Stereoselective syntheses of heptaprenylphosphoryl β-d-arabino-and β-d-ribo-furanoses

The stereoselective syntheses of heptaprenylphosphoryl β-d-arabinofuranose and heptaprenylphosphoryl β-d-ribofuranose are described. In the synthesis of the d-arabino product, the stereoselectivity was achieved by the coupling of a suitably protected β-d-arabinofuranosyl phosphate intermediate with an activated form of heptaprenol and subsequent deprotection. In the case of the ribo-analog, the desired β-anomer could be obtained by the more convenient phosphoramidite method. The products were successfully employed in the mycobacterial epimerase assay.     

Synthesis of d-fructopyranosides with 2-O-acyl-β-d-fructopyranosides

Glycosylation of 2-O-acyl fructopyranosides was investigated, which were shown to be effective glycosyl donors for d-fructopyranoside synthesis with good β-selectivity and yields. For bulky acceptor 4e, α-anomer 5e was obtained with α/β = 65:23. Unexpected ring-opening was observed during acetylation of 9, indicating the sensitivity of the fructopyranosyl ring.     

Synthesis of quercetin 3-O-β-d-apiofuranosyl-(1→2)-[α-l-rhamnopyranosyl-(1→6)]-β-d-glucopyranoside

A concise method to construct a unique 2,6-branched trisaccharide was established by regioselective glycosylation of three free hydroxyl groups on a 3-O-protected glucose moiety, and successfully used in the synthesis of quercetin 3-O-β-d-apiofuranosyl-(1→2)-[α-l-rhamnopyranosyl-(1→6)]-β-d-glucopyranoside, a flavonol O-glycoside isolated from glandless cotton seeds which showed notable antidepressant activities.     

An expeditious synthesis of quercetin 3-O-β-d-glucuronide from rutin

We report the synthesis of the major human metabolite of quercetin, quercetin 3-O-β-d-glucuronide, from rutin (quercetin-3-rutinoside), which is commercially available at low cost. This straightforward synthesis is based on the key intermediate 3′,4′,5,7-tetra-O-benzyl-quercetin which is obtained in only two steps by the total benzylation of rutin followed by acid hydrolysis of the rutinoside residue. Glycosylation of the free 3 hydroxyl group by 1-bromo-3,4,6-tetra-O-acetyl-α-d-glucopyranoside yields the protected glucoside. TEMPO-mediated oxidation of primary alcohol on the deprotected glucoside gives access to the benzylated glucuronide. Removal of the benzyl groups which protect the quercetin hydroxyl groups by H₂ (10% Pd/C) yields quercetin 3-O-β-d-glucuronide.     

Synthesis and RNA-selective hybridization of α-l-ribo- and β-d-lyxo-configured oligonucleotides

Three α-l-ribofuranosyl analogues of RNA nucleotides (α-l-RNA analogues) have been synthesized and incorporated into oligonucleotides using the phosphoramide approach on an automated DNA synthesizer. The 4′-C-hydroxymethyl-α-l-ribofuranosyl thymine monomer was furthermore synthesized. Relative to the unmodified duplexes, incorporation of a single α-l-RNA monomer into a DNA strand leads to reduced thermal stability of duplexes with DNA complements but unchanged thermal stability of duplexes with RNA complements, whereas incorporation of more than one α-l-RNA monomer lead to moderately decreased thermal stability also of duplexes with RNA complements. Efficient hybridization with an RNA complement and no melting transition with a DNA complement were observed with stereoregular chimeric oligonucleotides composed of a mixture of α-l-RNA and affinity enhancing α-l-LNA monomers (α-l-ribo-configured locked nucleic acid). Furthermore, duplexes formed between oligodeoxynucleotides containing an α-l-RNA monomer and complementary RNA were good substrates for Escherichia coli RNase H. RNA-selective hybridization was also achieved by the incorporation of 1-(4-C-hydroxymethyl-β-d-lyxofuranosyl)thymine monomers into a DNA strand, whereas stable duplexes were formed with both complementary DNA and RNA when these monomers were incorporated into an RNA strand.     

