Synthesis of a sulfonium ion analogue of the glycosidase inhibitor swainsonine

The synthesis of a bicyclic sulfonium ion analogue of a naturally occurring indolizidine alkaloid, swainsonine, in which the bridgehead nitrogen atom is replaced by a sulfonium ion, has been achieved by a multistep synthesis starting from (2S,3S,4R)-2,3-dibenzyloxy-4-formaldehyde-thiolane. The synthetic strategy relies on the intramolecular displacement of a leaving group on a pendant acyclic chain by a cyclic thioether. This bicyclic sulfonium salt provides a candidate with which to further probe the hypothesis that a sulfonium salt carrying a permanent positive charge would be an effective glycosidase inhibitor.     

New synthetic approach to enantiopure bicyclic sulfonium salts: swainsonine analogues

The enantioselective synthesis of bicyclic sulfonium salts 8 or 9, thioanalogues of swainsonine derivatives, is described. The synthetic strategy is based on a stereo- and regiospecific transannular cyclization reaction of nine-membered cyclic sulfides, mediated by Me(3)SiI or carried out under acidic catalysis.     

Stereoselective synthesis of the glycosidase inhibitor australine through a one-pot, double-cyclization strategy

[reaction: see text] A stereocontrolled, convergent synthesis of the alkaloid australine, a glycosidase inhibitor of the pyrrolizidine class, is described. The chiral starting materials were ketone 3, derived from L-erythrulose, and alpha-alkoxy aldehyde 4, prepared from L-malic acid. A key step of the synthesis was the highly stereoselective aldol reaction between 4 and a Z boron enolate derived from 3. Another key step was the one-pot construction of the bicyclic pyrrolizidine system by means of a three-step sequence of SN2 displacements induced by benzylamine on a trimesylate precursor.     

Synthesis of d- and l-erythro 1,5-dithiopent-1-enopyranoside sulfonium salts and their evaluation as glycosidase inhibitors

A series of sulfonium salts derived from 1,5-dithiopent-1-enopyranosides was prepared in a three-step sequence from protected d- and l-erythrofuranoses. The key step is the nucleophilic displacement of a leaving group by a sulfur atom of carbohydrate-derived ketene dithioacetals. Such compounds were assayed for their properties as glycosidase inhibitors.     

Synthesis and glycosidase inhibitory activity of isourea-type bicyclic sp2-iminosugars related to galactonojirimycin and allonojirimycin

A series of sp²-iminosugars featuring a fused piperidine–isourea bicyclic core and hydroxylation profiles of stereochemical complementarity with the ‘classical’ iminosugars galactonojirimycin and allonojirimycin have been prepared and their inhibitory activity evaluated against a panel of commercial glycosidases. The synthetic methodology involves 2-aminooxazoline pseudo-C-nucleosides, accessible from vic-hydroxycarbodiimide precursors, as key intermediates and is compatible with molecular diversity-oriented strategies. Alkyl, aryl and glycosyl substituents have been incorporated in order to assess the potential of non-glyconic interactions to modulate the enzyme selectivity. All the galactonojirimycin derivatives behaved as potent competitive inhibitors of β-glucosidases. The inhibition potency was higher for aliphatic substituents (in the nM range), but the highest selectivity within β-glucosidase isoenzymes was achieved for a N′-glucopyranosyl pseudodisaccharide analogue. Going from d-galacto to d-allo configuration further increased enzyme selectivity, but strongly penalized the inhibition potency.     

Synthesis and evaluation of isourea-type glycomimetics related to the indolizidine and trehazolin glycosidase inhibitor families

A practical synthesis of reducing isourea-derived azasugar glycomimetics related to the indolizidine and trehazolin glycosidase inhibitor families with different pK(a) values is disclosed. The polyhydroxylated bicyclic system was built from readily accessible hexofuranose derivatives through a synthetic scheme that involves the preparation of a 5-deoxy-5-carbodiimido adduct by triphenylphosphine-mediated tandem Staudinger--aza-Wittig-type coupling of azide and isothiocyanate precursors, intramolecular cyclization of a transient vic-hydroxycarbodiimide derivative, and nucleophilic addition of the endocyclic nitrogen atom of the generated 2-amino-2-oxazoline intermediate, with a pseudo-C-nucleoside structure, to the masked aldehyde group of the monosaccharide. The last step is pH-dependent so that the final compounds can pivot between the furanose and the 2-oxaindolizidine forms. Nevertheless, the indolizidine tautomer having the R configuration at the aminoacetalic center, fitting the anomeric effect, was the only species detected in solution at neutral or slightly acidic pH when starting from solutions at basic pH. Glycosidase inhibition tests (K(i) values down to 1.9 microM) showed a marked dependence of the selectivity and potency toward alpha- and beta-glucosidases upon the nature of the substituent at the exocyclic isourea nitrogen, shifting from alpha- to beta-selectivity when going from hydrophilic to hydrophobic substituents. Enzyme inhibition is also pH dependent, supporting a dominant role for the uncharged form of the polyhydroxyiminoindolizidine system in the inhibition of beta-glucosidases.     

