András Neszmélyi

Chemo-, stereo- and regioselective hydrogenolysis of carbohydrate benzylidene acetals. Synthesis of benzyl ethers of benzyl α-d-, methyl β-D-mannopyranosides and benzyl α-D-rhamnopyranoside by ring cleavage of benzylidene derivatives with the LiAlH4-AlCl3 reagent

Abstract Treatment of benzyl α-(1) and methyl β- d -mannopyranoside (2) with α,α-dimethoxytoluene gave the exo and endo isomers (3,5 and 4,6) of the dibenzylidene derivatives of 1 and 2. Hydrogenolysis of the exo isomers (3 and 5) with a molar equivalent of AlH2Cl gave the 3-0-benzyl-4,6-0-benzylidene derivatives (7 and 21), whereas the endo isomers (4 and 6) gave the 2-0-benzyl-4,6-0-benzylidene compounds (8 and 22). The 2-0-allyl ether 9 of 7, the 3-0-allyl derivative (10) of 8 and compounds 21 and 22 were treated with an additional molar equivalent of AlH2Cl at reflux and the products were the 4-0-benzyl-6-hydroxyl derivatives (11, 12, 23 and 24), whereas in the case of 22 the 6-0-benzyl-4-hydroxyl isomer (25) was also isolated. By deallylation of 11 and 12, 3,4-(13) and 2,4-di-0-benzyl (14) ethers of 1 were prepared. Tosylation of 11 and 12, and subsequent reduction of the products (15 and 16) made possible the preparation of the partially protected benzyl α- d -rhamnopyranoside derivatives (17–20). The structures of the compounds synthesized were characterized by 1H and 13C NMR spectroscopic investigation and by chemical methods.

Synthesis and 13C-NMR spectroscopic investigations of rhamnobioses

Abstract A convenient method has been developed for the synthesis of all mono- and di-O-benzyl ethers of methyl α-L-rhamnopyranoside applying a new stereoselective method for the hydrogenolytic ring-cleavage of benzylidene acetals. Using the prepared dibenzyl ethers as aglycones, the (1→2)-, (1→3)- and (l→4)-linked rhamnosyl-rhamnose derivatives ( 13 – 15 ) were synthesised. Hydrogenolysis of the latter compounds and subsequent acetylation gave the pentaacetates ( 16 – 18 ) of methyl dirhamnosides, which on saponification furnished the free methyl dirhamnosides ( 19 – 21 ). Acetolysis of 16 – 18 gave the corresponding dirhamnose-hexaacetates which were transformed into the three disaccharides by saponification. The structure of each product was investigated by 13 C-NMR spectroscopy, and for the purpose of 13 C-NMR studies the mono-O-methyl ethers of methyl α-L-rhamnopyranoside, the diacetates and di-O-benzyl ethers of the latter compounds, and, also the diacetates of methyl α-L-rhamnopyranoside were synthesised. It has been established that, for 13 C-NMR investigations of oligosaccharides, the benzyl ethers of monosaccharides are more suitable model compounds than the currently used monosaccharide methyl ethers.

Inhibition of the human leukocyte endopeptidases elastase and cathepsin G and of porcine pancreatic elastase by N-oleoyl derivatives of heparin

N-oleoyl-heparin derivatives differing in their oleic acid and sulfate contents were synthesized and studied for their abilities to inhibit human leukocyte elastase (HLE), human leukocyte cathepsin G (CatG) and porcine pancreatic elastase (PPE) at pH 8.0, ionic strength 0.05 M and 37 degrees. Heparin (Hep) as well as N-oleoyl-heparins behaved as tight-binding, hyperbolic noncompetitive inhibitors of HLE (KiHep = 75 pM) and CatG (KiHep < 25 pM). The main driving force for the interaction between enzymes and glycosaminoglycans was electrostatic in nature. Under the condition [enzyme] >> Ki, the stoichiometries of the interaction with Hep were 1:2 (Hep:HLE) and 1:4 (Hep:CatG). Coupling one oleic acid residue to three disaccharide units of partially N-desulfated Hep, Ol1:3Hep, lowered HLE inhibition (Ki = 0.3 nM) and the stoichiometry of binding was reduced to 1:1. Re-N-sulfation of a similar derivative, Ol1:5Hep(SO4), containing one fatty acid residue for five disaccharide units, led to a substance with similar HLE inhibitory characteristics as Hep (Ki = 92 pM) and stoichiometry 1:2. Ol1:5Hep(SO4) was also a more efficient inhibitor of CatG (Ki < 33 pM) than Ol1:3Hep (Ki = 9.5 nM). The residual activities of N-oleoyl-Hep complexes with CatG were much lower than the corresponding activities in the presence of Hep. While oleate and Hep could not inhibit PPE, N-oleoyl-Hep, independently of fatty acid substitution and sulfate content, could inhibit this enzyme with Ki congruent to 60 nM and low residual activity. The efficient endopeptidase inhibitory characteristics of N-oleoyl-Hep derivatives, together with their non-anticoagulant properties and their capacity to interact with elastin, may be therapeutically useful in connective tissue degenerative diseases.

