A new approach to asymmetric synthesis of (−)-epiquinamide from d-glucose

The asymmetric total synthesis of (?)-epiquinamide has been achieved starting from a 5-iodofuranoside synthon derived from d-glucose. The methods featured Bernet-Vasella reaction followed by Horner-Wadsworth-Emmons (HWE) reaction to provide a new chiral building block diene as the key steps. The bicyclic framework of this quinolizidine was constructed by selective reduction of α,β-unsaturated ester, intramolecular nucleophilic substitution and ring-closing metathesis.     

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.     

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.     

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.     

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.     

Structure-based study of antiamyloidogenic cyclic d,l-α-peptides

Protein misfolding and aggregation are the hallmarks of many devastating diseases. We have previously shown that cyclic d,l-α-peptide CP-2 reacts and stabilizes less toxic forms of amyloid β (Aβ), and protects the cells from Aβ-induced toxicity. Here, we performed extensive structure-based studies on CP-2 to elucidate the contribution of each residue to the total antiamyloidogenic activity and determine the interactions that are involved between CP-2 and Aβ. We showed that the hydrophobicity of CP-2 analogs correlates with their antiamyloidogenic potency, however, aromatic interactions are even more important for this activity. The antiamyloidogenic activity of CP-2 analogs also correlates with their ability to self-assemble, as shown by the critical micelle concentration measurements. The cell survival studies performed on rat pheochromocytoma PC-12 cells suggest that incorporation of an additional aromatic residue to the CP-2's sequence increases its protective effect against Aβ42-induced toxicity.     

Regiospecific synthesis of quercetin O-β-d-glucosylated and O-β-d-glucuronidated isomers

Quercetin, the polyphenolic compound, which has the highest daily intake, is well known for its protective effects against aging diseases and has received a lot of attention for this reason. Both quercetin 3-O-β-d-glucuronide and quercetin 3′-O-β-d-glucuronide are human metabolites, which, together with their regioisomers, are required for biological as well as physical chemistry studies. We present here a novel synthetic route based on the sequential and selective protections of the hydroxyl functions of quercetin allowing selective glycosylation, followed by TEMPO-mediated oxidation to the glucuronide. This methodology enabled us to synthesize the five O-β-d-glucosides and four O-β-d-glucuronides of quercetin, including the major human metabolite, quercetin 3-O-β-d-glucuronide.     

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.     

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 five and six membered aminocyclitols: stereoselective Michael and Henry reaction approach with d-glucose derived α,β-unsaturated ester

The stereoselective intermolecular Michael addition of nitromethane to d-glucose derived α,β-unsaturated ester 7 afforded l-ido-configurated nitroester 8 as the only product that on reduction of the ester functionality, cleavage of 1,2-acetonide and the intramolecular Henry reaction afforded exclusively muco-nitroinositol 9. While reduction of the ester functionality in 8, deprotection of 1,2-acetonide, oxidative cleavage with NaIO₄ and the intramolecular Henry reaction afforded nitrocyclopentitol 13. Nitrocyclitols 9 and 13 were converted to the hydroxyethyl substituted aminocyclohexitol 5 and aminocyclopentitol 6, respectively.     

Blends as a strategy towards tailored hydrolytic degradation of poly(?-caprolactone-co-d,l-lactide)-poly(ethylene glycol)-poly(?-caprolactone-co-d,l-lactide) co-polymers

Binary blends were prepared from poly(?-caprolactone) (PCL), and P(CL-co-d,l-lactic acid)-P(ethylene glycol)-P(CL-co-d,l-lactic acid) co-polymers, where the d,l-LA content in the side chains varied from 0 to 70 mol%. Blend discs were fabricated by melt-molding, and the effect of blend composition on hydrolytic degradation was studied. Variations in medium pH were monitored, and morphological changes were observed using scanning electron microscopy. Blending of these co-polymers was found to constitute a simple means by which intermediate rates of water absorption and mass loss were obtained, compared to those observed in pure co-polymer preparations. In one of the blends, prepared from the two components containing 70 or 0 mol% d,l-LA in the side chains and thereby exhibiting large differences in degradation rate, hydrolysis resulted in the formation of a porous material over time. Furthermore, all blend samples maintained their initial shape throughout the study. Such materials may be interesting for further investigations for applications in cellular therapy and controlled release.     

