•An efficient method of obtaining HA4 building block has been developed.•HA4 glycoclusters with wide molecular weight range (3 k–30 k) were synthesized.•Strategy for synthesis of glycosaminoglycan glycoclusters has been established.Hyaluronan is a glycosaminoglycan with a large number of biological activity. Hyaluronan of different molecular weight often shows different biological activity, sometimes even completely opposite, but the mechanism is not clear. Herein, the hyaluronan tetrasaccharide glycoclusters using hyaluronan tetrasaccharide obtained by enzymolysis of natural hyaluronan were firstly synthesized in high yield. The structurally determined and diverse glycoclusters were of wide molecular weight range and might be used for mimicking the biological activity of natural hyaluronan and facilitating the mechanism study.Download high-res image (134KB)Download full-size image

•Cobalt-propargyl cation is able to induce the cleavage of a CS bond.•Cobalt-propargyl cation facilitates glycosylation by activating the thio-glycoside.•New glycosylation reaction avoid the use of Tf2O or NIS.We discovered that the cobalt-propargyl cation can mediate the glycosylation reaction by activating the thioglycoside donor. The glyco-oxacarbenium cation was formed by transferring the thio-aglycone to the cobalt-propargyl cation that was generated from the cobalt-propargylated acceptor in situ via the activating with Lewis acid. The reactivity of the donor (Armed or dis-armed) and the amount of the Lewis acid control the releasing rate of the cobalt-propargyl group.Download high-res image (60KB)Download full-size image

•β-(1 → 3)-d-Glucan on ionic liquid (IL)-support was prepared with no chromatography required.•IL-support laminarihexaose was rapidly assembled in 15 h with an average yield of over 90% per step.•Combination of glycosylating agents were optimized by promoter, solvent, temperature.An efficient method for the preparation of β-(1 → 3)-d-glucan laminarihexaose on ionic liquid (IL)-support is described. A β-(1 → 3)-glucan laminarihexaose was rapidly assembled in 15 h in a stereoselective fashion with an average yield of over 90% per step using an optimized combination of glycosylating agents. This ionic liquid support approach provides an efficient and fast means for the assembly of β-(1 → 3)-glucans.Download high-res image (91KB)Download full-size image

•A series of new glycoclusters modified by potentially anti-oxidant activity pharmacophores were synthesized.•The anti-adhesion activities of these compounds were assessed by a static state cell-based assay.•The results showed that decoration of glycoclusters might enhance the anti-adhesion activities.According to our early researches, some glycoclusters having glucose, mannose, cellose and lactose residues showed good anti-adhesion activity of leukocytes to endothelial cells and exerted anti-inflammatory effects. Based on these results and combination principles of drugs, a series of new glycoclusters modifying with potentially anti-oxidant activity pharmacophores have been synthesized, and their anti-adhesion activities were assessed by static state cell-based adhesion assay. The results showed that some modified glycoclusters displayed better activities than their leading compound.Download high-res image (208KB)Download full-size image

A hydrophobically assisted switching phase (HASP) method is an efficient strategy for the synthesis of carrier-loaded oligosaccharides. We improved this method by using cetyl thioglycoside as the carrier, which made it possible to use the synthetic oligosaccharide block directly as the donor. We applied this improved HASP method in the successful assembly of a gp120-associated nona-mannoside. Our results indicated that the HASP method is an efficient strategy for the synthesis of complex oligosaccharides and glycoconjugates.

•A series of non-β-glucan glycoclusters can bind to dectin-1.•The strongest affinity property (KD) was 1.6 µM.•There may be a new carbohydrate binding site on dectin-1.Dectin-1, which specifically recognizes β-(1,3)-glucans, plays an important role in innate immune responses. For the first time, in this study we found that a series of non-β-glucan glycoclusters can bind to dectin-1 by means of surface plasmon resonance (SPR) assay. Hexavalent lactoside Ju-6 showed the strongest affinity property (KD = 1.6 µM). Interestingly, a continuous binding–dissociation experiment on SPR showed that Ju-6 and Laminarin binding to dectin-1 are independent of each other. Moreover, RT-PCR assay showed that Ju-6 cannot up-regulate cytokine gene expression or inhibit the promoting effect caused by Zymosan (a long-chain β-glucan). These results indicated that there might be a possible new carbohydrate binding site on dectin-1.

•The total synthesis of parkacine has not been reported before.•The intramolecular cycloaddition was highly stereoselective.•A mechanism for the epimerization of phenyl substituted chiral carbon was proposed.Intramolecular 1,3-dipolar cycloaddition of chiral hept-6-yne-azomethine ylide was attempted to construct the C/D ring system of a lycorine-type alkaloid parkacine (3). However, the cycloaddition reactions gave C/D ring-closure product with opposite configurations at 7- and 7a-carbons, comparing with the natural product. The unexpected epimerization of phenyl substituted chiral carbon may occur through imine–enamine tautomerism before the intramolecular cycloaddition.

A new method for cleaving methyl ethers off protected saccharides using Co2(CO)8/Et3SiH/CO system was developed. The method showed regioselectivity in different protected monosaccharides with various anomeric groups. The primary and equatorial secondary methyl ethers were preferentially removed. This method was successfully applied to the synthesis of the DEF trisaccharide segment of Idraparinux, which is highly methylated.

The hydrophobically assisted switching phase (HASP) method was applied in the assembly of oligomannosides. A new mannosyl donor with high reactivity was selected after a series of optimization studies, which was suitable for the synthesis of oligomannosides via the HASP method. The practicability of the HASP method towards the synthesis of branched oligosaccharides was explored and two branched penta-mannosides were assembled efficiently.

(−)-Dinemasones B and C were isolated from a culture of the endophytic fungus Dinemasporium strigosum and had shown attractive antimicrobial activities in vitro. Described herein is the concise synthesis of their analogue, ent-4-deoxy-2,3-di-epi-dinemasone BC, from glucal derivatives, including C-glycoside and 3-deoxy-glucal, and the strategies proceeded in 7 steps in 13% overall yield and in 9 steps in 17% overall yield respectively.

