Synthesis of bis-(methyl 3,4,6-tri-O-acetyl-D-glucopyranosid-2-yl)-oxamides

The synthesis of a new bis-(D-glucopyranosid-2-yl)oxamides via the key intermediate, N-acetyl N-(methyl 3,4,6-tri-O-acetyl-alpha-D-glucopyranosid-2-yl) oxamic acid chloride (2alpha) is described. Treatment of compound 2alpha with methyl 3,4,6-tri-O-acetyl-2-amino-2-deoxy-beta-D-glucopyranoside afforded N-(methyl 3,4,6-tri-O-acetyl-alpha-D-glucopyranosid-2-yl)-N'-(methyl 3,4,6-tri-O-acetyl-beta-D-glucopyranosid-2-yl)-oxamide. Reaction of 2alpha with 1,2-diaminoethane afforded 1,2-bis-[N,N'-(methyl 3',4',6'-tri-O-acetyl-alpha-D-glucopyranosid-2'-yl)]ethyloxamide as a main product, while 2-N-[N'-(methyl 3',4',6'-tri-O-acetyl-alpha-D-glucopyranosid-2'-yl)oxamide]-ethyl acetamide was formed as a side product. Reaction of 2alpha with 1,3-diamino-2-hydroxypropane gave only 1,3-bis-N,N-[N'-(methyl 3',4',6'-tri-O-acetyl-2'-deoxy-alpha-D-glucopyranosid-2'-yl)-oxamido]-2-propanol.     

Synthesis and solid state 13C and 1H NMR analysis of new oxamide derivatives of methyl 2-amino-2-deoxy-alpha-D-glucopyranoside and ester of amino acids or dipeptides

The syntheses of new oxamide derivatives of methyl 2-amino-2-deoxy-alpha-D-glucopyranoside and amino acid or peptide esters are presented. The reaction of methyl 3,4,6-tri-O-acetyl-2-acetamido-2-deoxy-alpha-D-glucopyranoside and oxalyl chloride gave N-(methyl 3,4,6-tri-O-acetyl-2-deoxy-alpha-D-glucopyranosid-2-yl) oxamic acid chloride which on reaction with the ester of Gly, L-Ala, L-Phe, GlyGly, Gly-L-Phe and Gly-L-Ala afforded N-(methyl 3,4,6-tri-O-acetyl-2-deoxy-alpha-D-glucopyranosid-2-yl), N'-oxalyl-amino acid or dipeptide esters. The structure of the oxamides was studied using 1H, 13C NMR in solution and solid state.     

Synthesis and reactions of O-acetylated benzyl alpha-glycosides of 6-O-(2-acetamido-2-deoxy-beta-D-glucopyranosyl)-N-acetylmuramoyl-L- alanyl-D-isoglutamine esters: the base-catalysed isoglutamine in equilibrium glutamine rearrangement in peptidoglycan-related structures

