiety

We previously developed cyclic ADP-carbocyclic ribose (cADPcR, 2) as a stable mimic of cyclic ADP-ribose (cADPR, 1), a Ca(2+)-mobilizing second messenger. A series of the N1-ribose modified cADPcR analogues, designed as novel stable mimics of cADPR, which were the 2"-deoxy analogue 3, the 3"-deoxy analogue 4, the 3"-deoxy-2"-O-(methoxymethyl) analogue 5, the 3"-O-methyl analogue 6, the 2",3"-dideoxy analogue 7, and the 2",3"-dideoxydidehydro analogue 8, were successfully synthesized using the key intramolecular condensation reaction with phenylthiophosphate-type substrates. We investigated the conformations of these analogues and of cADPR and found that steric repulsion between both the adenine and N9-ribose moieties and between the adenine and N1-ribose moieties was a determinant of the conformation. The Ca(2+)-mobilizing effects were evaluated systematically using three different biological systems, i.e., sea urchin eggs, NG108-15 neuronal cells, and Jurkat T-lymphocytes. The relative potency of Ca(2+)-mobilization by these cADPR analogues varies depending on the cell-type used: e.g., 3"-deoxy-cADPcR (4) > cADPcR (2) > cADPR (1) in sea urchin eggs; cADPR (1) > cADPcR (2) approximately 3"-deoxy-cADPcR (4) in T-cells; and cADPcR (2) > cADPR (1) > 3"-deoxy-cADPcR (4) in neuronal cells, respectively. These indicated that the target proteins and/or the mechanism of action of cADPR in sea urchin eggs, T-cells, and neuronal cells are different. Thus, this study represents an entry to cell-type selective cADPR analogues, which can be used as biological tools and/or novel drug leads.     

Enzymes in Organic Synthesis: Application to the Problems of Carbohydrate Recognition (Part 2)

Recognition of carbohydrates by proteins and nucleic acids is highly specific, but the dissociation constants are relatively high (generally in the mM to high μM range) because of the lack of hydrophobic groups in the carbohydrates. The high specificity of this weak binding often comes from many hydrogen bonds and the coordination of metal ions as bridge between sugars and receptors. Though weak hydrophobic interactions between sugars and proteins have also been identified, the unique shape of a complex carbohydrate under the influence of anomeric and exo anomeric effects (the glycosidic torsion angles are therefore often not flexible but are typically somewhat restricted) and the topographic orientation of the hydroxyl and charged groups contribute most significantly to the recognition process. Studies on the structure–function relationship of a complex carbohydrate therefore require deliberate manipulation of its shape and functional groups, and synthesis of oligosaccharide analogs from modified monosaccharides is often useful to address the problem. The availability of various monosaccharides and their analogs for the synthesis of complex carbohydrates together with the information resulting from structural studies (such a NMR or X-ray studies on sugar–protein complexes) will certainly provide a basic understanding of complex carbohydrate recognition. An ultimate goal is to develop simple and easy-to-make non-carbohydrate molecules that resemble the active structure involved in carbohydrate–receptor interaction or the transition-state of an enzyme-catalyzed transformation (for example, glycosidase or glycosyltransferase reactions) and have the approprite bioavailability to be used to control the carbohydrate function in a specific manner. In part one of this review we described various enzymatic approaches to the synthesis of monosaccharides, analogs, and related structures. We describe in this part enzymatic and chemoenzymatic approaches to the synthesis of oligosaccarides and analogs, including those involved in E-selectin recognition, and strategies to inhibit glycosidases and glycosyltransferases.     

Interactive metabolic regulations during biomethanation ofLeucaena leucocephala

Biomethanation of leaves of the legumeL. leucocephala operated in batch reactors at different input volatile solids (12–18 g/L) proceeded in distinct metabolic phases. An initial cellulolytic phase of 4 d was followed by an early and active methanogenic phases (5–21 d) and a terminal phase of low-rate methanogenesis. Hydrolysis of cellulose was concentration-dependent and resulted in increased volatile acid levels. The trend of changes showed some variations at different input volatile solids. The changes in the levels of volatile acids followed an oscillatory pattern. The controlled rate of cellulose hydrolysis, levels of volatile acids, and steady-state levels of soluble carbohydrates and reducing sugars observed during active methanogenesis are indicative of interactive metabolic regulations.     

