Synthesis of mannoheptose derivatives and their evaluation as inhibitors of the lectin LecB from the opportunistic pathogen Pseudomonas aeruginosa.

Biofilm formation and chronic infections with Pseudomonas aeruginosa depend on lectins produced by the bacterium. The bacterial C-type lectin LecB binds to the two monosaccharides l-fucose and d-mannose and conjugates thereof. Previously, d-mannose derivatives with amide and sulfonamide substituents at C6 were reported as potent inhibitors of the bacterial lectin LecB and LecB-mediated bacterial surface adhesion. Because d-mannose establishes a hydrogen bond via its 6-OH group with Ser23 of LecB in the crystal structure and may be beneficial for binding affinity, we extended d-mannose and synthesized mannoheptoses bearing the free 6-OH group as well as amido and sulfonamido-substituents at C7. Two series of diastereomeric mannoheptoses were synthesized and the stereochemistry was determined by X-ray crystallography. The potency of the mannoheptoses as LecB inhibitors was assessed in a competitive binding assay. The data reveal a diastereoselectivity of LecB for (6S)-mannoheptose derivatives with increased activity over methyl α-d-mannoside.

Selective 4,6-O-benzylidene formation of methyl α-D-mannopyranoside using 2,6-dimethylbenzaldehyde.

While methyl α-d-glucopyranosides and α-d-galactopyranosides selectively form 4,6-O-benzylidenes when reacted with excess benzaldehyde in the presence of acid catalyst methyl α-d-mannopyranosides does not exhibit the same selectivity because of the cis-arrangement of the C2 and C3 hydroxyl groups. The selectivity for the 4,6-O-benzylidene is restored by using 2,6-dimethylbenzaldehyde instead of benzaldehyde. In addition the excess 2,6-dimethylbenzaldehyde is easily recovered from the reaction by extraction with petroleum ether and can be reused without further purification. The 2,6-dimethylbenzylidene exhibits properties similar to the unsubstituted benzylidene with regard to chemical synthesis.

Solid-state NMR characterization of the molecular conformation in disordered methyl α-L-rhamnofuranoside.

A combination of solid-state (13)C NMR tensor data and DFT computational methods is utilized to predict the conformation in disordered methyl α-L-rhamnofuranoside. This previously uncharacterized solid is found to be crystalline and consists of at least six distinct conformations that exchange on the kHz time scale. A total of 66 model structures were evaluated, and six were identified as being consistent with experimental (13)C NMR data. All feasible structures have very similar carbon and oxygen positions and differ most significantly in OH hydrogen orientations. A concerted rearrangement of OH hydrogens is proposed to account for the observed dynamic disorder. This rearrangement is accompanied by smaller changes in ring conformation and is slow enough to be observed on the NMR time scale due to severe steric crowding among ring substituents. The relatively minor differences in non-hydrogen atom positions in the final structures suggest that characterization of a complete crystal structure by X-ray powder diffraction may be feasible.

From mannose to morphan analogues: methyl α-D-mannoside as chiral building block for the synthesis of mono- and bicyclic σ receptor ligands.

Previously the synthesis and high σ(1) receptor affinity of mannose derived pyrans 3-5 with equatorially oriented amino groups have been reported. Herein the synthesis and receptor affinities of the corresponding axially substituted pyrans and oxa-morphans are described. Key step in the diastereoselective synthesis was an S(N)2 substitution of tosylate 10 with NaN(3). Heating of the azide 6 with acid led unexpectedly to the oxa-morphan 13, which showed remarkable affinity toward the σ(1) receptor (K(i)=860 nM). The benzylamine 15α and the dimethylamine 16α were obtained by reduction of the azide 6 and subsequent reductive alkylation. In contrast to the equatorial amines 3-5, the axial amines 15α and 16α did not interact with the σ(1) receptor or another investigated receptor system.

Asymmetric synthesis of methyl 6-deoxy-3-O-methyl-alpha-L-mannopyranoside from a non-carbohydrate precursor.

A novel method is reported for preparing methyl 6-deoxy-3-O-methyl-alpha-L-mannopyranoside (1) by asymmetric synthesis, using 2-acetylfuran (2), a non-chiral simple molecule, as the starting material and achieving high yields via (S)-1-(2-furyl)ethanol and (S)-1-(2,5-dihydro-2,5-dimethoxy-2-furyl)ethanol.

Mannose derived hexacoordinated phosphate--a generally efficient chiral anion for asymmetric applications.

Mannose derived hexacoordinated phosphate--prepared in two steps from methyl-alpha-D-mannopyranoside--is a chiral anionic auxiliary with broad asymmetric efficiency.

Synthesis, intramolecular migrations and enzymic hydrolysis of partially pivaloylated methyl alpha-D-mannopyranosides.