Condensation of benzyl 2-acetamido-6-O-(2-acetamido-3,4,6-tri-O-acetyl-2- deoxy-3-O-[(R)-1-carboxyethyl]-alpha-D-glucopyranoside (2) and its 4-acetate (4) with L-alanyl-D-isoglutamine benzyl ester via the mixed anhydride method yielded N-(2-O-[benzyl 2-acetamido-6-O-(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-beta-D- glucopyranosyl)-2,3-dideoxy-alpha-D-glucopyranosid-3-yl]-(R)-lacto yl)-L- alanyl-D-isoglutamine benzyl ester (5) and its 4-acetate (6), respectively. Condensation by the dicyclohexylcarbodi-imide-N-hydroxysuccinimide method converted 2 into benzyl 2-acetamido-6-O-(2-acetamido-3,4,6-tri-O-acetyl- 2-deoxy-beta-D-glucopyranosyl)-3-O-[(R)-1-carboxyethyl]-2-deoxy-alpha-D- glucopyranoside 1',4-lactone (7). In the presence of activating agents, 7 underwent aminolysis with the dipeptide ester to give 5. Zemplén O-deacetylation of 5 and 6 led to transesterification and alpha----gamma transamidation of the isoglutaminyl residue to give N-(2-O-[benzyl 2-acetamido-6-O-(2- acetamido-2-deoxy-beta-D-glucopyranosyl)-2,3-dideoxy-alpha-D-glucopyr anosid-3- yl]-(R)-lactoyl)-L-alanyl-D-isoglutamine methyl ester (8) and -glutamine methyl ester (9). Treatment of 6 with MgO-methanol caused deacetylation at the GlcNAc residue to give a mixture of N-(2-O-[benzyl 2-acetamido-6-O-(2-acetamido-2- deoxy-beta-D-glucopyranosyl)-4-O-acetyl-2,3-dideoxy-alpha-D-glucopyra nosid-3- yl]-(R)-lactoyl)-L-alanyl-D-isoglutamine methyl ester (11) and -glutamine methyl ester (12). Benzyl or methyl ester-protection of peptidoglycan-related structures is not compatible with any of the reactions requiring alkaline media. Condensation of 2 with L-alanyl-D-isoglutamine tert-butyl ester gave N-(2-O-[benzyl 2-acetamido- 6-O-(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-beta-D-glucopyranosyl)-2,3-d ideoxy- alpha-D-glucopyranosid-3-yl]-(R)-lactoyl-L-alanyl-D-isoglutamine tert-butyl ester (16), deacetylation of which, under Zemplén conditions, proceeded without side-reactions to afford N-(2-O-[benzyl 2-acetamido-6-O-(2-acetamido-2-deoxy-beta-D- glucopyranosyl)-2,3-dideoxy-alpha-D-glucopyranosid-3-yl]-(R)-la cotyl)-L- alanyl-D-isoglutamine tert-butyl ester (17).     

Synthesis of a peripheral trisaccharide sequence of lutropin, a pituitary glycoprotein hormone; use of chitobiose as a key starting material

A chitobiose derivative, methyl O-(3,4,6-tri-O-acetyl-2-deoxy-2-phthalimido-beta-D-glucopyranosyl)-(1--- -4)-3,6 - di-O-acetyl-2-deoxy-2-phthalimido-beta-D-glucopyranoside, was derived from the corresponding N-acetyl derivative and this was converted into the glycosyl bromide (5). Glycosidation reaction between 5 and methyl 3,4,6-tri-O-benzyl-alpha-D-mannopyranoside in the presence of silver trifluoromethanesulfonate gave a beta-D-linked trisaccharide derivative. Replacement of the N,N-phthaloyl group by acetyl groups resulted in a product that was converted into methyl O-(2-acetamido-3,6-di-O-benzyl-2-deoxy-beta-D-glucopyranosyl)-(1----4)-O -(2- acetamido-3,6-di-O-benzyl-2-deoxy-beta-D-glucopyranosyl)-(1----2)-3,4,6- tri-O- benzyl-alpha-D-mannopyranoside (11) by use of a few reaction steps. The 4(3)-hydroxyl group of 11 was methanesulfonylated, and the product subjected to SN2 replacement with acetate anion, to give the D-galactosamine-containing trisaccharide derivative (12). After basic hydrolysis of 12, the 4(3)-hydroxyl group was sulfated, and all benzyl groups were removed by hydrogenolysis, giving methyl O-(2-acetamido-2-deoxy-4-O-sulfo-beta-D-galactopyranosyl)-(1----4)-O-(2- acetamido-2-deoxy-beta-D-glucopyranosyl)-(1----2)-alpha-D-mannopyranosid e monosodium salt, the methyl alpha-glycoside derivative of the peripheral trisaccharide sequence of the pituitary glycoprotein hormone lutropin.     