非糖类化合物合成碳环糖

碳环糖是一类呋喃或吡喃糖环中的氧原子被亚甲基取代后形成的糖类似物。碳环糖作为糖类化合物的类似物,和糖类化合物有着不同的活性和稳定性,已经引起了人们的广泛关注。本文综述了从非糖类化合物合成五元及六元碳环糖研究的最新进展。重点介绍了以环二烯基硅烷、奎宁酸、降冰片烯等碳环化合物为原料合成碳环糖的进展。     

Aminopolyols from Carbohydrates: Amination of Sugars and Sugar‐Derived Tetrahydrofurans with Transaminases

Carbohydrates are the major component of biomass and have unique potential as a sustainable source of building blocks for chemicals, materials, and biofuels because of their low cost, ready availability, and stereochemical diversity. With a view to upgrading carbohydrates to access valuable nitrogen‐containing sugar‐like compounds such as aminopolyols, biocatalytic aminations using transaminase enzymes (TAms) have been investigated as a sustainable alternative to traditional synthetic strategies. Demonstrated here is the reaction of TAms with sugar‐derived tetrahydrofuran (THF) aldehydes, obtained from the regioselective dehydration of biomass‐derived sugars, to provide access to cyclic aminodiols in high yields. In a preliminary study we have also established the direct transamination of sugars to give acyclic aminopolyols. Notably, the reaction of the ketose d ‐fructose proceeds with complete stereoselectivity to yield valuable aminosugars in high purity.     

Synthesis of Chiral Spiroacetals from Carbohydrates

Chiral spiroacetals of the 1,7-dioxaspiro[5.5]undecane, 1,6-dioxaspiro[4.5]decane, and 1,6-dioxaspiro[4.4]nonane types have been prepared from carbohydrates in pyranose or furanose forms. The spirocyclization reaction has been accomplished from a conveniently homologated carbohydrate by an intramolecular hydrogen abstraction reaction promoted by alkoxy radicals. Thus, 2,3,4,6-tetra-O-benzyl-1-deoxy-1-(3'-hydroxypropyl)-alpha-D-glucopyranose (2) was photolyzed with visible light in the presence of (diacetoxyiodo)benzene and iodine to give a mixture of (1R)-(3) and (1S)-2,3,4,6-tetra-O-benzyl-1-deoxy-D-glucopyranose-1-spiro-2'-tetrahydrofuran (4). The photolysis of methyl 6-deoxy-6-(2'-hydroxyethyl)-2,3,4-tri-O-methyl-alpha-D-glucopyranoside (8) gave the isomeric spiroacetals methyl (5S)- (9) and (5R)-6-deoxy-5,2'-epoxy-6-ethyl-2,3,4-tri-O-methyl-alpha-D-glucopyranoside (10) in which the spirocenter is now located at C-5. The spiroacetals of the [5.5]undecane series: methyl (5R)- (19) and (5S)-6-deoxy-5,3'-epoxy-2,3,4-tri-O-methyl-6-propyl-beta-D-glucopyranoside (20) have been prepared starting from methyl 6-deoxy-6-(3'-hydroxypropyl)-2,3,4-tri-O-methyl-beta-D-glucopyranoside (18). The reaction has also been applied to hexofuranoses and 1-deoxy-1-(3'-hydroxypropyl)-2,3:5,6-di-O-isopropylidene-alpha-D-mannofuranose (21) gave rise to (1S)- (22) and (1R)-1-deoxy-2,3:5,6-di-O-isopropylidene-D-mannofuranose-1-spiro-2'-tetrahydrofuran (23); and 1-deoxy-1-(4'-hydroxybutyl)-2,3:5,6-di-O-isopropylidene-alpha-D-mannofuranose (28) to (1R)- (30) and (1S)-1-deoxy-2,3:5,6-di-O-isopropylidene-D-mannofuranose-1-spiro-2'-tetrahydropyran (32). Both spiroacetal enantiomers are formally available from the same carbohydrate.     

Intra- and intermolecular complexation in C6 monoazacoronand substituted cyclodextrins

The preparation of 6(A)-deoxy-6(A)-(6-(2-(1,4,7,10-tetraoxa-13-azacyclopentadecan-13-yl)acetamido)hexylamino)-alpha-cyclodextrin, 3, 6(A)-deoxy-6(A)-(6-(2-(1,4,7,10,13-pentaoxa-16-azacyclooctadecan-16-yl)acetamido)hexylamino)-alpha-cyclodextrin, 4, and their beta-cyclodextrin analogues, 5 and 6, are described. (1)H (600 MHz) ROESY NMR spectra of the C(6) substituted beta-cyclodextrins, 5 and 6, are consistent with the intramolecular complexation of their azacyclopentadecanyl- and azacyclooctadecanyl(acetamido)hexylamino substituents in the beta-cyclodextrin annulus in D(2)O at pD = 8.5 whereas those of their alpha-cyclodextrin analogues, 3 and 4 are not complexed in the alpha-cyclodextrin annulus. This is attributed to the monoazacoronand components of the substituents being able to pass through the beta-cyclodextrin annulus whereas they are too large to pass through the alpha-cyclodextrin annulus. However, the substituents of 3 and 4 are intermolecularly complexed by beta-cyclodextrin to form pseudo [2]-rotaxanes. Metallocyclodextrins are formed by 5 through complexation by the monoazacoronand substituent component for which log (K/dm(3) mol(-1))= <2, 6.34 and 5.38 for Ca(2+), Zn(2+) and La(3+), respectively, in aqueous solution at 298.2 K and I= 0.10 mol dm(-3)(NEt(4)ClO(4)).     