First synthesis of natural phosphatidyl-β-d-glucoside

Herein, we report the chemical synthesis of naturally occurring mammalian phosphatidyl-β-d-glucoside (PtdGlc), in order to confirm the proposed structure and to clarify its stereochemistry. We designed a convergent synthetic strategy, suitable to prepare sensitive PtdGlc derivatives. As an initial demonstration of our strategy, we successfully prepared both PtdGlc diastereomers as well as its sensitive arachidonyl analogue. The presence of both diastereomers in the natural sample was confirmed.     

A convenient new route to protected and free 2,6-anhydro-d-glycero-d-gulo-heptoses (1-formyl-β-d-glucopyranosides)

A new and efficient process has been developed for the synthesis of 1-formyl-β-d-glucopyranosides from d-glucose.     

Facile synthesis of 4-deoxy-4-fluoro-α-d-talopyranoside, 4-deoxy-4-fluoro-α-d-idopyranoside and 2,4-dideoxy-2,4-difluoro-α-d-talopyranoside

The title compounds were prepared by two independent syntheses using inexpensive commercially available starting materials. 4-Deoxy-4-fluoro-α-d-talopyranoside served as a precursor to 4-deoxy-4-fluoro-α-d-idopyranoside, allowing for inversion of configuration at C-3 via a three-step protocol. The synthesis of 2,4-dideoxy-2,4-difluoro-α-d-talopyranoside is based on two nucleophilic fluorination events at C-2 then at C-4 using TBAF·3H₂O and TBAF·4tBuOH as a fluoride source. All compounds are prepared as pure stereoisomers and are therefore suitable probes for OH?F H-bonding studies by ¹H NMR spectroscopy.     

Synthesis of analogues of naturally occurring 3-O-(β-d-glucopyranosyl)-fagomine

Stereoselective synthesis of 3-α-C-glucosides of d- and l-fagomine from the corresponding C-disaccharides is reported. The ethyl glycoside of perbenzylated C-disaccharide 8 was converted via the corresponding thioglycoside 10 and reducing C-disaccharide 11, into substituted alditol 12 which, upon oxidation and double reductive amination stereoselectively afforded pure perbenzylated d-fagomine C-glucoside 14. In the same manner, the ethyl glycoside of perbenzylated C-disaccharide 9 was stereoselectively converted into perbenzylated l-fagomine C-glucoside 15.     

Stereoselective synthesis of decaprenylphosphoryl β-d-arabinofuranose

Decaprenylphosphoryl β-d-arabinofuranose (DPA) is known to be a key arabinose donor in mycobacteria. In order to study the biosynthesis of the major polysaccharides from the mycobacterial cell wall, it was necessary to develop a practical and stereoselective synthetic scheme for DPA. This goal was achieved by coupling of a suitably protected β-d-arabinofuranosyl phosphate intermediate with an activated form of decaprenol and subsequent deprotection.     

Increasing the inhibitory potency of l-arabino-imidazolo-[1,2]-piperidinose towards β-d-glucosidase and β-d-galactosidase

The synthesis of some potent inhibitors of two retaining β-glycosidases was achieved by introducing aglycon-mimics into the imidazole moiety of l-arabino azasugar 1. The strongest inhibition was observed with the phenyl-ethyl substituent at C(2) of 1 against β-d-galactosidase and β-d-glucosidase, whereas the hydroxymethyl group at C(2) increased only slightly the inhibitory properties.     

One pot protecting group free synthesis of multifunctional biphenyl methyl-C-β-d-glycosides in aqueous medium

One pot synthesis of the butenonyl-C-β-d-glycosides with malononitrile in the presence of K₂CO₃ in water under mild and green reaction conditions leading to the formation of small library of multifunctional biphenyl methyl-C-β-d-glycosides in good yields has been reported. The reaction is equally applicable with the substrates having different glycosyl pyranoses and aromatic rings with different substituents.     