Mēthylation de dērivēs n-acylēs du 2-amino-2-dēsoxy-D-glucose en prēsence de sels d'argent: observations sur le comportement du groupement ambident acetamido (ou benzamido)

The behavior of the acetamido (and benzamido) ambident, nucleophilic group under methylation with methyl iodide and silver oxide has been studied for several 2-acetamido-2-deoxy-D-glucose derivatives. When silver perchlorate was added, alkylation occurred at the oxygen atom, giving methyl imidates that were labile in acidic medium. Benzyl 2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-D-glucopyranoside was converted into N-(benzyl 3,4,6-tri-O-acetyl-2-deoxy-β-D-glucopyranoside-2-yl) methyl acetimidate (83%), which was subsequently hydrolyzed quantitatively in acidic medium into the corresponding amine salt. Similar results were obtained with benzyl 3,4,6-tri-O-acetyl-2-benzamido-2-deoxy-β-d-glucopyranoside, methyl 2-acetamido-2-deoxy-3,4,6-tri-O-methyl-β-D-glucopyranoside, and benzyl 2-acetamido-3,4,6-tri-O-benzyl-2-deoxy-β-D-glucopyranoside. Under Kuhn's methylation conditions (methyl iodide-silver oxide-N,N-dimethylformamide), alkylation of the just mentioned derivatives occurred at both oxygen and nitrogen atoms.     

Synthesis of two oligosaccharides, the GPI anchor glycans from S. cerevesiae and A. fumigatus

Two oligosaccharides, alpha-D-Manp-(1-->2)-alpha-D-Manp-(1-->2)-alpha-D-Manp-(1-->6)-alpha-D-Manp-(1-->4)-alpha-D-GlcpNAc (I) and alpha-D-Manp-(1-->3)-alpha-D-Manp-(1-->2)-alpha-D-Manp-(1-->2)-alpha-D-Manp-(1-->6)-alpha-D-Manp-(1-->4)-alpha-D-GlcpNAc (II), the glycosylphosphatidylinositol (GPI) anchor glycans from S. cerevesiae and A. fumigatus were synthesized as their methyl glycosides in a regio- and stereoselective manner. The pentasaccharide I was obtained from 6-O-selective glycosylation of methyl 2,3-di-O-benzoyl-alpha-D-mannopyranosyl-(1-->4)-2-acetamido-3,6-di-O-benzoyl-2-deoxy-alpha-D-glucopyranoside (8) with 2-O-acetyl-3,4,6-tri-O-benzoyl-alpha-D-mannopyranosyl-(1-->2)-3,4,6-tri-O-benzoyl-alpha-D-mannopyranosyl trichloroacetimidate (9), followed by benzoylation, deacetylation, and mannosylation, and then by deprotection. The hexasaccharide (II) was obtained via condensation of allyl 3,4,6-tri-O-benzoyl-alpha-D-mannopyranosyl-(1-->2)-3,4,6-tri-O-benzoyl-alpha-D-mannopyranoside (17) with 2,3,4,6-tetra-O-benzoyl-alpha-D-mannopyranosyl-(1-->3)-2,4,6-tri-O-acetyl-alpha-D-mannopyranosyl trichloroacetimidate (16), followed by deallylation, trichloroacetimidation, and coupling with acceptor (8), and finally by deprotection.     

New class of quaternary ammonium salts, derivatives of methyl D-glucopyranosides

Reactions of two aromatic and two aliphatic amines with methyl 6-O-p-toluenesulfonyl-alpha-D-glucopyranoside or methyl 6-O-p-toluenesulfonyl-beta-D-glucopyranoside were performed on a micro-scale. The synthesis and preparative isolation methods have been developed for quaternary N-(methyl 2,3,4-tri-O-acetyl-6-deoxy-alpha- and -beta-D-glucopyranoside-6-yl)ammonium salts derived from three amines: trimethylamine, 2-methylpyridine, and pyridine. The reaction products were examined with 1H, 13C NMR spectroscopy. N-(Methyl 2,3,4-tri-O-acetyl-6-deoxy-beta-d-glucopyranoside-6-yl)trimethylammonium tosylate was additionally analyzed with X-ray crystallography.     