A mild and efficient method to selectively cleave p-methoxybenzyl (PMB) ether with a catalytic amount of Co2(CO)8, hydrosilane and CO (1 atm) is presented. The cleavage reaction shows regioselectivity to primary O-PMB of a variety of permethoxybenzylated saccharides and chemoselectivity to O-Bn, sulfur-containing group and common ester protecting groups.

•A new series of homoglycoclusters and heteroglycoclusters were synthesized.•The anti-adhesion activities of these compounds were assessed by SPR and a static state cell-based assay.•These results did not show significant difference of anti-adhesion activities between flexible scaffold and rigid scaffold.A new series of mixed-type heteroglycoclusters containing mannose and lactose were synthesized. In the synthesis of rigid scaffold of heteroglycocluster, we found that trans-isomer could be prepared stereoselectively by means of Grubbs olefin cross-metathesis reactions. Moreover, sequential acylation using cyclic anhydride as scaffold could give cis-isomer. These two methods may provide complementarity of stereochemistry in heteroglycocluster assembling. The anti-adhesion activities of these compounds were assessed by Surface Plasmon Resonance (SPR) and static state cell-based adhesion assay. These results indicated that the rigid scaffold might not affect the anti-adhesion activities.

An efficient, stereoselective, and base-controlled procedure for the preparation of polyhydroxy bicyclic diazenes and polyhydroxy bicyclic hydrazones is described, starting from sugar-derived methyl 6-deoxy-6-iodo-hexosides. The one-pot synthesis involves a three-step reaction, including ring-opening, condensation with tosylhydrazine, and intramolecular cycloaddition with terminal alkene, which affords important synthetic precursors of bicyclic diazenes and hydrazones.

We report here the syntheses of mono- to tetravalent glycoclusters containing 1-methylene-C-β-lactose. The 1-methylene-C-β-lactose moiety has been synthesized from octa-acetyl-β-lactose using the key carbonyl insertion reaction and linked to a series of alkynlated scaffolds via CuAAC reaction to afford mono- to tetravalent glycoclusters. The binding affinities of the final products to galectin-3 were found in the range of 10–100 μM.

N-Galactosyl aziridines were synthesized via BF3·OEt2 promoted addition of carbenes generated from diazocarbonyl compounds with O-pivaloylated β-D-galactosylimines in good yields and high diastereoselectivity. The ring-opening reactions with p-toluenethiol of the aziridines provided enantiometrically pure β-S-substituted phenylalanine derivatives in a highly regioselective manner.

Neomangiferin, a natural xanthone derivative bearing both O- and C-glucosides, was isolated from the leaves of Gentiana asclepiadea L. and has shown potential anti-diabetic activity. We describe herein the first semi-synthesis of neomangiferin from the natural C-glucoside mangiferin and glucose. The developed synthesis presents a facile protection strategy using Jurd’s method to distinguish the different phenolic hydroxyl groups. Following this strategy, the regioselective protection of 1,3,6-hydroxyl groups was accomplished and neomangiferin was prepared by glycosylation under the phase-transfer catalysis conditions.

We utilized the glycosyl acceptor tagging method with ionic liquid support for synthesis of the core segment of Clostridium botulinum C2 toxin ligand through a divergent synthetic strategy without chromatographic purification. The total yield was 57.1% and the reaction was completed in 10 h. The efficient ionic liquid supported glycosylation and purification procedure was applied for the synthesis of branched glucosamine-containing oligosaccharides for the first time, which expanded the scope of ionic liquid supported synthesis of biologically important oligosaccharides.The core segment of Clostridium botulinum C2 toxin ligand was synthesized in 57.1% yield with the glycosyl acceptor tagged on an ionic liquid support through a divergent synthetic strategy without chromatographic purification. The efficient ionic liquid supported glycosylation and purification procedure was applied for the synthesis of branched glucosamine-containing oligosaccharides for the first time, which expanded the scope of ionic liquid supported synthesis of biologically important oligosaccharides.

An efficient route to prepare l-glucose and l-galactose is described. The l-sugars are achieved by using the strategy of switching the functional groups at C1 and C5 of d-glucose and d-mannose. The oxidation and reduction of the silyl enol ether at C1 and the lead(IV) tetraacetate mediated oxidative decarboxylation at C5 are the key steps. l-Glucose and l-galactose are prepared in a convenient and inexpensive way.An efficient route to prepare l-glucose and l-galactose derivatives by using the strategy of switching the functional groups at C1 and C5 of d-glucose and d-mannose, respectively, was developed. l-Sugars could be prepared on a large scale by this strategy with high overall yields.

A metal-free and 4-methyl aniline mediated method for the oxidative C–C bond cleavage has been developed. The reaction proceeds in air using molecular oxygen as the oxidant, affording one-carbon shortened esters in moderate to good yields within a short time. Moreover, it provides a model reaction for the highly enantioselective synthesis of (D)-serine esters by combining with a L-proline catalyzed Mannich reaction.

•A new series of homoglycoclusters and heteroglycoclusters were synthesized.•The anti-adhesion activity of these compounds was assessed.•Tetravalent saccharides loaded on l-glutamic acid showed good anti-adhesion activity.Adhesion of leukocytes to endothelium plays an important role in inflammatory diseases. We previously found that the tetravalent lactoside Gu-4 was able to inhibit leukocyte-endothelial cell adhesion significantly and that CD11b was the target of Gu-4 on the surface of leukocytes. In this report, we aimed to explore the relationship between structural characteristics of glycoclusters and anti-adhesion activity. Using selective glycosylation method and convergent strategy, we synthesized a new series of homoglycoclusters and heteroglycoclusters with diverse structures. And the bioactivities of these compounds were assessed by a static state cell-based adhesion assay. We found that when the linked saccharide fragments are the same, the anti-adhesion activities of compounds with flexible linkers were stronger than those with rigid scaffold such as the benzene ring, and the best flexible linker in the tested compounds was l-glutamic acid. When l-glutamic acid was employed as the linker, glycoclusters with four valences, but not other valences, exhibited the most significant anti-adhesion activity; however, no significant differences in anti-adhesion activity were found among the tetravalentglycosides that were made by linking glucose (32), mannose (TMa-4), cellobiose (34), or lactose (Gu-4). Thus, we conclude that a flexible linker with proper length, such as that of l-glutamic acid, and the linking of four saccharide fragments might be the preferable structural characteristics for the glycocluster compounds with potent anti-adhesion activity.20 Multivalent homo-, and heteroglycosides have been synthesized and their inhibition of leukocyte-endothelial cell adhesion has been assessed.

