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N-Aryl-protecting groups were introduced in glucosamines to achieve β-selective glycosylation. Various N-aryl aminosugars were synthesized via Buchwald–Hartwig reaction. Glycosylation using glycosyl trichloroacetimidates of N-aryl aminosugars smoothly proceeded in the presence of trimethylsilyl trifluoromethanesulfonate. Use of a glycosyl donor comprising an electron-donating 2,4-dimethoxyphenyl (DMP) group led to the glycosylation proceeding with high β selectivity. This stereoselectivity seemed to be derived from the formation of an aziridine intermediate. The DMP-protecting group can be removed immediately by using ammonium hexanitratocerate (IV).

Formal [4+4] reaction of the unsaturated benzyl- or allylimines, which is efficiently mediated by primary amine, provides the 2,6,9-triazabicyclo[3.3.1]nonane derivatives. Variously substituted homo- and hetero-coupling products are obtained in good to excellent yields by quite a simple procedure under mild conditions: by mixing the unsaturated aldehydes with the amines at room temperature.

Derivatization of ursolic acid, one of the natural ursene-type pentacyclic triterpenes, was investigated by the oxidation with dioxoruthenium(VI) tetraphenylporphyrins. Oxidation selectivity on the terpene structure was modulated by the auxiliaries introduced on the tetraphenylporphyrin. Chemical oxidation of the ursolic acid affected the cytotoxic activity against tumor cell lines.

In this Letter, a new synthetic method of sulfonamide-containing cyclic sulfides using a microwave-assisted traceless solid-phase approach is described. Using this new method, many highly pure cyclic sulfides were efficiently synthesized based on intramolecular alkylation of the sulfides followed by elimination of the desired products from the generated sulfonium salts.

The synthesis of crosslinked peptidoglycan (PGN) fragments from Streptococcus pneumoniae cell wall was achieved. The immunostimulatory activities, including the induction of IL-6 and the stimulation of the intracellular receptor Nod2, were also determined. The crosslinked PGN fragments were not major human Nod2 ligands.

The synthesis of immunoregulatory glycoconjugates, namely the active entity of lipopolysaccharide (LPS) from Helicobacter pylori was achieved. The results of biological activities of the LPS partial structures provide the structural basis for the immunobiological activity, especially for the immune inhibitory activity of H. pylori LPS.

Acceleration of Cu(I)-mediated Huisgen 1,3-dipolar cycloaddition (Sharpless ‘click reaction’) by non-basic histidine derivatives was found. An efficient ‘self-activating’ click reaction between the azide- and acetylene-containing peptides on the solid-phase has also been achieved by introducing the N im -benzylhistidine residue on the reacting peptides.

Fluorescence- and biotin-labeled lipid A analogues were synthesized for the investigation of bacterial lipopolysaccharide (LPS)/lipid A recognition in the innate immune system. For the introduction of the labeling moiety, a hydrophilic glutaryl-glucose linker was used for maintaining the bioactivity and also for preventing self-aggregation, which causes quenching of the fluorescence. We also observed the biological activity of the labeled compounds.

Partial structures of peptidoglycan, a potent immunostimulating glycoconjugate of bacteria, were synthesized for precise biological studies. A key disaccharide glucosaminyl-β(1–4)-muramic acid was prepared by stereoselective glycosylation of a N -Troc (Troc=2,2,2-trichloroethoxycarbonyl) muramic acid acceptor with a N -Troc-glucosaminyl trichloroacetimidate. The disaccharide was converted to either a disaccharide acceptor or a donor. They were then coupled together by the same glycosylation method to give a tetrasaccharide in a good yield. Octasaccharide was also obtained in a good yield in a similar manner. N -Acetylation and coupling with the dipeptide moiety of l -alanyl- d -isoglutamine followed by deprotection afforded the repeating peptidoglycan tetrasaccharide and octasaccahride peptide conjugates for the first time.