Unexpected stereochemical outcome of activated 4,6-O-benzylidene derivatives of the 2-deoxy-2-trichloroacetamido-D-galacto series in glycosylation reactions during the synthesis of a chondroitin 6-sulfate trisaccharide methyl glycoside

The synthesis of methyl (beta-D-glucopyranosyluronic acid)-(1-->3)-(2-acetamido-2-deoxy-6-O-sulfonato-beta-D-galactopyr anosyl)-(1-->4)-(beta-D-glucopyranosid)uronate trisodium salt, a chondroitin 6-sulfate trisaccharide derivative, is described. Loss of stereocontrol in glycosylation reactions involving activated 4,6-O-benzylidene derivatives of the 2-deoxy-2-trichloroacetamido-D-galacto series and D-glucuronic acid-derived acceptors was highlighted. This draw-back was overcome through the use of phenyl 3,4,6-tri-O-acetyl-2-deoxy-1-thio-2-trichloroacetamido-beta-D-gala ctopyranoside, which afforded the desired beta-linked disaccharide derivative in high yield with an excellent stereoselectivity. This later was submitted to acid-catalyzed methanolysis, followed by benzylidenation, and condensed with methyl 2,3,4-tri-O-benzoyl-1-O-trichloroacetimidoyl-alpha-D-glucopyran uronate to afford the expected trisaccharide derivative. Subsequent transformation of the N-trichloroacetyl group into N-acetyl, mild acid hydrolysis, selective O-sulfonation at C-6 of the amino sugar moiety, and saponification afforded the target molecule as its sodium salt in high yield.     

Studies on the stereoselective synthesis of a protected α-D-Gal-(1→2)-D-Glc fragment

A novel 1,2-cis stereoselective synthesis of protected α-D-Gal-(1→2)-D-Glc fragments was developed. Methyl 2-O-acetyl-3-O-allyl-4,6-O-benzylidene-α-D-galactopyranosyl-(1→2)-3-O-benzoyl-4,6-O-benzylidene-α-D-glucopyranoside (13), methyl 2-O-acetyl-3-O-allyl-4,6-O-benzylidene-α-D-galactopyranosyl-(1→2)-3,4,6-tri-O-benzoyl-α-D-glucopyranoside (15), methyl 2-O-acetyl-3-O-allyl-4,6-O-benzylidene-α-D-galactopyranosyl-(1→2)-3-O-benzoyl-4,6-O-benzylidene-β-D-glucopyranoside (17), and methyl 2-O-acetyl-3-O-allyl-4,6-O-benzylidene-α-D-galactopyranosyl-(1→2)-3,4,6-tri-O-benzoyl-β-D-glucopyranoside (19) were favorably obtained by coupling a new donor, isopropyl 2-O-acetyl-3-O-allyl-4,6-O-benzylidene-1-thio-β-D-galactopyranoside (2), with acceptors, methyl 3-O-benzoyl-4,6-O-benzylidene-α-D-glucopyranoside (4), methyl 3,4,6-tri-O-benzoyl-α-D-glucopyranoside (5), methyl 3-O-benzoyl-4,6-O-benzylidene-β-D-glucopyranoside (8), and methyl 3,4,6-tri-O-benzoyl-β-D-glucopyranoside (12), respectively. By virtue of the concerted 1,2-cis α-directing action induced by the 3-O-allyl and 4,6-O-benzylidene groups in donor 2 with a C-2 acetyl group capable of neighboring-group participation, the couplings were achieved with a high degree of α selectivity. In particular, higher α/β stereoselective galactosylation (5.0:1.0) was noted in the case of the coupling of donor 2 with acceptor 12 having a β-CH(3) at C-1 and benzoyl groups at C-4 and C-6.     

Acid-base properties and copper(II) complexes of dipeptides containing histidine and additional chelating bis(imidazol-2-yl) residues

Copper(II) complexes of dipeptides of histidine containing additional chelating bis(imidazol-2-yl) agent at the C-termini (PheHis-BIMA [N-phenylalanyl-histidyl-bis(imidazol-2-yl)methylamine] and HisPhe-BIMA [N-histidyl-phenylalanyl-bis(imidazol-2-yl)methylamine]) were studied by potentiometric, UV-Visible and Electron Paramagnetic Resonance (EPR) techniques. The imidazole nitrogen donor atoms of the bis(imidazol-2-yl)methyl group are described as the primary metal binding sites forming stable mono- and bis(ligand) complexes at acidic pH. The formation of a ligand-bridged dinuclear complex [Cu2L2]4+ is detected in equimolar solutions of copper(II) and HisPhe-BIMA. The coordination isomers of the dinuclear complex are described via the metal binding of the bis(imidazol-2-yl)methyl, amino-carbonyl and amino-imidazole(His) functions. In the case of the copper(II)-PheHis-BIMA system the [NH2, N-(amide), N(Im)] tridentate coordination of the ligand is favoured and results in the formation of di- and trinuclear complexes [Cu2H(-1)L]3+ and [Cu3H(-2)L2]4+ in equimolar solutions. The presence of these coordination modes shifts the formation of "tripeptide-like" ([NH2, N-, N-, N(Im)]-coordinated) [CuH(-2)L] complexes into alkaline pH range as compared to other dipeptide derivatives of bis(imidazol-2-yl) ligands. Although there are different types of imidazoles in these ligands, the deprotonation and coordination of the pyrrole-type N(1)H groups does not occur below pH 10.     