A metal-free method for the direct regioselective fluorination of anilides has been developed. In the presence of bis(tert-butylcarbonyloxy)iodobenzene (PhI(OPiv)2) and hydrogen fluoride-pyridine, the para-fluorination products of anilides were obtained in moderate to good yields. Because of its operational safety and the use of readily available reagents, this new procedure provides facile access to a variety of para-fluorinated anilides.

A series of conformationally constrained kanamycin A derivatives with a 2′-hydroxyl group in ring I and a 5-hydroxyl group in ring II tethered by carbon chains were designed and synthesized. Pivotal 5,2′-hydroxyl groups were exposed, and the kanamycin A intermediate was synthesized from 5, 2′, 4″, 6″-di-O-benzylidene-protected tetraazidokanamycin A. Cyclic kanamycin A derivatives with intramolecular 8-, 9-, 10-, and 11-membered ethers were then prepared by cesium carbonate mediated Williamson ether synthesis or a ring-closing metathesis reaction. The kanamycin A derivatives were assayed against both susceptible and resistant bacterial strains. Although no derivative showed better antibacterial activities than kanamycin A, the antibacterial activities of these cyclic kanamycin A derivatives indeed varied with the length of the bridge. Moreover, different variations of activities were observed between the susceptible and resistant bacterial strains. More tightly constrained derivative 2 with a one-carbon bridge showed better activity than the others against susceptible strains, but it was much less effective for resistant bacterial strains than derivative 3 with a two-carbon bridge and derivative 6 with an unsaturated four-carbon bridge.

(−)-Dinemasone B was isolated by Krohn and co-workers from a culture of the endophytic fungus Dinemasporium strigosum and has shown promising antimicrobial activity. Described herein is the first total synthesis of (−)-dinemasone B, (+)-4a-epi-dinemasone B, (−)-7-epi-dinemasone B, and (+)-4a,7-di-epi-dinemasone B. Their absolute configurations were also determined. The developed synthesis features a stereoselective reduction of C-glycosidic ketone, lactonization, and E-olefination of aldehyde starting from d-glucose.

A novel method for the organocatalytic syn diacetoxylation of alkenes has been developed using aryl iodides as efficient catalysts. A broad range of substrates, including electron-rich as well as electron-deficient alkenes, are smoothly transformed by the new procedure, furnishing the desired products in good to excellent yields with high diastereoselectivity (up to >19:1 dr).

A convenient, metal-free intramolecular aminofluorination of alkenes has been developed. Employing readily available PhI(OPiv)2 and hydrogen fluoride–pyridine in the presence of BF3·OEt2, tosyl-protected pent-4-en-1-amines were converted to 3-F-piperidines in one step in good yields as well as high stereoselectivity.

An efficient synthesis method for fusing triazole ring onto the naphthalimide core was described. The anti-cancer activities of the generated triazolonaphthalimide derivatives were evaluated with five cancer cell lines. The compounds generally displayed higher potency than amonafide. 4d,4e carrying two amino side chains showed the strongest cytotoxicities. N-oxide 5, a prodrug of 4a, was designed and synthesized. The agent was expected to be activated under the hypoxic condition in tumor tissue. Compared with 4a, 5 manifested much lower cytotoxicity both in cancer cell lines and human normal cells in the in vitro assays. However, N-oxide 5 performed potent anti-cancer activity in vivo using S-180 sarcoma bearing mice. All the results suggested that 5 was a promising anti-cancer agent.Highlights► A series of novel triazolonaphthalimide derivatives were synthesized via a new method. ► Cytotoxicity evaluation with five cancer cell lines was conducted and a preliminary SAR was summarized. ► Much higher cytotoxic effects were observed compared with the lead compound amonafide. ► N-oxide 5 as tumor-activated prodrug was further tested with an in vivo tumor model (S-180 cancer cell formed xenograft).

An antimetastatic tetrasaccharide T1, β-d-Gal-(1 → 4)-β-d-GlcpNAc-(1 → 6)-α-d-Manp-(1 → 6)-β-d-Manp-OMe, was synthesized with two approaches. The first approach was a conventional method employing thioglycoside and Koenigs–Knorr glycosylation reaction in 24% overall yield. The second one was a novel route through the azidoiodo-glycosylation strategy by using 2-iodo-2-deoxylactosyl azide as the donor in 36% overall yield.

QDs with different fluorescence emission wavelengths were coated with galactose, glucose, and lactose respectively. The formulas of glyco-QDs were determined by NMR and ICP-OES, and the interactions between glyco-QDs and PNA lectin were investigated by SPR. The results showed that multivalent presentation achieved by using QDs as the scaffold is an effective way to enhance the carbohydrate–protein interactions. The KD for the interaction of PNA with multivalent glyco-QDs is over 3 × 106-fold lower than those with the same free sugars. The specific recognition for the sugar coated on the QDs by lectin is maintained. These sugar-coated QDs could be used as a fluorescent probe to label and identify glycoproteins.Graphical abstractHighlights► QDs is an ideal scaffold for the construction of multivalent glyco-cluster. ► NMR can be used in analysis of the sugar coated on QDs. ► The protein binding activity of glyco-QDs can be dramatically enhanced. ► KD of the interaction between glyco-QDs and protein was calculated.

Rheumatoid arthritis (RA) is an inflammatory disorder that is characterized by persistent recurrence of joint inflammation leading to cartilage and bone destruction. The present anti-arthritis therapies failed to achieve satisfactory remission in all patients; therefore, it is still necessary to develop novel approaches to fulfill the demand in clinic. Here, we reported the therapeutic effects of lactosyl derivative Gu-4, a synthetic compound that was previously identified as a selective inhibitor against leukocyte integrin CD11b, in a bovine type II collagen induced arthritis (CIA) rat model. First, prophylactic administration of Gu-4 (1.2728 mg/kg) to rats by intraperitoneal injection every 2 days from the first day of collagen immunization significantly decreased the incidence of CIA, diminished the mean paw volume increase, and reduced the number of swollen paws. Second, administration of Gu-4 (1.2728 mg/kg) to rats at early-onset stage of CIA prevented the progression of the pathological process of RA, accelerated the remission of paw edema, and declined the arthritis score; after 5 weeks treatment, X-ray and histological examinations were carried out, the ankle joint of hind limb of Gu-4 treated CIA rats exhibited slighter bone erosion and much less inflammatory cell infiltration compared to those of saline treated animals; furthermore, Gu-4 remarkably attenuated the production of rheumatoid factor (RF) in the serum of CIA rats as determined by ELISA. Moreover, we performed in vitro lymphocyte proliferation assay and found that Gu-4 significantly inhibited the proliferation of splenic lymphocytes isolated from CIA rats in a dose-dependent manner. Our results suggest that Gu-4 can effectively ameliorate CIA and might be an alternative option for the treatment of RA.