Synthesis of lipid A 1 isolated from Helicobacter pylori strain 206-1 has been achieved in 2.2% total yield through 14 steps from d -glucosamine by employing a p-(trifluoromethyl)benzyl group for protection of the hydroxy group on the 3-hydroxy fatty acid residue. The synthetic specimen was identical with the natural counterpart in chromatographic, spectroscopic, and biological aspects. A structural analogue 2 which lacks the ethanolamine residue of 1 was also synthesized, and 2 was found to exhibit less potent IL-1β-inducing activity than 1.

A new method for affinity purification of synthetic compounds by using crown ether-ammonium ion interaction and its application to the synthesis of several peptides and heterocycles are described. The desired compounds possessing the crown ether (32-crown-10) moiety were readily isolated from the reaction mixture by the following procedure. After each reaction cycle, the reaction mixture was applied to the aminomethylated polystyrene column (trifluoroacetic acid form). The compound possessing the crown ether was selectively adsorbed on the column, whereas other impurities without the crown ether such as excess reagents and byproducts were washed off. Subsequent desorption by Et 3 N or CH 2 Cl 2 :MeOH (1:1) afforded the desired compound with high purity. This new strategy is expected to be useful, for, in particular, multiple parallel synthesis and combinatorial library preparation.

New glycosyl donors, 3-nitro-2-pyridyl and 5-nitro-2-pyridyl glycosides, proved to be effective for transglycosylation reaction catalyzed by glycosidases, such as β-galactosidase, β-glucosidase, and N -acetyl-β-hexosaminidase. The high solubility in water and the high reactivity of the nitropyridyl glycosides enabled the reactions under high concentrations of the donors and consequently rapid glycosyl transfer to glycosyl acceptors. The yields of the transglycosylated products with the nitropyridyl glycosides were much higher than those with conventional p -nitrophenyl glycosides.

A microfluidic system was applied to aldol reaction in aqueous biphasic medium. Advantageous aspects of microfluidic conditions, that is, efficient mixing, fast heat transfer, and residence time control led to the high-yielding reaction of acetone enolate with even α-proton-containing aldehydes in biphasic aqueous-acetone system, by minimizing the formation of self-condensation products.

The title trisaccharide-serine conjugate 1 constituting the linkage region between glycosaminoglycan and protein in proteoglycan, was synthesized via a trisaccharide p -nitrophenyl (PNP) glycoside prepared by stepwise enzymatic transglycosidation to Xyl-PNP with a β- d -galactosidase. In the second transglycosidation step, partial protection of the disaccharide intermediate, Gal-Xyl-PNP, furnished selective galactosylation at the 3′-position. Cleavage of the PNP group after peracetylation, chemical coupling with serine and final deprotection afforded 1 . Fluorescence labeled trisaccharide, Gal(β1-3)Gal(β1-4)Xyl(β)-MU (MU: 4-methylumbelliferyl) ( 2 ) was also synthesized in a similar way.

To determine the specific site(s) in heparin necessary for binding to platelets, synthesis of a model compound containing the disaccharide sequence, O-(2-deoxy-2-sulfamido-6-O-sulfo-α-D-glucopyranosyl)-(1→4)-2-O-sulfo-α-L-idopyranuronic acid, found in heparin was performed by α-selective glycosidation using a phenyl thioglycoside as a donor. The compound inhibited 125 I-labelled heparin binding to human platelets to a greater extent than a heparin-derived disaccharide, obtained by the heparinase I digestion, yet contained the same number of sulfate groups per molecule.

A synthetic route for 14 C-labeling of a phosphonooxyethyl (PE) analogue of E. coli lipid A was established by cold experiments. The PE analogue is chemically more stable than natural lipid A but shows practically identical biological activity. The glycosidation of ethylene glycol unit as the 14 C-labeled position was effected with a-disaccharide thioglycoside by use of a hypervalent iodine reagent, PhIO-SnClO 4 -AgClO 4 , as an activator. p -Methoxybenzyl group used for the protection of the distal hydroxyl group of ethylene glycol was selectively removed by trimethylsilyl triflate in CH 3 CNCH 2 Cl 2 followed by phosphorylation and deprotection gave the target compound.