Synthesis and in vitro antitumor activity of thiophene analogues of 5-chloro-5,8-dideazafolic acid and 2-methyl-2-desamino-5-chloro-5,8-dideazafolic acid

N-[5-[N-(2-Amino-5-chloro-3,4-dihydro-4-oxoquinazolin-6-yl)methylamino]-2-thenoyl]-L-glutamic acid (6) and N-[5-[N-(5-chloro-3,4-dihydro-2-methyl-4-oxoquinazolin-6-yl)methylamino]-2-thenoyl]-L-glutamic acid (7), the first reported thiophene analogues of 5-chloro-5,8-dideazafolic acid, were synthesized and tested as inhibitors of tumor cell growth in culture. 4-Chloro-5-methylisatin (10) was converted stepwise to methyl 2-amino-5-methyl-6-chlorobenzoate (22) and 2-amino-5-chloro-3,4-dihydro-6-methyl-4-oxoquinazoline (19). Pivaloylation of the 2-amino group, followed by NBS bromination, condensation with di-tert-butyl N-(5-amino-2-thenoyl)-L-glutamate (28), and stepwise cleavage of the protecting groups with ammonia and TFA yielded. Treatment of 9 with acetic anhydride afforded 2,6-dimethyl-5-chlorobenz[1,3-d]oxazin-4-one (31), which on reaction with ammonia, NaOH was converted to 2,6-dimethyl-5-chloro-3,4-dihydroquinazolin-4-one (33). Bromination of, followed by condensation with and ester cleavage with TFA, yielded. The IC(50) of and against CCRF-CEM human leukemic lymphoblasts was 1.8+/-0.1 and 2.1+/-0.8 microM, respectively.     

Synthesis and rearrangements of D-glucosyl esters of aspartic acid linked through the 1- or 4-carboxyl group.

Catalytic hydrogenation of 2,3,4,6-tetra-O-benzyl-1-O-[1-benzyl N-(benzyloxycarbonyl)-L-aspart-4-oyl]-alpha-D-glucopyranose (1alpha) in acetic acid-2-methoxyethanol gave 1-O-(L-beta-aspartyl)alpha-D-glucopyranose (2alpha) contaminated with 2-O-(L-alpha-aspartyl)-D-glucopyranose (8). Evidence that 8 was formed from the 1-oyl isomer of 1alpha, namely 2,3,4,6-tetra-O-benzyl-1-O-[4-benzyl N-(benzyloxycarbonyl)-L-aspart-1-oyl]-alpha-D-glucopyranose (7alpha), via 1 leads to 2 acyl migration, was obtained by submitting the deprotected D-glucosyl ester to successive N-acetylation, esterification, and O-acetylation; the final product was identified as a approximately 4:1 mixture of 2,3,4,6-tetra-O-acetyl-1-O-[1-methyl N-(acetyl)-L-aspart-4-oyl]-alpha-D-glucopyranose (4alpha) and 1,3,4,6-tetra-O-acetyl-2-O-[4-methyl N-(acetyl)-L-aspart-1-oyl]-D-glucopyranose (6) which were also prepared by definitive methods. On the other hand, deprotection of 1beta gave isomerically pure 2beta which was converted into the peracetylated ester derivative 4beta; an explanation for the differences in aglycon isomeric purity of 2alpha and 2beta is given. Hydrogenolysis of 7beta under the above conditions led to intermolecular transesterification with scission of the C-1 ester bond to give 1-(2-methoxyethyl) L-aspartic acid and D-glucose. Catalytic hydrogenation of 7alpha and 7beta, performed in the presence of trifluoroacetic acid, afforded 1-O-(L-alpha-aspartyl)-alpha- and -beta-D-glucopyranoside trifluoroacetate salts (11alpha and 11beta), respectively. The structure of 11beta was established by successive conversion into 2,3,4,6-tetra-O-acetyl-1-O-[4-methyl N-(acetyl)-L-aspart-1-oyl]-beta-D-glucopyranose (5beta) which was also prepared by definitive methods. Analogous treatment of 11alpha gave the N-acetyl derivative 12 which underwent 1 leads to 2 acyl migration during esterification with diazomethane to give the N-acetyl methyl ester derivative 10; acetylation of 10 afforded 6.     