A series of 4,5-substituted chiral γ-lactams were synthesized through a highly diastereoselective addition—rearrangement approach from 2,3-unsaturated sugar lactones. The single-crystal X-ray structure of one product indicated that the sugar ring was attacked from the axial side. Partial reduction of the nitro group produced N-hydroxy-γ-lactams, which were further reduced with TiCl3 to yield the 4,5-substituted chiral γ-lactams. The absolute configuration of C5 of the γ-lactam was determined by NOESY spectra.

An improved method for the synthesis of large and complex oligosaccharides on ionic liquid (IL) support was developed. A strategy to attach the acceptor on IL using a more stable ether linker was used to prevent undesirable decomposition and side products. A “dissolution–evaporation–precipitation” purification procedure was also developed by combining the advantages of precipitation and solid–liquid extraction to reduce mechanical loss and purification time. This approach was successfully used for the rapid assembly of ionic liquid supported homolinear α(1→2)-linked nonamannoside in 25.2% overall yield within 28.5 h.

An improved method for the deprotection of benzyl ethers using a catalytic amount of Co2(CO)8 in the presence of Me2PhSiH and CO (1 atm) is described. The deprotection reaction is compatible with double bond or sulfur-containing substrates. The method also tolerates other functional groups, such as Ac, Piv, and Bz, and shows potential selectivity in perbenzylated monosaccharides.

Selective syn and anti diacetoxylations of alkenes have been achieved using a PhI(OAc)2/BF3·OEt2 system in the presence and absence of water, respectively. A broad range of substrates including electron-deficient alkenes (such as α,β-unsaturated esters) could be elaborated efficiently at room temperature with this methodology, furnishing the desired products in good to excellent yields and diastereoselectivity. In particular, a multigram-scale diastereoselective diacetoxylation of methyl cinnamate (5.00 g) was also accomplished in a few hours, maintaining the same efficiency as small-scale reaction. This novel methodology provides an alternative approach for the preparation of various 1,2-diols.

A highly efficient and mild method for the de-O-benzylation of protected saccharides was developed by transforming terminal benzyl ethers into silyl ethers using Co2(CO)8-Et3SiH under 1 atm of CO. The method was successfully used for the de-O-benzylation of perbenzylated monosaccharides with various anomeric protecting groups, as well as natural disaccharides and trisaccharides such as sucrose, raffinose, and melezitose in good yields (>80%).

We have previously reported a facile and convenient method for the preparation of a new type of lactose-CdSeS/ZnS quantum dots conjugates (Lac-QDs) that exhibit biocompatibility, noncytotoxicity and specificity to leukocytes. In order to further study the carbohydrate–protein interactions, a series of Lac-QDs with different lactose densities and a PEGylated (n = 3) lactose-QDs conjugate (LacPEG-QDs) with more flexible sugar ligands were prepared. The amount of the sugar molecules on QDs can be determined by NMR, which was in agreement with the results from TGA determination. The formula of the conjugates was determined with ICP-OES. The interactions between the conjugated QDs and the PNA protein were measured using SPR, which revealed that higher lactose density favored binding affinity under the same concentration, and Lac-QDs exhibit higher affinity than LacPEG-QDs. We further used a solid phase assay to assess the anti-adhesion activity of Lac-QDs and LacPEG-QDs on the cell level. The results showed that Lac-QDs had stronger activity in preventing THP1 from adhering to HUVEC than LacPEG-QDs, which was consistent with the SPR results. We reasoned that decrease in the conformational entropy induced by appropriate restriction of sugar flexibility could enhance the binding affinity of glyco-QDs, which implies that entropy change may be the main contributor to the interaction between high valent glyco-QDs and protein. The fabrication of lactose on QDs provides a fluorescent multivalent carbohydrate probe that can be used as mimics of glycoprotein for the study of carbohydrate–protein interactions and cell imaging.

γ-Aminobutyric acid analogs based on sugar scaffolds were prepared in six to nine steps starting from d-glucal and d-galactal. The key step in the synthesis is the Vilsmeier–Haack reaction that affords the corresponding 2-C-formyl glycal on treatment with DMF and POCl3. Oxidation of the aldehyde and reduction of the 4-azido group provided the corresponding GABA analog. Acylamide and tetrazole analogs were also prepared as the bioisosteres of the carboxylic acid.

Multivalent lactose (Lac-QDs)- and galactose (Gal-QDs)- coated CdSeS-ZnS core-shell quantum dots (QDs) were prepared. The formula of the glyco-QDs was determined by nuclear magnetic resonance (NMR) and inductively coupled plasma-optical emission spectrometry (ICP-OES). The uptake of the Gal-containing glyco-QDs by HepG2 cells was investigated. Flow cytometry (FCM) and fluorescence microscopy analysis indicated that the uptake is receptor mediated and selective. The prepared multivalent glyco-QDs could be used to mimic the oligosaccharides in the study of hepatic endocytosis. Furthermore, this type of glyco-QDs can be used as a useful fluorescent probe in cell imaging and analysis of carbohydrate–protein interactions.

A novel approach to synthesize glucose-based 3-acetyl-5-alkyl-2,3-dihydro-1,3,4-oxadiazoles with the assistance of microwave irradiation was developed. The effects of different catalysts on the heterocyclization process were investigated, and the reaction conditions were optimized, with NaOAc emerging as the catalyst of choice. Under the optimized conditions, a series of novel 3-acetyl-5-alkyl-2,3-dihydro-1,3,4-oxadiazole derivatives 4 and 5 were successfully synthesized from hydrazones 2 and 3. The absolute configurations of hydrazones 2, 3 and oxadiazoles 4, 5 were confirmed by NMR spectroscopic data. The ratio of the isomers 4 and 5 was ∼1:1.