A series of methyl O-pivaloyl-alpha-D-mannopyranosides was synthesized using pivaloyl chloride in pyridine. The 3,6-di-O-pivaloyl derivative 6 undergoes intramolecular transesterification in neutral conditions (buffer, pH 7.2) to give its 2,6-di-O-pivaloyl analogue 5. The course of this migration was followed using 14C-labelled 6. As opposed to 6 compound 5 was shown to be a good substrate for esterases present in rabbit serum. Thus, regioselective enzymic hydrolysis led to the preferential cleavage of the 2-OPiv group to yield a mixture of 2- and 6-O-monopivalates in a ratio of 1:2.6.

Improved synthesis and the crystal structure of methyl 4,6-dideoxy-4-(3-deoxy-L-glycero-tetronamido)-alpha-D-mannopyrano side, the methyl alpha-glycoside of the intracatenary repeating unit of the O-polysaccharide of Vibrio cholerae O:1.

The crude product of deamination of the commercially available L-homoserine was acetylated and the 2-O-acetyl-3-deoxy-L-glycero-tetronolactone (18) formed was used to N-acylate methyl perosaminide (methyl 4-amino-4,6-dideoxy-alpha-D-mannopyranoside, 12) and its 2,3-O-isopropylidene derivative. The major product isolated from the reaction was the crystalline methyl 4-(4-O-acetyl-3-deoxy-L-glycero-tetronamido)-4,6-dideoxy-alpha-D-+ ++mannopyranoside (1, 70-75%) resulting from acetyl group migration in the initially formed 2'-O-acetyl derivative. O-Deacetylation of 1 gave the title amide 2. Compound 2, obtained crystalline for the first time, was fully characterized, and its crystal structure was determined. Deoxytetronamido derivatives diastereomeric with 1 and 2, respectively, were obtained by the acylation of 12 with 2-O-acetyl-3-deoxy-D-glycero-tetronolactone (prepared from D-homoserine), and subsequent deacetylation. Structures of several byproducts of the reaction of 12 with 18 have been deduced from their spectral characteristics. Since these byproducts were various O-acetyl derivatives of 2, the title compound could be obtained in approximately 90% yield by deacetylating (Zemplén) the crude mixture of N-acylation products, followed by chromatography.

Synthesis of an artificial antigen that corresponds to a disaccharide repeating unit of the capsular polysaccharide of Haemophilus influenzae type d. A facile synthesis of methyl 2-acetamido-2-deoxy-beta-D-mannopyranoside.

The synthesis is described of p-nitrophenyl 2-acetamido-3-O-(2-acetamido-2-deoxy-beta-D-glucopyranosyl)-2-deoxy-beta -D- mannopyranosiduronic acid, corresponding to the disaccharide repeating unit of the capsular polysaccharide of Haemophilus influenzae type d, which, after conversion of the p-nitro- into a p-amino-phenyl residue, may be attached to a protein to make an artificial antigen for immunological studies. The synthesis incorporates a facile route to the 2-acetamido-2-deoxy-beta-D-mannopyranosyl unit.

Stereoselective total synthesis of glycopeptides bearing the dimeric and trimeric sialosyl-Tn epitope.

The dimeric and trimeric sialosyl-Tn epitopes, [alpha-D-Neup5Ac-(2----6)-alpha-D-GalpNAc-(1----3)-L-Ser]n-L-Val (n = 2 and 3), which represent part of a clustered carbohydrate region of glycophorin A, a human erythrocyte glycoprotein, have been synthesised stereoselectively. 2-Azido-3-O-benzyl-4,6-O-benzylidene-2-deoxy-D-galactopyranosyl fluoride (GalpNAc unit), Fmoc-L-serine phenacyl ester (Ser unit), and benzyl 5-acetamido-4,7,8,9-tetra-O-benzyl-5-deoxy-3-S-phenyl-3-thio-D-erythro-L - gluco-2-nonulopyranosylonate bromide (Neup5Ac unit) were the key intermediates for stereoselective glycosylation. 2-Ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline-promoted elongation of the peptide chain and then hydrogenolysis afforded the title compounds.

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.

[Synthetic studies of polyene macrolide antibiotics. 2. Synthesis of methyl-4,6-dideoxy-2,3-isopropylidene-4-C-methyl-alpha-L- mannopyranoside]. / Sinteticheskie issledovaniia v riadu polienovykh makrolidnykh antibiotikov. 2. Sintez metil-4,6-didezoksi-2,3-O-izopropiliden-4-C-metil-alpha-L- mannopiranozida.

The synthesis of methyl 4,6-dideoxy-2,3-O-isopropylidene-4-C-methyl-alpha-L-mannopyranoside, a key intermediate on the preparation of C33-C38 fragment of amphotericin B, from L-rhamnose is described.