Synthesis of N4-(2-acetamido-2-deoxy-beta-D-glucopyranosyl)-L-asparagine analogues: succinamide, L-2-hydroxysuccinamide, and L-2-hydroxysuccinamic acid hydrazide analogues

The syntheses of three analogues of N4-(2-acetamido-2-deoxy-beta-D-glucopyranosyl)-L-asparagine are described. N-(2-Acetamido-2-deoxy-beta-D-glucopyranosyl)succinamide was synthesized by the reaction of pentafluorophenyl succinamate with 2-acetamido-2-deoxy-beta-D-glucopyranosylamine. 2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-beta-D-glucopyranosylamine was synthesized, and the complete assignment of the 1H NMR spectrum is given. Reaction of the protected beta-D-glycosylamine with L-malic acid chloralid in the presence of a coupling agent (EEDQ) gave N4-(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-beta-D-glucopyranosyl)-L-malamic acid chloralid that was deprotected two ways: (1) using ammonia, which gave N4-(2-acetamido-2-deoxy-beta-D-glucopyranosyl)-L-2-hydroxysuccinamide, and (2) using hydrazine, which gave N4-(2-acetamido-2-deoxy-1-D-glucopyranosyl)-L-2-hydroxysuccinamic acid hydrazide.     

Design, synthesis, and biological evaluation of substituted-N-(thieno[2,3-b]pyridin-3-yl)-guanidines, N-(1H-pyrrolo[2,3-b]pyridin-3-yl)-guanidines, and N-(1H-indol-3-yl)-guanidines

Sulfonylureas stimulate insulin secretion independent of the blood glucose concentration and therefore cause hypoglycemia in type 2 diabetic patients. Over the last years, a number of aryl-imidazoline derivatives have been identified that stimulate insulin secretion in a glucose-dependent manner. In the present study, we have developed three series of substituted N-(thieno[2,3-b]pyridin-3-yl)-guanidine (2a-l), N-(1H-pyrrolo[2,3-b]pyridin-3-yl)-guanidine (3a-l), and N-(1H-indol-3-yl)-guanidine (4a-l) as new class of antidiabetic agents. In vitro glucose-dependent insulinotropic activity of test compounds 2a-l, 3a-l, and 4a-l was evaluated using RIN5F (Rat Insulinoma cell) based assay. All the test compounds showed concentration-dependent insulin secretion, only in presence of glucose load (16.7mmol). Some of the test compounds (2c, 3c, and 4c) from each series were found to be equipotent to BL 11282 (standard aryl-imidazoline), which indicated that the guanidine group acts as a bioisostere of imidazoline ring system.     

Montmorillonite K-10 clay-catalyzed Ferrier rearrangement of 2-C-hydroxymethyl-d-glycals, 3,4,6-tri-O-alkyl-d-glycals, and 3,4-(dihydro-2H-pyran-5-yl)methanol: a few unexpected domino transformations