A series of novel alkyl substituted fructose-based oxadiazoles were synthesized and their cytotoxic activities toward tumor cells were investigated. We studied the reaction mechanism and the stereochemistry of the reaction. Tautomerization between isomers 2 and 3 was observed in solution. The tautomerization was accelerated by heating or in the presence of acetic acid. An intermediate 6 during the heterocyclization was isolated, and two different pathways for the heterocyclization were suggested. On the basis of these findings, an efficient method, with the assistance of microwave irradiation was developed for the synthesis of 4 and 5. The yields were satisfactory and no by-products were found. We also proposed that the (R/S)-configurations of oxadiazoles were determined by the E/Z configurations of hydrazones.E-3-Acetylhydrazono-1,2:4,5-di-O-isopropylidene-β-d-erythro-2-hexulopyranoseC14H22N2O6[α]D25=-276.3 (c 0.97, MeOH)Source of chirality: d-fructoseAbsolute configuration: (E)Z-3-Acetylhydrazono-1,2:4,5-di-O-isopropylidene-β-d-erythro-2-hexulopyranoseC14H22N2O6[α]D25=-208.0 (c 1.00, MeOH)Source of chirality: d-fructoseAbsolute configuration: (Z)E-3-Propionylhydrazono-1,2:4,5-di-O-isopropylidene-β-d-erythro-2-hexulopyranoseC15H24N2O6[α]D25=-237.7 (c 1.06, MeOH)Source of chirality: d-fructoseAbsolute configuration: (E)Z-3-Propionylhydrazono-1,2:4,5-di-O-isopropylidene-β-d-erythro-2-hexulopyranoseC15H24N2O6[α]D25=-160.7 (c 1.17, MeOH)Source of chirality: d-fructoseAbsolute configuration: (Z)E-3-Butyrylhydrazono-1,2:4,5-di-O-isopropylidene-β-d-erythro-2-hexulopyranoseC16H26N2O6[α]D25=-220.0 (c 1.00, MeOH)Source of chirality: d-fructoseAbsolute configuration: (E)Z-3-Butyrylhydrazono-1,2:4,5-di-O-isopropylidene-β-d-erythro-2-hexulopyranoseC16H26N2O6[α]D25=-192.2 (c 1.02, MeOH)Source of chirality: d-fructoseAbsolute configuration: (Z)E-3-Valerylhydrazono-1,2:4,5-di-O-isopropylidene-β-d-erythro-2-hexulopyranoseC17H28N2O6[α]D25=-211.8 (c 1.02, MeOH)Source of chirality: d-fructoseAbsolute configuration: (E)Z-3-Valerylhydrazono-1,2:4,5-di-O-isopropylidene-β-d-erythro-2-hexulopyranoseC17H28N2O6[α]D25=-167.6 (c 1.05, MeOH)Source of chirality: d-fructoseAbsolute configuration: (Z)E-3-Caproylhydrazono-1,2:4,5-di-O-isopropylidene-β-d-erythro-2-hexulopyranoseC18H30N2O6[α]D25=-192.0 (c 1.00, MeOH)Source of chirality: d-fructoseAbsolute configuration: (E)Z-3-Caproylhydrazono-1,2:4,5-di-O-isopropylidene-β-d-erythro-2-hexulopyranoseC18H30N2O6[α]D25=-178.6 (c 1.03, MeOH)Source of chirality: d-fructoseAbsolute configuration: (Z)E-3-Heptanoylhydrazono-1,2:4,5-di-O-isopropylidene-β-d-erythro-2-hexulopyranoseC19H32N2O6[α]D25=-195.9 (c 0.98, MeOH)Source of chirality: d-fructoseAbsolute configuration: (E)Z-3-Heptanoylhydrazono-1,2:4,5-di-O-isopropylidene-β-d-erythro-2-hexulopyranoseC19H32N2O6[α]D25=-170.9 (c 1.03, MeOH)Source of chirality: d-fructoseAbsolute configuration: (Z)E-3-Oxtanoylhydrazono-1,2:4,5-di-O-isopropylidene-β-d-erythro-2-hexulopyranoseC20H34N2O6[α]D25=-234.3 (c 0.99, MeOH)Source of chirality: d-fructoseAbsolute configuration: (E)Z-3-Oxtanoylhydrazono-1,2:4,5-di-O-isopropylidene-β-d-erythro-2-hexulopyranoseC20H34N2O6[α]D25=-192.2 (c 1.02, MeOH)Source of chirality: d-fructoseAbsolute configuration: (Z)E-3-Nonanoylhydrazono-1,2:4,5-di-O-isopropylidene-β-d-erythro-2-hexulopyranoseC21H36N2O6[α]D25=-210.1 (c 0.99, MeOH)Source of chirality: d-fructoseAbsolute configuration: (E)Z-3-Nonanoylhydrazono-1,2:4,5-di-O-isopropylidene-β-d-erythro-2-hexulopyranoseC21H36N2O6[α]D25=-193.9 (c 0.99, MeOH)Source of chirality: d-fructoseAbsolute configuration: (Z)E-3-Decanoylhydrazono-1,2:4,5-di-O-isopropylidene-β-d-erythro-2-hexulopyranoseC22H38N2O6[α]D25=-196.6 (c 1.03, MeOH)Source of chirality: d-fructoseAbsolute configuration: (E)Z-3-Decanoylhydrazono-1,2:4,5-di-O-isopropylidene-β-d-erythro-2-hexulopyranoseC22H38N2O6[α]D25=-157.2 (c 0.97, MeOH)Source of chirality: d-fructoseAbsolute configuration: (Z)E-3-Lauroylhydrazono-1,2:4,5-di-O-isopropylidene-β-d-erythro-2-hexulopyranoseC24H42N2O6[α]D25=-192.0 (c 1.00, MeOH)Source of chirality: d-fructoseAbsolute configuration: (E)Z-3-Lauroylhydrazono-1,2:4,5-di-O-isopropylidene-β-d-erythro-2-hexulopyranoseC24H42N2O6[α]D25=-154.8 (c 0.93, MeOH)Source of chirality: d-fructoseAbsolute configuration: (Z)E-3-Palmitoylhydrazono-1,2:4,5-di-O-isopropylidene-β-d-erythro-2-hexulopyranoseC28H50N2O6[α]D25=-193.9 (c 0.99, MeOH)Source of chirality: d-fructoseAbsolute configuration: (E)Z-3-Palmitoylhydrazono-1,2:4,5-di-O-isopropylidene-β-d-erythro-2-hexulopyranoseC28H50N2O6[α]D25=-134.7 (c 1.01, MeOH)Source of chirality: d-fructoseAbsolute configuration: (Z)E-3-Stearoylhydrazono-1,2:4,5-di-O-isopropylidene-β-d-erythro-2-hexulopyranoseC30H54N2O6[α]D25=-148.6 (c 1.05, MeOH)Source of chirality: d-fructoseAbsolute configuration: (E)Z-3-Stearoylhydrazono-1,2:4,5-di-O-isopropylidene-β-d-erythro-2-hexulopyranoseC30H54N2O6[α]D25=-114.9 (c 1.01, MeOH)Source of chirality: d-fructoseAbsolute configuration: (Z)(2R,3a′,6′S,7a′R)-3-Acetyl-2′,2′,2″2″tetramethyl-5-methyl-2,3-dihydro-1,3,4-oxadiazole-2-spiro-7′-{1′,3′-dioxolano[4,5-c]pyrano}-6′-spiro-4″(1″3″diaoxolane)C16H24N2O7[α]D25=-11.2 (c 1.07, MeOH)Source of chirality: d-fructoseAbsolute configuration: (2R,3a′R,6′S,7a′R)(2S,3a′R,6′S,7a′R)-3-Acetyl-2′,2′,2″2″tetramethyl-5-methyl-2,3-dihydro-1,3,4-oxadiazole-2-spiro-7′-{1′,3′-dioxolano[4,5-c]pyrano}-6′-spiro-4″(1″,3″-diaoxolane)C16H24N2O7[α]D25=-18.5 (c 0.96, MeOH)Source of chirality: d-fructoseAbsolute configuration: (2S,3a′R,6′S,7a′R)(2R,3a′R,6′S,7a′R)-3-Acetyl-2′,2′,2″,2″-tetramethyl-5-ethyl-2,3-dihydro-1,3,4-oxadiazole-2-spiro-7′-{1′,3′-dioxolano[4,5-c]pyrano}-6′-spiro-4″-(1″,3″-diaoxolane)C17H26N2O7[α]D25=-35.0 (c 1.03, MeOH)Source of chirality: d-fructoseAbsolute configuration: (2R,3a′R,6′S,7a′R)(2S,3a′R,6′S,7a′R)-3-Acetyl-2′,2′,2′′,2′′-tetramethyl-5-ethyl-2,3-dihydro-1,3,4-oxadiazole-2-spiro-7′-{1′,3′-dioxolano[4,5-c]pyrano}-6′-spiro-4′′-(1′′,3′′-diaoxolane)C17H26N2O7[α]D25=-34.3 (c 1.04, MeOH)Source of chirality: d-fructoseAbsolute configuration: (2S,3a′R,6′S,7a′R)(2R,3a′R,6′S,7a′R)-3-Acetyl-2′,2′,2′′,2′′-tetramethyl-5-propyl-2,3-dihydro-1,3,4-oxadiazole-2-spiro-7′-{1′,3′-dioxolano[4,5-c]pyrano}-6′-spiro-4′′-(1′′,3′′-diaoxolane)C18H28N2O7[α]D25=-16.7 (c 1.05, MeOH)Source of chirality: d-fructoseAbsolute configuration: (2R,3a′R,6′S,7a′R)(2S,3a′R,6′S,7a′R)-3-Acetyl-2′,2′,2′′,2′′-tetramethyl-5-propyl-2,3-dihydro-1,3,4-oxadiazole-2-spiro-7′-{1′,3′-dioxolano[4,5-c]pyrano}-6′-spiro-4′′-(1′′,3′′-diaoxolane)C18H28N2O7[α]D25=-33.0 (c 1.08, MeOH)Source of chirality: d-fructoseAbsolute configuration: (2S,3a′R,6′S,7a′R)(2R,3a′R,6′S,7a′R)-3-Acetyl-2′,2′,2′′,2′′-tetramethyl-5-butyl-2,3-dihydro-1,3,4-oxadiazole-2-spiro-7′-{1′,3′-dioxolano[4,5-c]pyrano}-6′-spiro-4′′-(1′′,3′′-diaoxolane)C19H30N2O7[α]D25=-29.8 (c 0.94, MeOH)Source of chirality: d-fructoseAbsolute configuration: (2R,3a′R,6′S,7a′R)(2S,3a′R,6′S,7a′R)-3-Acetyl-2′,2′,2′′,2′′-tetramethyl-5-butyl-2,3-dihydro-1,3,4-oxadiazole-2-spiro-7′-{1′,3′-dioxolano[4,5-c]pyrano}-6′-spiro-4′′-(1′′,3′′-diaoxolane)C19H30N2O7[α]D25=-11.0 (c 1.09, MeOH)Source of chirality: d-fructoseAbsolute configuration: (2S,3a′R,6′S,7a′R)(2R,3a′R,6′S,7a′R)-3-Acetyl-2′,2′,2′′,2′′-tetramethyl-5-pentyl-2,3-dihydro-1,3,4-oxadiazole-2-spiro-7′-{1′,3′-dioxolano[4,5-c]pyrano}-6′-spiro-4′′-(1′′,3′′-diaoxolane)C20H32N2O7[α]D25=-24.0 (c 1.00, MeOH)Source of chirality: d-fructoseAbsolute configuration: (2R,3a′R,6′S,7a′R)(2S,3a′R,6′S,7a′R)-3-Acetyl-2′,2′,2′′,2′′-tetramethyl-5-pentyl-2,3-dihydro-1,3,4-oxadiazole-2-spiro-7′-{1′,3′-dioxolano[4,5-c]pyrano}-6′-spiro-4′′-(1′′,3′′-diaoxolane)C20H32N2O7[α]D25=-43.5 (c 0.92, MeOH)Source of chirality: d-fructoseAbsolute configuration: (2S,3a′R,6′S,7a′R)(2R,3a′R,6′S,7a′R)-3-Acetyl-2′,2′,2′′,2′′-tetramethyl-5-hexyl-2,3-dihydro-1,3,4-oxadiazole-2-spiro-7′-{1′,3′-dioxolano[4,5-c]pyrano}-6′-spiro-4′′-(1′′,3′′-diaoxolane)C21H34N2O7[α]D25=-8.4 (c 0.95, MeOH)Source of chirality: d-fructoseAbsolute configuration: (2R,3a′R,6′S,7a′R)(2S,3a′R,6′S,7a′R)-3-Acetyl-2′,2′,2′′,2′′-tetramethyl-5-hexyl-2,3-dihydro-1,3,4-oxadiazole-2-spiro-7′-{1′,3′-dioxolano[4,5-c]pyrano}-6′-spiro-4′′-(1′′,3′′-diaoxolane)C21H34N2O7[α]D25=-25.0 (c 1.12, MeOH)Source of chirality: d-fructoseAbsolute configuration: (2S,3a′R,6′S,7a′R)(2R,3a′R,6′S,7a′R)-3-Acetyl-2′,2′,2′′,2′′-tetramethyl-5-heptyl-2,3-dihydro-1,3,4-oxadiazole-2-spiro-7′-{1′,3′-dioxolano[4,5-c]pyrano}-6′-spiro-4′′-(1′′,3′′-diaoxolane)C22H36N2O7[α]D25=-46.3 (c 0.95, MeOH)Source of chirality: d-fructoseAbsolute configuration: (2R,3a′R,6′S,7a′R)(2S,3a′R,6′S,7a′R)-3-Acetyl-2′,2′,2′′,2′′-tetramethyl-5-heptyl-2,3-dihydro-1,3,4-oxadiazole-2-spiro-7′-{1′,3′-dioxolano[4,5-c]pyrano}-6′-spiro-4′′-(1′′,3′′-diaoxolane)C22H36N2O7[α]D25=-47.3 (c 1.10, MeOH)Source of chirality: d-fructoseAbsolute configuration: (2S,3a′R,6′S,7a′R)(2R,3a′R,6′S,7a′R)-3-Acetyl-2′,2′,2′′,2′′-tetramethyl-5-octyl-2,3-dihydro-1,3,4-oxadiazole-2-spiro-7′-{1′,3′-dioxolano[4,5-c]pyrano}-6′-spiro-4′′-(1′′,3′′-diaoxolane)C23H38N2O7[α]D25=-11.5 (c 1.04, MeOH)Source of chirality: d-fructoseAbsolute configuration: (2R,3a′R,6′S,7a′R)(2S,3a′R,6′S,7a′R)-3-Acetyl-2′,2′,2′′,2′′-tetramethyl-5-octyl-2,3-dihydro-1,3,4-oxadiazole-2-spiro-7′-{1′,3′-dioxolano[4,5-c]pyrano}-6′-spiro-4′′-(1′′,3′′-diaoxolane)C23H38N2O7[α]D25=-30.5 (c 1.05, MeOH)Source of chirality: d-fructoseAbsolute configuration: (2S,3a′R,6′S,7a′R)(2R,3a′R,6′S,7a′R)-3-Acetyl-2′,2′,2′′,2′′-tetramethyl-5-octyl-2,3-dihydro-1,3,4-oxadiazole-2-spiro-7′-{1′,3′-dioxolano[4,5-c]pyrano}-6′-spiro-4′′-(1′′,3′′-diaoxolane)C24H40N2O7[α]D25=-33.0 (c 0.97, MeOH)Source of chirality: d-fructoseAbsolute configuration: (2R,3a′R,6′S,7a′R)(2S,3a′R,6′S,7a′R)-3-Acetyl-2′,2′,2′′,2′′-tetramethyl-5-octyl-2,3-dihydro-1,3,4-oxadiazole-2-spiro-7′-{1′,3′-dioxolano[4,5-c]pyrano}-6′-spiro-4′′-(1′′,3′′-diaoxolane)C24H40N2O7[α]D25=-53.6 (c 0.97, MeOH)Source of chirality: d-fructoseAbsolute configuration: (2S,3a′R,6′S,7a′R)(2R,3a′R,6′S,7a′R)-3-Acetyl-2′,2′,2′′,2′′-tetramethyl-5-undecyl-2,3-dihydro-1,3,4-oxadiazole-2-spiro-7′-{1′,3′-dioxolano[4,5-c]pyrano}-6′-spiro-4′′-(1′′,3′′-diaoxolane)C26H44N2O7[α]D25=-23.5 (c 1.36, MeOH)Source of chirality: d-fructoseAbsolute configuration: (2R,3a′R,6′S,7a′R)(2S,3a′R,6′S,7a′R)-3-Acetyl-2′,2′,2′′,2′′-tetramethyl-5-undecyl-2,3-dihydro-1,3,4-oxadiazole-2-spiro-7′-{1′,3′-dioxolano[4,5-c]pyrano}-6′-spiro-4′′-(1′′,3′′-diaoxolane)C26H44N2O7[α]D25=-39.3 (c 1.12, MeOH)Source of chirality: d-fructoseAbsolute configuration: (2S,3a′R,6′S,7a′R)(2R,3a′R,6′S,7a′R)-3-Acetyl-2′,2′,2′′,2′′-tetramethyl-5-pentadecyl-2,3-dihydro-1,3,4-oxadiazole-2-spiro-7′-{1′,3′-dioxolano[4,5-c]pyrano}-6′-spiro-4′′-(1′′,3′′-diaoxolane)C30H52N2O7[α]D25=-3.6 (c 1.11, MeOH)Source of chirality: d-fructoseAbsolute configuration: (2R,3a′R,6′S,7a′R)(2S,3a′R,6′S,7a′R)-3-Acetyl-2′,2′,2′′,2′′-tetramethyl-5-pentadecyl-2,3-dihydro-1,3,4-oxadiazole-2-spiro-7′-{1′,3′-dioxolano[4,5-c]pyrano}-6′-spiro-4′′-(1′′,3′′-diaoxolane)C30H52N2O7[α]D25=-11.3 (c 1.06, MeOH)Source of chirality: d-fructoseAbsolute configuration: (2S,3a′R,6′S,7a′R)(2R,3a′R,6′S,7a′R)-3-Acetyl-2′,2′,2′′,2′′-tetramethyl-5-heptadecyl-2,3-dihydro-1,3,4-oxadiazole-2-spiro-7′-{1′,3′-dioxolano[4,5-c]pyrano}-6′-spiro-4′′-(1′′,3′′-diaoxolane)C32H56N2O7[α]D25=-12.6 (c 0.95, MeOH)Source of chirality: d-fructoseAbsolute configuration: (2R,3a′R,6′S,7a′R)(2S,3a′R,6′S,7a′R)-3-Acetyl-2′,2′,2′′,2′′-tetramethyl-5-heptadecyl-2,3-dihydro-1,3,4-oxadiazole-2-spiro-7′-{1′,3′-dioxolano[4,5-c]pyrano}-6′-spiro-4′′-(1′′,3′′-diaoxolane)C32H56N2O7[α]D25=-24.0 (c 0.5, MeOH)Source of chirality: d-fructoseAbsolute configuration: (2S,3a′R,6′S,7a′R)