Synthesis of an analog of a biosynthetic precursor of lipid A containing four ( S )-3-hydroxytetradecanoic acids was effected via an improved synthetic route to investigate the relationship between the bioactivity and the chirality of the 3-hydroxy fatty acid residues in lipid A. The S -analog inhibited endotoxin-induced interleukin-6 (IL-6) production from human peripheral whole blood cells more strongly than the natural-type biosynthetic precursor with ( R )-hydroxy acids, a known antagonist of LPS-induced cytokine release in human peripheral blood mononuclear cells.

Reactivity of LiAlH4 was controlled by using solid-phase reaction conditions. Tertiary amides bound to gel-type polystyrene support were reduced with LiAlH4 to give tertiary amines with satisfactory purity, whereas the reduction of similar tertiary amides in solution gave secondary amines as main products. Solid-phase synthesis of tertiary amine libraries was achieved by using this method.

A reagent prepared in situ from iodosobenzene (PhIO) and trifluoromethanesulfonic anhydride (Tf2O) was successfully applied to the activation of thioglycosides. Glycosidation with benzyl-protected methyl thioglycosides as glycosyl donors proceeded smoothly under mild reaction conditions. The same reagent also promoted glycosidation with less reactive acylated methyl thioglycosides in the presence of silica gel to form 1, 2-trans glycosides.

4-Pivaloylaminobenzyl (PAB) group is a new benzyl-type protecting group which can be introduced either by initial introduction of 4-nitrobenzyl group followed by reduction and N-acylation or by the reaction of a hydroxyl compound with the corresponding halogenide or trichloroacetimidate. PAB ethers have higher acid stability than 4-methoxybenzyl ethers but are readily cleaved with DDQ in a manner similar to the latter.

3-Nitro-2-pyridyl (3NPy) glycosides, which act as versatile glycosyl donors in enzymatic transglycosylation, can also be chemically activated. Chemical glycosylation with protected 3NPy glycosides was readily effected at −20°C by using TMSOTf as a catalyst to afford the desired glycosides in good yields. A trisaccharide serine conjugate Gal(β1-3)Gal(β1-4)Xylβ-Ser was synthesized by combined use of enzymatic and chemical glycosylations. The trisaccharide 3NPy glycoside was prepared by stepwise transglycosylation of a Gal-3NPy donor to a Xyl-3NPy acceptor by using a β-galactosidase. After protection of the free hydroxy groups of the trisaccharide by acetylation, the 3NPy glycoside was then subjected to chemical glycosylation of a serine residue to afford the trisaccharide serine conjugate.

The 2,2,2-trichloroethoxycarbonyl (Troc) group was efficiently removed in high yields with (Bu3Sn)2 in DMF under microwave heating. The present method was applied to deprotection of the Troc group on solid support.

The propargyloxycarbonyl group readily introduced to both amino and hydroxy groups by using propargyl chloroformate is stable to neat TFA but is readily cleaved at ambient temperature by treatment with Co 2 (CO) 8 and TFA in CH 2 Cl 2 via formation of an alkyne-Co complex. The propargyl ester similarly serves as a good protecting group for carboxy functions.

Versatile use of the p-nitrophenyl group for anomeric protection of carbohydrates is described. It can be readily removed via conversion into a p-acetamidophenyl group followed by ammonium cerium(IV) nitrate oxidation.

The 4-azidobenzyl ether can be readily formed and cleaved either by direct oxidation with 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) or by oxidation after conversion to the 4-aminobenzyl ether or the corresponding iminophosphorane derivative. In the latter two-step cleavage methods the azidobenzyl group is removed in preference to the 4-methoxybenzyl (MPM) group, whereas the MPM group can be selectively removed by the direct DDQ oxidation.

Total synthesis of a lanthionine peptide nisin was successfully achieved for the first time by application of new methods for preparations of dehydroalanine and lanthionine moieties, resulting in a confirmation of the proposed structure.

The structure of lanthiopeptin, a new lanthionine peptide effective against Herpes virus, was newly determined. It has a unique tetracyclic sequence which is very similar to but different from the proposed structure for Ro 09-0198. However, Ro 09-0198 was found to be quite the same compound as lanthiopeptin in all respects.