Efficient access to 2-isobetulinic acid, 2-isooleanolic acid, and 2-isoursolic acid

An efficient access to 2-isobetulin, 2-isobetulinic acid, 2-isooleanolic acid, and 2-isoursolic acid has been developed. The key step is a novel one-pot conversion of 2,3-dihydroxy triterpenes to 3-deoxy-2-oxo triterpenes. This method provides a new access to 3-deoxy-2-substituted pentacyclic triterpenes as potential therapeutic agents against metabolic diseases, tumors, and HIV infection.     

Convergent approach toward the synthesis of the stereoisomers of C-6 homologues of 1-deoxynojirimycin and their analogues: evaluation as specific glycosidase inhibitors

A new and stereoselective strategy is developed to synthesize an appropriate template 9 to obtain C-6 homologues of 1-deoxyazasugars such as 1-deoxy-D-galactohomonojirimycin (5), 1-deoxy-4-hydroxymethyl-D-glucohomonojirimycin (6), and their enantiomers. The template 9 is also used to obtain neutral nonbasic pseudo-glyconolactam (8), C-4 amino, and methyl analogues of 1-deoxy-homonojirimycin as new analogues of 1-deoxyhomoazasugars. Compound 5 is found to be a potent and specific inhibitor to alpha-galactosidase (Ki = 1.7 microM). Similarly compounds 6 (Ki= 28 microM), ent-5 (Ki= 129 microM), and ent-6 (Ki= 12 microM) exhibited specific inhibition of beta-glucosidase.     

Characterization of the TDP-D-ravidosamine biosynthetic pathway: one-pot enzymatic synthesis of TDP-D-ravidosamine from thymidine-5-phosphate and glucose-1-phosphate

Ravidomycin V and related compounds, e.g., FE35A-B, exhibit potent anticancer activities against various cancer cell lines in the presence of visible light. The amino sugar moieties (D-ravidosamine and its analogues, respectively) in these molecules contribute to the higher potencies of ravidomycin and analogues when compared to closely related compounds with neutral or branched sugars. Within the ravidomycin V biosynthetic gene cluster, five putative genes encoding NDP-D-ravidosamine biosynthetic enzymes were identified. Through the activities of the isolated enzymes in vitro, it is demonstrated that ravD, ravE, ravIM, ravAMT and ravNMT encode TDP-D-glucose synthase, TDP-4-keto-6-deoxy-D-glucose-4,6-dehydratase, TDP-4-keto-6-deoxy-D-glucose-3,4-ketoisomerase, TDP-3-keto-6-deoxy-D-galactose-3-aminotransferase, and TDP-3-amino-3,6-dideoxy-D-galactose-N,N-dimethyl-transferase, respectively. A protocol for a one-pot enzymatic synthesis of TDP-D-ravidosamine has been developed. The results presented here now set the stage to produce TDP-D-ravidosamine routinely for glycosylation studies.     

Utilisation d'ylides du phosphore en chimie des sucres XXIII Eliminations accompagnant certaines réactions de Wittig

Some reactions of 3-O-alkyl-6-deoxy-1,2-O-isopropylidene-α-D-xylo-hexofuranos-5-uloses (1 and 2) with Wittig reagents are described. These ketosugars react with methylenetriphenylphosphorane and benzylidenetriphenylphosphorane to give the expected unsaturated branched-chain sugars and dienes formed by elimination of H–C(4) and the 3-alkyloxy group. Structural studies on all these compounds have been effected using NMR. spectroscopy and particularly, when necessary, nuclear Overhauser Effect. One important by-product of these reactions is an unsaturated ketone 3,6-dideoxy-1,2-O-isopropylidene-α-D-glycero-hex-3-enofuranos-5-ulose (6). Compounds 1 and 2 do not react with cyanomethylenetriphenylphosphorane.