3,4,6-Tri-O-acetyl-d-galactal, 3,4,6-tri-O-acetyl-d-glucal and 3,6,2′,3′,4′6′-hexa-O-acetyl-d-lactal were reacted with N-hydroxymethylphthalimide and boron trifluoride etherate to produce the corresponding phthalimidomethyl unsaturated glycosides via Ferrier rearrangement. When the galactal derivative was used, a non-Ferrier rearrangement product was also isolated as a minor product under classical Ferrier conditions. Phthalimidomethyl deoxy glycosides were readily prepared by hydrogenation of the unsaturated glycosides. Following deacetylation, the anti-inflammatory activities of these compounds were tested on mice and three were found to possess potent activity compared to hydrocortisone sodium succinate (HSS).

The first total synthesis of syringalide B, 2-(4-hydroxyphenyl)ethyl 4-O-[(E)-feruloyl]-β-d-glucopyranoside, is described. The hydroxyl groups were protected with allyloxycarbonyl (Aoc) and allyl groups, which successfully prevent the migration of the feruloyl group during the deblocking procedure.A natural phenylpropanoid glycoside syringalide B, 2-(4-hydroxyphenyl)ethyl 4-O-[(E)-feruloyl]-[β-d-glucopyranoside, was synthesized by using the allyloxycarbonyl (Aoc) and allyl groups for the protection of hydroxy groups.