Synthesis of some sulfonium salts and ylides containing the isoxazole nucleus

Some dimethylisoxazolylmethylsulfonium salts and the corresponding ylides were synthetized and their chemical behaviour studied. Dimethylsullonium-5-isoxazolyl methylides (XIa,b) give 5-isoxazolyloxiranes (XIIa,d) and XIII when allowed to react with carbonyl compounds. Ring opening products from these oxiranes are also reported.     

Synthesis and crystallographic analysis of a bicyclic core related to the esperamicin/calichemicin aglycones

The synthesis and crystallographic analysis of a bicyclic core related to the esperamicin/calichemicin aglycones is reported. A key reaction involves the skeletal rearrangement of a mesylate derived from a type II Diels-Alder cycloadduct.     

Synthesis of alkylated deoxynojirimycin and 1,5-dideoxy-1,5-iminoxylitol analogues: polar side-chain modification, sulfonium and selenonium heteroatom variants, conformational analysis, and evaluation as glycosidase inhibitors

The syntheses of N-alkylated deoxynojirimycin and 1,5-dideoxy-1,5-iminoxylitol derivatives having either a D- or an L-erythritol-3-sulfate functionalized N-substituent are reported. The alkylating agent used was a cyclic sulfate derivative, whereby selective attack of the nitrogen atom at the least hindered primary center afforded the desired ammonium salt. In aqueous solution, these salts were configurationally labile at the ammonium center. Sulfonium and/or selenonium analogues of the ammonium salts were prepared by analogous reactions. The chalcogen salts were obtained as mixtures of diastereomers, separable in some cases, differing only in the stereochemistry at the configurationally stable sulfur or selenium atoms. Proof of configuration and conformation of each compound was obtained by detailed NMR experiments. The compounds are six-membered ring analogues of salacinol, a known sulfonium-salt glucosidase inhibitor. Evaluation of the target compounds for enzyme inhibition of the glucosidase enzyme glucoamylase G2 indicated that these compounds were either inactive or, at best, only weak inhibitors of maltose hydrolysis.     

Synthesis and nitration of dimethyl-(3-thienyl)sulfonium salts

Conclusions A method was developed for the synthesis of the difficultly accessible methyl (5-nitro-3-thienyl) sulfide, which consisted in the conversion of methyl 3-thienyl sulfide to the sulfonium salt, with subsequent nitration and demethylation.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 5, pp. 1161–1163, May, 1973.     

Synthesis of selenium analogues of the naturally occurring glycosidase inhibitor salacinol and their evaluation as glycosidase inhibitors

The syntheses of two selenium analogues (10 and 11) of the naturally occurring sulfonium ion, salacinol (3), are described. Salacinol is one of the active principles in the aqueous extracts of Salacia reticulata that are traditionally used in Sri Lanka and India for the treatment of diabetes. The synthetic strategy relies on the nucleophilic attack of a 2,3,5-tri-O-benzyl-1,4-anhydro-4-seleno-D-arabinitol at the least hindered carbon of benzyl- or benzylidene-protected D- or L-erythritol-1,3-cyclic sulfate. The use of 1,1,1,3,3,3-hexafluoro-2-propanol as a solvent in the coupling reaction proves to be beneficial. Enzyme inhibition assays indicate that 10 is a better inhibitor (K(i) = 0.72 mM) of glucoamylase than 3, which has a K(i) value of 1.7 mM. In contrast, 11 showed no significant inhibition of glucoamylase. Compounds 10 and 11 showed no significant inhibition of barley-alpha-amylase or porcine pancreatic-alpha-amylase.     