Enantiomerically pure chiral pyridino-crown ethers: Synthesis and enantioselectivity toward the enantiomers of α-(1-naphthyl)ethylammonium perchlorate

Abstract Seven new enantiomerically pure chiral pyridino-crown ethers ( S,S )- 4 –( R,R )- 10 were prepared. Three of them [( S,S )- 4 , ( S,S )- 7 and ( R,R )- 10 ] contain one, and two of them [( S,S )- 5 and ( S,S )- 8 ] contain two linker chains with a terminal double bond. These linker chains were connected to the carbon atom at position 9 (opposite the pyridine moiety) of the macrocycle. The terminal double bond of the linker makes it possible to attach these ligands to silica gel to obtain chiral stationary phases (CSPs). The enantioselectivity of the new ligands toward the enantiomers of α-(1-naphthyl)ethylammonium perchlorate (NEA) was also determined by a titration 1 H NMR method.

Synthesis, and carbon-13 n.m.r. study, of O-α-l-rhamnopyranosyl-(1→3)-O-α-l-rhamnopyranosyl-(1→2)-l-rhamnopyranose and O-α-l-rhamnopyranosyl-(1→3)-O-α-l-rhamnopyranosyl (1→3)-l-rhamnopyranose, constituents of bacterial, cell-wall polysaccharides

Abstract O -α- l -Rhamnopyranosyl-(1→3)- l -rhamnopyranose ( 19 ) and O -α- l -rhamnopyranosyl-(1→2)- l -rhamnopyranose were obtained by reaction of benzyl 2,4- ( 7 ) and 3,4-di- O -benzyl-α- l -rhamnopyranoside ( 8 ) with 2,3,4-tri- O -acetyl-α- l -rhamnopyranosyl bromide, followed by deprotection. The per- O -acetyl α-bromide ( 18 ) of 19 yielded, by reaction with 8 and 7 , the protected derivatives of the title trisaccharides ( 25 and 23 , respectively), from which 25 and 23 were obtained by Zemplen deacetylation and catalytic hydrogenolysis, With benzyl 2,3,4-tri- O -benzyl-β- d -galactopyranoside, compound 18 gave an ≈3:2 mixture of benzyl 2,3,4-tri- O -benzyl-6- O -[2,4-di- O -acetyl-3- O -(2,3,4-tri- O -acetyl-α- l -rhamnopyranosyl)-α- l -rhamnopyranosyl]-β- d -galactopyranoside and 4- O -acetyl-3- O -(2,3,4-tri- O -acetyl-α- l -rhamnopyranosyl)-β- l -rhamnopyranose 1,2-(1,2,3,4-tetra- O -benzyl-β- d -galactopyranose-6-yl (orthoacetate). The downfield shift at the α-carbon atom induced by α- l -rhamnopyranosylation at HO-2 or -3 of a free α- l -rhamnopyranose is 7.4-8.2 p.p.m., ≈1 p.p.m. higher than when the (reducing-end) rhamnose residue is benzyl-protected (6.6-6.9 p.p.m.). α- l -Rhamnopyranosylation of HO-6 of gb- d -galactopyranose deshields the C-6 atom by 5.7 p.p.m. The 1 2-orthoester ring structure [O 2 ,C(me)OR] gives characteristic resonances at 24.5 ±0.2 p.p.m. for the methyl, and at 124.0 ±0.5 p.p.m. for the quaternary, carbon atom.