Montmorillonite K-10 clay-catalyzed substitution reactions of 3,4,6-tri-O-alkyl-2-C-hydroxymethyl-d-glycals, 3,4,6-tri-O-acetyl-d-glycals, 3,4,6-tri-O-alkyl-d-glycals, and 3,4-(dihydro-2H-pyran-5-yl)methanol with a few alcohols and phenols are described. The reactions of 2-C-hydroxymethyl-d-glycals with phenols were similar to those of 2-C-acetoxymethyl-d-glycals and afforded pyrano[2,3-b]benzopyrans. This montmorillonite K-10 clay-catalyzed transformation is facile both under ambient (Method 1) and microwave conditions (Method 2). Ferrier rearrangement of 3,4-(dihydro-2H-pyran-5-yl)methanol with p-cresol, 2,6-xylenol, and ethanol led to totally unexpected transformations. Reaction of 2-C-hydroxymethyl-d-galactal with 2,6-dimethylphenol in the presence of montmorillonite K-10 led to a novel domino transformation affording 4-(5',6'-dihydro-4H-pyran-3'-ylmethyl)-2,6-dimethylphenol. In contrast, 3,4,6-tri-O-acetyl-d-glucal furnished the Ferrier rearrangement product, 2,6-dimethylphenyl 4,6-di-O-acetyl-2,3-dideoxy-α-d-erythro-hex-2-enopyranoside. Also, isomerization of 3,4,6-tri-O-alkyl-d-glycals to products of allylic rearrangement, 2,3-unsaturated-O-glycosides in good yields is reported.     

Preparation of piperazine derivatives as 5-HT7 receptor antagonists

Twenty-four compounds of 4-methoxy-N-[3-(4-substituted phenyl-piperazine-1-yl)propyl] benzene sulfonamides and N-[3-(4-substituted phenyl-piperazine-1-yl)propyl] naphthyl sulfonamides were prepared and evaluated as 5-HT(7) receptor antagonists. Most of the compounds showed the IC(50) values of 12-580nM. Four methyl branched analogues were also obtained, but the activity for methyl branched analogues was almost same as its straight chain congeners. Among the synthesized compounds, 3c showed a good activity on 5-HT(7) receptors and a good selectivity on 5-HT(1a), 5-HT(2a), 5-HT(2c), and 5-HT(6) receptors.     

The synthesis and structure of the derivatives of 2-deoxy-2-hydroxyimino-D-lyxo-hexopyranosyl-L-cysteine and -thiophenol

3,4,6-Tri-O-acetyl-2-deoxy-2-hydroxyimino-beta and -alpha-D-lyxo-hexopyranosides of thiophenol (3, 4) and the methyl ester of N-benzoyl-L-cysteine have been synthesised by condensation of 3,4,6-tri-O-acetyl-2-deoxy-2-nitroso-alpha-D-galactopyranosyl chloride with thiophenol and the L-cysteine derivative, respectively. The conformation of the sugar residue and configuration of the anomeric centre as well as of the hydroxyimino group were established on the basis of the 1H NMR (DQF-COSY, ROESY, TOCSY) spectrometric techniques and polarimetric data. Additionally, the structure of S-[3,4,6-tri-O-acetyl-2-deoxy-2-(Z)-hydroxyimino-beta-D-lyxo -hexopyranosyl]-thiophenol (3) was supported by X-ray diffraction data.     

The thulium complex of 1,4,7,10-tetrakis{[N-(1H-imidazol-2-yl)carbamoyl]methyl}-1,4,7,10-tetraazacyclododecane (dotami) as a ParaCEST contrast agent

1,4,7,10-Tetrakis{[N-(1H-imidazol-2-yl)carbamoyl]methyl}-1,4,7,10-tetraazacyclododecane (dotami), a tetra(1H-imidazol-2-yl) derivative of the well-studied octadentate 1,4,7,10-tetrakis[(carbamoyl)methyl]-1,4,7,10-tetraazacyclododecane (dotam) ligand, was synthesized by reaction of 1,4,7,10-tetraazacyclododecane with N-(1H-imidazol-2-yl)chloroacetamide in high yield. Its tricationic thulium complex was isolated as a water-soluble chloride salt. The detection of the mildly acidic amide and amine protons by direct proton NMR in aqueous solution was unsuccessful, but such exchangeable protons could be detected via their chemical exchange-dependent saturation transfer (CEST) effect. The observed CEST effect was distinctly different from that found for respective dotam complexes and is, therefore, ascribed to exchangeable protons associated with the imidazole substituent.     