The structure and conformational behavior of sulfonium salt glycosidase inhibitors in solution: a combined quantum mechanical NMR approach

We present the conformational analysis of an inhibitor of alpha-mannosidase, based on a novel sulfonium salt structure (1) that mimics the mannosyl cation intermediate. Because of the number of possible isomeric structures for 1, as well as its complex molecular structure, traditional conformational analysis by NMR was not applicable. Instead, a single experimentally consistent structure was obtained from finite perturbation quantum mechanical calculations of the NMR J-couplings at the B3LYP/6-311G** level. Using a full relaxation matrix analysis, we showed that the quantum-predicted NMR structure was the only isomer that was consistent with the experimental NOE intensities. The results illustrate the potential for finite perturbation calculations to be useful in the analysis of complex charged molecules.     

Synthesis of sulfonium sulfate analogues of disaccharides and their conversion to chain-extended homologues of salacinol: new glycosidase inhibitors

Four chain extended homologues of salacinol, a naturally occurring glycosidase inhibitor, were prepared for evaluation as inhibitors of glucosidase enzymes involved in the breakdown of carbohydrates. The syntheses involved the reactions of 1,4-anhydro-2,3,5-tri-O-benzyl-4-thio-D-arabinitol with cyclic sulfate derivatives of different monosaccharides. Debenzylation of the products afforded the novel sulfonium sulfate derivatives of D-glucose, D-galactose, D-arabinose, and D-xylose that are of interest in their own right as glycosidase inhibitors. Reduction to the corresponding alditols then afforded the homologues of salacinol containing polyhydroxylated, acyclic chains of 5- and 6-carbons, differing in stereochemistry at the stereogenic centers. Three of the chain-extended homologues inhibited recombinant human maltase glucoamylase, one of the key intestinal enzymes involved in the breakdown of glucose oligosaccharides in the small intestine, with Ki values in the low micromolar range, of approximately the same magnitude as salacinol, thus providing lead candidates for the treatment of Type 2 diabetes.     

Stereoselectivity in the alkylation of sulfonium salts

The stereoselectivity in the alkylation of sulfonium salts is attributed to the formation of an intermediate lithio-sulfonium salt rather than a free ylid.     

Electroorganic chemistry—XV : Electroreduction of sulfonium and ammonium salts. Formation of sulfonium ylids

In the electroreduction of sulfonium and ammonium salts, sulfonium ylid was generated from the sulfonium salt, whereas in the case of the ammonium salt, nitrogen ylid was not formed but the N+C bond was reductively cleaved. On the basis of the controlled potential electrolysis, it seems acceptable that the mechanism of formation of sulfonium ylid involves the direct electron transfer to the sulfonium salt as the initiation step.     

Synthesis of primary-alkyl selenols and selenides from primary-alkyl thiols involving diphenyl sulfonium salts

Hexyl thiol has been transformed to hexyl selenol and related selenides and selenocyanate by substitution of the corresponding hexyldiphenylsulfonium tetrafluoroborate with selenium nucleophiles.     

Sulfide extrusion from the methylsulfonium salts of 8-thiabicyclo [3.2.1]oct-2-enes and the related sulfonium salts by methyllithium

The methysulfonium salts of 2-methylene-8-thiabicyclo[3.2.1]octane and 8-thiabicyclo[3.2.1]oct-2-enes underwent sulfide extrusion by methyllithium to give dimethyl sulfide and the hydrogen shift products (cycloheptadienes) and/or the closure products (bicycloheptenes).     

Crystal structure of the sulfonium salts of natural azulenes

The molecular and crystal structure of dimethyl-(1,4-dimethyl-7-ethylazulyl)-sulfonium perchlorate and dimethyl-(1,4-dimethyl-7-isopropylazulyl)-sulfonium perchlorate was determined by X-ray diffraction analysis. Their crystal structure is mainly determined by C-H...π intermolecular interactions.     

Synthesis and conformational study of acridine derivatives related to 1,4-dihydropyridines

Novel acridine derivatives have been synthesized from dimedone and different aromatic aldehydes by following the classical Hantzsch's procedure. The particular substitution pattern of these compounds is responsible for the observed strong push-pull effect. Quantum chemical calculations were carried out on these molecules by using the AM1 method with complete geometry optimization. The calculated heats of formation reveal two equally favoured conformations. The parameter of planarity and the charge density calculations are in agreement with the ¹³C nmr spectroscopic data.