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.     

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.     

First synthesis and full characterization of mexiletine N-carbonyloxy β-d-glucuronide

A simple, convergent synthesis of the N-carbonyloxy β-d-glucuronide of mexiletine (sodium salt) in moderate yield is described. The compound is now available as an authentic reference standard for analytical studies, enabling more detailed investigation on the metabolism of mexiletine.     

First synthesis of an α-d-Fucp3NAc containing oligosaccharide: a study on d-Fucp3NAc glycosylation

3-Acetamido-3,6-dideoxy-d-galactopyranose (d-Fucp3NAc) is an aminosugar almost exclusively found in phytopathogenic O-antigens. The glycosylation reaction involving d-Fucp3NAc donors was studied with several rhamnosyl acceptors, revealing that the best yields and highest α-stereoselectivity were obtainable by coupling a N-phenyl trifluoroacetimidate glycosyl donor in a ternary mixture (dioxane/DME/toluene 4:1:1) as solvent. For the first time a synthetic access to α-d-Fucp3NAc containing oligorhamnans, that are interesting molecules for studying the effects of O-antigen model oligosaccharides on the modulation of plant response to bacteria, was reported. An example is the pentasaccharide repeating unit of the major O-antigen component from Pseudomonas syringae pv. holci IMV 8300, which was synthesized as its methyl glycoside.     

A practical synthesis of fully protected l-γ-carboxyglutamic acid

We have developed a new synthetic route for the preparation of Fmoc protected l-γ-carboxyglutamic acid in 60% overall yield (>99% ee) via a six-step synthesis from d-Garner’s aldehyde. An aldol condensation and the selective cleavage of the acetonide protective group are key steps.     

Synthesis of C1- and C8a-epimers of (+)-castanospermine from d-glucose derived γ,δ-epoxyazide: intramolecular 5-endo epoxide opening approach

A concise synthesis of two diastereomers of (+)-castanospermine namely 1- and 8a-epi-castanospermine 1b and 1c, respectively, is reported from d-glucose. The methodology involves stereoselective cross metathesis of d-glucose derived alkene 2 with 4-bromo-1-butene followed by azide displacement and m-CPBA oxidation to afford diastereomeric γ,δ-epoxyazides 5a/5b. The Staudinger reaction of epoxyazide 5a followed by reaction with benzylchloroformate (CbzCl) unexpectedly furnished 1,3-oxazinan-2-one derivative 7 whose stereochemistry was establish by single crystal X-ray. This helps to assign the stereochemistry in the epoxidation reaction. The reduction of 5a/5b was then carried out by transfer hydrogenation to provide γ,δ-epoxyamine that concomitantly undergoes intramolecular 5-endo-tet cyclization to afford hydroxypyrrolidine ring skeleton with sugar framework-a precursor to castanospermine analogues 1b/1c.     

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.     

Facile synthesis of 2-C-methyl-d-arabino-γ-1,4-lactones and mechanism study

In our previous research on the synthesis of 3,5-di-O-benzoyl-2-C-methyl-d-arabino-γ-lactone 4a, the reaction mechanism of DMSO-mediated configuration inversion of C2 hydroxyl group in the lactone was ambiguous. As a follow-up to this research, we used ¹⁸O-labelled H₂O and DMSO to investigate the mechanism. It was surprisingly discovered that DMSO served as an oxygen donor to stereoselectively displace the leaving group, and was regenerated in the reaction. The protecting groups had no influence on the inversion, but would significantly affect the yield. We also disclosed another approach for the synthesis of 4a without using the expensive Tf₂O, which was more suitable for application.