Synthesis of 2-O-α-, 3-O-α-, 3-O-β-, and 4-O-α-l-rhamnopyranosyl-d-galactose

Condensation of benzyl 3-O-benzoyl-4,6-O-benzylidene-, benzyl 2-O-benzoyl-4,6-O-benzylidene- (2), and benzyl2,3,6-tri-O-benzyl-⨿-d-galactopyranoside, separately, with tri-O-acetyl-α-l-rhamnopyranosyl bromide gave mainly α-linked disaccharide derivatives. An appreciable proportion of the ⨿-linked disaccharide was also obtained from 2. An anomalous deacylation reaction was found for the (1→3)-linked disaccharide, and the partially benzoylated products were isolated and characterised. The anomeric configuration of each disaccharide was established on the basis of JC-1,H-1 values. The chemical shifts for the galactose moieties of the α- and β-l-rhamnopyranosyl derivatives differed in a systematic way.

Triumbellin, A tricoumarin rhamnopyranoside from Daphne mezereum

Abstract From Daphne mezereum bark, a new tricoumarin glycoside, triumbellin and the corresponding aglycone triumbelletin were isolated and structurally elucidated by one- and TD-HF-NMR spectroscopy including two dimensional phase sensitive NOE experiments as 7-O-(α- l -rhamnopyranosyl)-3-[(2-oxo-2H-1-benzopyran-7-yl)oxy]-8-(2-oxo-2H-1-benzopyran-8-yl)-2H-1-benzopyran-2-one. The possible molecule conformations in solution were examined by theoretical conformation energy calculations. Beside the known coumarins daphnetin, umbelliferone, daphnoretin and daphnorin as well as the known diterpene esters daphnetoxin and mezerein, the following compounds are reported for the first time from this plant: the coumarins 7-hydroxy-8-methoxycoumarin and daphnorin-6″-hydroxymethylglutarate (rutarensin), the coumarinolignan daphneticin, the lignans, lariciresinol, syringaresinol, pinoresinol and dihydrosesamin and the diterpene esters gniditrin and daphneolone.

Synthesis of 4-O-α-d-galactopyranosyl-l-rhamnose and 4-O-α-d-galactopyranosyl-2-O-β-glucopyranosyl-l-rhamnose using dioxolane-type benzylidene acetals as temporary protecting-groups

Abstract The Halide ion-catalysed reaction of benzyl exo -2,3- O -benzylidene-α- l -rhamnopyranoside with tetra- O -benzyl-α- d -galactopyranosyl bromide and hydrogenolysis of the exo -benzylidene group of the product 2 gave benzyl 3- O -benzyl-4- O -(2,3,4,6-tetra- O -benzyl-α- d -galactopyranosyl)-α- l -rhamnopyranoside ( 6 ). Compound 2 was converted into 4- O -α- d -galactopyranosyl- l -rhamnose. The reaction of 6 with tetra- O -acetyl-α- d -glucopyranosyl bromide and removal of the protecting groups from the product gave 4- O -α- d -galactopyranosyl-2- O -β- d -glucopyranosyl- l -rhamnose.

A synthesis of l-ristosamine and a derivative of its C-4 epimer

Abstract A synthesis of l -ristosamine from l -rhamnal is described, involving the sequence of reactions: methoxymercuration, tosylation, azide displacement, and reduction, which gave methyl α- l -ristosaminide (10) . Acid hydrolysis then afforded l -ristosamine hydrochloride. Trifluoroacetylation of the hydrochloride of 10 followed by saponification and oxidation with ruthenium tetraoxide gave methyl 2,3,6-tri-deoxy-3-trifluoroacetamido-α- l - erythro -hexopyranosid-4-ulose (17). Borohydride reduction of 17 gave a separable, 1:1 mixture of methyl 2,3,6-trideoxy-3-trifluoroacetamido-α- l - ribo - and α- l - xylo -hexopyranoside.

Synthesis and stereochemistry of substituted bi- and tri-cyclic 4,5-dihydropyrazoles

A series of bi- and tricyclic 4,5-dihydropyrazoles have been studied by 1H n.m.r. and 13C n.m.r. spectroscopy and X-ray crystallography. They were synthesised by treating the corresponding mono-and dibenzylidenecycloalkanones and 2-benzylidene-3,4-dihydronaphthalen-1(2H)-one with semi-carbazide, which gave two diastereoisomers, and thiosemicarbazide, which gave only one. The 1H n.m.r. parameters allowed an unambiguous identification of the diastereoisomers and the configuration of one of the isomeric pairs was confirmed by 13C n.m.r. spectroscopy and X-ray crystallography. The crystallographic analysis shows that the six-membered rings assume an intermediate shape between the chair, half-chair and envelope forms, while the five-membered rings have a perfect envelope conformation with C(5) on the flap.