Based on the two antigenic peptides, 26–43 (P26) and 116–131 (P116), derived from 28 kDa glutathione S-transferase of Schistosoma mansoni (Sm28GST), two multiple antigenic peptides (MAPs), (P26)4-MAP and (P116)4-MAP with the same oligomeric lysine core, were synthesized by stepwise solid-phase peptide synthesis method. The antigenicities and protective effects of these two MAPs were examined on experimental animals. As shown in the dot-ELISA result, the synthetic MAPs could be recognized and bound by immunoglobins in both patient’s and infected-rabbit’s sera. After Kunming mice were immunized with (P26)4-MAP, the worm burden reduction rate and the liver egg reduction rate were 59.9% and 61.1%. In (P26)4-MAP or (P116)4-MAP immunized BALB/c mice, the worm burden reduction rates were 37.5% and 62.5%, respectively, and the liver egg reduction rates were 35.1% and 54.0%, respectively.

Anomers of monovalent and divalent β-d-galactopyranosyl-(1→4)-2-acetamido-2-deoxy-d-gluco-pyranosides were synthesized under different glycosylation conditions, and evaluated for in vitro antimetastatic activity. Three compounds showed promising inhibitory effects on cancer cell attachment, spreading, migration, and invasion.Six divalent O-β-d-galactopyranosyl-(1→4)-2-acetamido-2-deoxy-d-glucopyranosides (29–34) were synthesized and their antimetastatic activities were studied.

A hydrophobically assisted switching phase (HASP) method is an efficient strategy for the synthesis of carrier-loaded oligosaccharides. We improved this method by using cetyl thioglycoside as the carrier, which made it possible to use the synthetic oligosaccharide block directly as the donor. We applied this improved HASP method in the successful assembly of a gp120-associated nona-mannoside. Our results indicated that the HASP method is an efficient strategy for the synthesis of complex oligosaccharides and glycoconjugates.

N-Galactosyl aziridines were synthesized via BF3·OEt2 promoted addition of carbenes generated from diazocarbonyl compounds with O-pivaloylated β-D-galactosylimines in good yields and high diastereoselectivity. The ring-opening reactions with p-toluenethiol of the aziridines provided enantiometrically pure β-S-substituted phenylalanine derivatives in a highly regioselective manner.

A convenient, metal-free intramolecular aminofluorination of alkenes has been developed. Employing readily available PhI(OPiv)2 and hydrogen fluoride–pyridine in the presence of BF3·OEt2, tosyl-protected pent-4-en-1-amines were converted to 3-F-piperidines in one step in good yields as well as high stereoselectivity.

A metal-free and 4-methyl aniline mediated method for the oxidative C–C bond cleavage has been developed. The reaction proceeds in air using molecular oxygen as the oxidant, affording one-carbon shortened esters in moderate to good yields within a short time. Moreover, it provides a model reaction for the highly enantioselective synthesis of (D)-serine esters by combining with a L-proline catalyzed Mannich reaction.

We report here the syntheses of mono- to tetravalent glycoclusters containing 1-methylene-C-β-lactose. The 1-methylene-C-β-lactose moiety has been synthesized from octa-acetyl-β-lactose using the key carbonyl insertion reaction and linked to a series of alkynlated scaffolds via CuAAC reaction to afford mono- to tetravalent glycoclusters. The binding affinities of the final products to galectin-3 were found in the range of 10–100 μM.

The hydrophobically assisted switching phase (HASP) method was applied in the assembly of oligomannosides. A new mannosyl donor with high reactivity was selected after a series of optimization studies, which was suitable for the synthesis of oligomannosides via the HASP method. The practicability of the HASP method towards the synthesis of branched oligosaccharides was explored and two branched penta-mannosides were assembled efficiently.