C-(β-d-Glucopyranosyl)formamidrazones,formic acid hydrazides and their transformations into 3-(β-d-glucopyranosyl)-5-substituted-1,2,4-triazoles: a synthetic and computational study

Synthesis of O-perbenzoylated 3-(β-d-glucopyranosyl)-5-substituted-1,2,4-triazoles, precursors of potent inhibitors of glycogen phosphorylase, was studied by ring closures of N¹-acyl-carboxamidrazone type intermediates. Reactions of C-(β-d-glucopyranosyl)formimidate or C-(β-d-glucopyranosyl)formamidine with acid hydrazides as well as acylation of C-(β-d-glucopyranosyl)formamidrazone by acid chlorides unexpectedly gave the corresponding 1,3,4-oxadiazoles instead of 1,2,4-triazoles. The desired triazoles were obtained in reactions of C-(β-d-glucopyranosyl)formamidine or C-(β-d-glucopyranosyl)formyl chloride with arenecarboxamidrazones, and also in acylations of N¹-tosyl-C-(β-d-glucopyranosyl)formamidrazone with acid chlorides. Theoretical calculations (B3LYP and M06-2X DFT with the standard 6-31G(d,p) basis set) on simple model compounds with methyl and phenyl substituents to understand the bifurcation of the ring closure of N¹-acyl-carboxamidrazones indicated that in general the reaction led to 1,2,4-triazoles. However, the probability of the 1,3,4-oxadiazole forming pathway was shown to be significantly higher with N¹-benzoyl-acetamidrazones, which were closest analogues of the intermediates resulting in C-glucosyl-1,3,4-oxadiazoles. It was thereby demonstrated that the substitution pattern of the N¹-acyl-carboxamidrazones played a fundamental role in determining the direction of the ring closing reaction.     

Stereoselectivity in the synthesis of polyprenylphosphoryl β-d-ribofuranoses

Decaprenylphosphoryl β-d-arabinofuranose (DPA) is a key arabinose donor in mycobacteria. The ribo analog of DPA (DPR) has also been found in mycobacteria. It has recently been confirmed that DPA is formed via a two-step epimerization of DPR. The stereoselective synthesis of DPR as well as two shorter analogs of DPR is described.     

Conformational search and spectroscopic analysis of bis-β-d-glucopyranosyl azacrown derivative

1,10-N,N′-bis-(β-d-ureidoglucopyranosyl)-4,7,13-trioxa-1,10-diazacyclopentadecane is a new, recently synthesized compound, which exhibits complexation ability towards drugs. In the present study various theoretical methods, including molecular mechanics, computer simulations, semiempirical and DFT calculations, are applied to find the lowest energy conformers of this molecule in vacuo and in aqueous solution. For the most stable structures the vibrational frequencies as well as the C and H chemical shifts were computed. Along with the theoretical investigation the IR in the KBr discs and the NMR spectra in water and in pyridine were experimentally recorded. It is shown that in the lowest energy structures the two glucosyl units are placed on the same side of the diazacrown ring with their mutual orientations favoring formation of hydrogen bonds. The “open” structure, in which no such hydrogen bonds can be formed, is found to have much higher energy. The computed and measured IR spectra and NMR chemical shifts are compared and discussed in detail. The most stable structures are analyzed with respect to the possible mechanism of complexation of drugs.     

Chemo-enzymatic synthesis of 2′,3′-dideoxy-3′-fluoro-β-d-guanosine via 2,3-dideoxy-3-fluoro-α-d-ribose 1-phosphate

2,3-Dideoxy-3-fluoro-α-d-ribose 1-phosphate 2 was stereoselectively synthesized and converted to 2′,3′-dideoxy-3-fluoro-β-d-guanosine 1 by enzymatic reaction using purine nucleoside phosphorylase. This chemo-enzymatic strategy was first applied to the synthesis of 1.     