A convenient synthetic route to the disaccharide repeating-unit of peptidoglycan

Glycosylation of the readily accessible benzyl 2-acetamido-6-O-benzyl-2-deoxy-3-O-[(R)-1-(methoxycarbonyl)ethyl]-alpha- D- glucopyranoside with 3,4,6-tri-O-acetyl-2-deoxy-2-phthalimido-beta-D-glucopyranosyl chloride (2), using the silver triflate method in the absence of a base, afforded 65-70% of the fully protected [beta-D-GlcNPhth-(1----4)-MurNAc] methyl ester derivative 4, the structure of which was ascertained on the basis of 500-MHz 1H-n.m.r. data. 2,2'-Dideoxy-2,2'-diphthalimido-beta,beta-trehalose hexa-acetate was a by-product. Removal of the Phth group from 4, followed by acetylation, yielded 90% of the acetylated 1,6-di-O-benzyl derivative 5, which, on saponification and catalytic hydrogenation, afforded 2-acetamido-4-O-(2-acetamido-2-deoxy-beta-D-glucopyranosyl)-3-O-[(R)-1- carboxyethyl]-2-deoxy-D-glucopyranose. Similarly, 5 was converted into the acetylated methyl ester derivative, which, on selective removal of the methyl ester group, gave benzyl 2-acetamido-4-O-(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-beta-D- glucopyranosyl)-6-O-benzyl-3-O-[(R)-1-carboxyethyl]-2-deoxy-alpha-D- glucopyranoside. An alternative route for the preparation of 2 is described.     

Synthesis of some D-mannosyl-oligosaccharides containing the methyl and 4-nitrophenyl beta-D-mannopyranoside units

Methyl 3,4,6-tri-O-benzyl-beta-D-mannopyranoside (2), methyl 2,3-O-isopropylidene-beta-D-mannopyranoside (11), and 4-nitrophenyl 2,3-O-isopropylidene-beta-D-mannopyranoside (12) were each condensed with 2,3,4,6-tetra-O-acetyl-alpha-D-mannopyranosyl bromide (1) in the presence of mercuric cyanide, to give after deprotection, methyl 2-(5) and 6-O-alpha-D-mannopyranosyl-beta-D-mannopyranoside (15), and 4-nitrophenyl 6-O-alpha-D-mannopyranosyl-beta-D-mannopyranoside (20), respectively. A similar condensation of 11 with 3,4,6-tri-O-acetyl-2-O-(2,3,4,6-tetra-O-acetyl-alpha-D-mannopyranosyl)-a lpha-D- mannopyranosyl bromide (21) and 2,3,4-tri-O-acetyl-6-O-(2,3,4,6-tetra-O-acetyl-alpha-D-mannopyranosyl)-a lpha D-mannopyranosyl bromide (25), followed by removal of protecting groups, afforded methyl O-alpha-D-mannopyranosyl-(1----2)-O-alpha-D-mannopyranosyl-(1----6)-beta -D- mannopyranoside (24) and methyl O-alpha-D-mannopyranosyl-(1----6)-O-alpha-D-mannopyranosyl-(1----6)-beta -D- mannopyranoside (28), respectively. Bromide 25 was also condensed with 12 to give a trisaccharide derivative which was deprotected to furnish 4-nitrophenyl O-alpha-D-mannopyranosyl-(1----6)-alpha-D-mannopyranosyl-(1----6)-beta-D - mannopyranoside (31). Phosphorylation of methyl 3,4,6-tri-O-benzyl-2-O-alpha-D-mannopyranosyl-beta-D-mannopyranoside and 15 with diphenyl phosphorochloridate in pyridine gave the 6'-phosphates 6 and 16, respectively. Hydrogenolysis of the benzyl and phenyl groups provided methyl 2-O-(disodium alpha-D-mannopyranosyl 6-phosphate)-beta-D-mannopyranoside (7) and methyl 6-O-(disodium alpha-D-mannopyranosyl 6-phosphate)-beta-D-mannopyranoside (17) after treatment with Amberlite IR-120 (Na+) cation-exchange resin. The structures of compounds 5, 7, 15, 17, 20, 24, 28, and 31 were established by 13C-n.m.r. spectroscopy.