Electrochemical polymerization of 3,4-ethylenedioxythiophene in aqueous solution containing N-dodecyl-β-d-maltoside

Poly(3,4-ethylenedioxythiophene) (PEDOT) films were synthesized electrochemically by direct anodic oxidation of 3,4-ethylenedioxythiophene (EDOT) at relatively low monomer concentration (0.005-0.01 mol L⁻¹) in aqueous solution containing green nonionic sugar-based surfactant N-dodecyl-β-d-maltoside (DM), which has good biocompatibility and biodegradability. The moderate interaction between DM through the hydroxy groups and EDOT monomer led to the decrease of monomer oxidation onset. Different surfactants, such as anionic sodium dodecylbenzenesulfate (SDBS), nonionic triton X-100 (TX100), were also tested for comparison. As-formed PEDOT films were characterized electrochemically and spectroscopically using FTIR and UV-visible techniques. PEDOT nano-materials with good thermal stability and conductivity of 26.2 S cm⁻¹ can be synthesized in water-DM micellar solution, which can be proved by the results of scanning electron microscopy (SEM). PEDOT prepared from water-DM media with good biocompatibility can be a good candidate for application in biosensors.     

Direct access to new β-d-galactofuranoconjugates: application to the synthesis of galactofuranosyl-l-cysteine and l-serine

Galactofuranose post-translational modifications, although quite rare, were detected in some biomolecules produced by parasites. While hexopyranosides were already linked to various peptides and proteins, few hexofuranosides have been artificially conjugated to amino acids. We thus report herein a robust glycosylation methodology to obtain S-alkyl, O-serine and S-cysteine-β-d-galactofuranosides starting from readily available galactofuranose donors. O-Acetyl, thioimidoyl and acetimidoyl donors were compared in terms of yields and selectivity when reacted with mercaptans, l-cysteine and l-serine. Acetimidates turned out to be the best notably for amino acids glycosylation.     

New alkaloids sinomacutines A–E,and cephalonine-2-O-β-d-glucopyranoside from rhizomes of Sinomenium acutum

Phytochemical investigation on the rhizomes of Sinomenium acutum led to the isolation of new alkaloids sinomacutines A–E (1–5), and cephalonine-2-O-β-d-glucopyranoside (6), along with known tetrahydroisoquinoline alkaloids (7–9). Among them, sinomacutines A–C were new bistetrahydroisoquinoline alkaloids with morphinane–proaporphine and morphinane–benzyltetrahydroisoquinoline types, and coupled with unique C–CH₂–N unit. Their structures with absolute configuration were elucidated on the basis of 1D and 2D NMR, and ECD spectra analysis. The new compounds were evaluated for their anti-inflammatory and cytotoxic activities, and sallisonine B (2) showed moderate ability to inhibit NO production of LPS-stimulated RAW264.7 macrophages, as well as sallisonine A (1) showed weak inhibitory effects against five cancer cell lines.     

Synthesis of novel photolabile glycosides from methyl 4,6-O-(o-nitro)benzylidene-α-d-glycopyranosides

Novel photolabile sugar derivatives bearing a 4- or 6-O-(o-nitro)benzyl group have been prepared from the corresponding methyl 4,6-O-(o-nitro)benzylidene α-d-glycopyranosides. Regioselective cleavage with BF₃·Et₂O/Et₃SiH led to the methyl 6-O-(o-nitro)benzyl gluco- and manno-α-d-glycopyranosides 3 and 6. Inversion of configuration at 4-OH position of gluco and manno derivatives offered the otherwise inaccessible methyl 6-O-(o-nitro)benzyl galacto- and talo-α-d-glycopyranosides 4, 5, and 7. Careful reaction with PhBCl₂/Et₃SiH (3 equiv of reagents, 10 min at −78 °C) led to the desired methyl 4-O-(o-nitro)benzyl gluco- and manno-α-d-glycopyranosides 8 and 9 in very good yield. However, prolonged reaction with 6 equiv of PhBCl₂/Et₃SiH transformed the methyl 4,6-O-(o-nitro)benzylidene α-d-glucopyranoside 11 into the reduced d-glucitol derivative 15. Oxidative cleavage of 5,6-diol function of 15 gave the corresponding photolabile l-xylose 17. The photolabile glucosides 3 and 8 have been further transformed into the photolabile α-C-allyl d-glucopyranosides 20 and 22.