Intramolecular azide-alkene cycloaddition-elimination reaction in an aldohex-2-enonic acid derivative.

A 6-azido-2-tosylenolate, obtained from D-glucono-1,5-lactone in six steps, underwent an intramolecular cycloaddition-elimination pathway under mild conditions, yielding a chiral, substituted 5,6-dihydro-4H-pyrrolo[1,2-c]-1,2,3-triazole. The conditions were optimized to give exclusive formation of the triazole. The mechanism appears to involve intramolecular ring closure via a 1,3-dipolar azide-alkene cycloaddition to give a 1,2,3-triazoline, followed by elimination of p-toluenesulfonic acid, leading to aromatization. Triazole products, obtained by chemical modification, are expected to display activity as enzyme inhibitors. Furthermore, partially protected derivatives of the 2-hexenoate were prepared as useful synthetic intermediates.

Synthesis of Enantiomeric Polyhydroxyalkylpyrrolidines from 1,3-Dipolar Cycloadducts. Evaluation as Inhibitors of a ß-Galactofuranosidase.

Enantiomeric 2,3,4-tris(hydroxyalkyl)-5-phenylpyrrolidines have been synthesized from the major cycloadducts obtained by the 1,3-dipolar cycloaddition of sugar enones with azomethine ylides derived from natural amino acids. Reduction of the ketone carbonyl group of the cycloadducts, which possess a basic structure of bicyclic 6-(menthyloxy)hexahydropyrano[4,3-c]pyrrol-7(6H)one, afforded a number of pyrrolidine-based bicyclic systems. A sequence of reactions, which involved hydrolysis of the menthyloxy substituent, reduction, N-protection, and degradative oxidation, afforded varied pyrrolidine structures having diverse configurations and patterns of substitution; in particular, polyhydroxylated derivatives have been obtained. The unprotected products were isolated as pyrrolidinium trifluoroacetates. Because of the furanose-like nature of the target trihydroxyalkyl pyrrolidines, these molecules have been evaluated as inhibitors of the ß-galactofuranosidase from Penicillium fellutanum. The compounds showed practically no inhibitory activity for concentration of pyrrolidines in the range of 0.1-1.6 mM.

Stereospecific synthesis of pyrrolidines with varied configurations via 1,3-dipolar cycloadditions to sugar-derived enones.

Enantiomerically pure pyrrolidines have been obtained by 1,3-dipolar cycloaddition of stabilized azomethine ylides and sugar enones (dihydropyranones) derived from pentoses. Thus, the S-enone (menthyl 3,4-dideoxy-(1S)-pent-3-enopyranosid-2-ulose) was prepared from D-xylose, while the R analogue was obtained from L-arabinose. The dipoles were generated in situ from α-arylimino esters of common amino acids (glycine, alanine, or phenylalanine) and aromatic aldehydes (benzaldehyde, 3-formylpyridine and 4-methoxybenzaldehyde). Under optimized conditions, the cycloaddition reactions were highly diastereo- and regioselective to yield, in most of the cases, a very major adduct of the 16 theoretically possible. The diastereoselectivity relies on the strict stereocontrol exerted by the stereogenic center of the pyranone. Thus, the (S)-enone, derived from D-xylose, gave tetrasubstituted pyrrolidines having a defined stereochemistry for the four stereocenters of the ring, while they had the opposite configuration when starting from the (R)-dihydropyranone. Furthermore, some endo-cycloadducts underwent isomerization of the carbons vicinal to the nitrogen atom to afford pyrrolidines with a rather unusual stereochemistry for the direct dipolar cycloadditions.

Synthesis of the (1→6)-linked thiodisaccharide of galactofuranose: inhibitory activity against a ß-galactofuranosidase.

A new (1→6)-linked thiodisaccharide formed by two galactofuranosyl units has been synthesized. Methyl (methyl α,ß-D-galactofuranosid)uronate was employed as the starting compound, which was per-O-silylated with TBSCl and reduced with LiAlH4 to afford methyl 2,3,5-tri-O-tert-butyldimethylsilyl-ß-D-galactofuranoside (2ß) as a key precursor for the preparation of methyl per-O-tert-butyldimethylsilyl-6-thio-ß-D-galactofuranoside (12). The free thiol group of 12 was glycosylated and the product O-deprotected to afford the target ß-D-Galf-S-(1→6)-ß-d-Galf-OMe (14). The conformations of this thiodisaccharide were preliminarily studied using combined theoretical calculations and NMR data. Furthermore, the glycomimetic 14 showed to be a competitive inhibitor of the ß-galactofuranosidase from Penicillum fellutanum (K(i)=3.62 mM).

Synthesis of branched dithiotrisaccharides via ring-opening reaction of sugar thiiranes.

Satisfactory procedures are described for the synthesis of 5,6- and 3,4-thiirane derivatives from the respective hexofuranose or hexopyranose epoxide precursors. The controlled ring-opening reaction of thiiranes by 1-thioaldoses was successfully accomplished to afford, regio- and stereoselectively, ß-S-(1→4)-3,4-dithiodisaccharides. For instance, the regioselective attack of per-O-acetyl-1-thioglucose (16) to C-4 of 2-propyl 2,6-di-O-acetyl-3,4-epithio-α-D-galactopyranoside (14) gave the derivative of Glcp-ß-S-(1→4)-3,4-dithioGlcp-O-iPr (17). This thiodisaccharide was accompanied by the (1→3)-disulfide 18, formed between 16 and 17, and the symmetric (3→3)-disulfide 19, which resulted from the oxidative dimerization of 17. However, the S-acetyl derivative of 17 could be obtained in good yield (62%) by LiAlH(4) reduction of the crude mixture 17-19, followed by acetylation. The same sequence of reactions starting from 14 and the 1-thiolate of Galp afforded the per-O,S-acetyl derivative of Galp-ß-S-(1→4)-3,4-dithio-α-D-Glcp-O-iPr (23), which was selectively S-deacetylated to give 25. The dithiosaccharides 17 and 25 are 3,4-di-S-analogues of derivatives of the natural disaccharides cellobiose and lactose, respectively. The ring-opening reaction of 5,6-epithiohexofuranoses of D-galacto (8) or L-altro (11) configuration with 1-thioaldoses was also regio- and stereoselective to give the respective ß-S-(1→6)-linked 5,6-dithiodisaccharides 26 or 29 in excellent yields. Glycosylation of the free thiol group of 17, 25, or 26, using trichloroacetimidates as glycosyl donors, led to the corresponding branched dithiotrisaccharides. Some of them are sulfur analogues of derivatives of branched trisaccharides found in natural polysaccharides.

Thiodisaccharides with galactofuranose or arabinofuranose as terminal units: synthesis and inhibitory activity of an exo beta-D-galactofuranosidase.

Thiodisaccharides having beta-D-Galf or alpha-L-Araf units as non-reducing end have been synthesized by the SnCl(4)- or MoO(2)Cl(2)-promoted thioglycosylation of per-O-benzoyl-D-galactofuranose (1), its 1-O-acetyl analogue 4, or per-O-acetyl-alpha-L-arabinofuranose (16) with 6-thioglucose or 6-thiogalactose derivatives. After convenient removal of the protecting groups, the free thiodisaccharides having the basic structure beta-D-Galf(1-->6)-6-thio-alpha-D-Glcp-OMe (5) or beta-D-Galf(1-->6)-6-thio-alpha-D-Galp-OMe (15) were obtained. The respective alpha-L-Araf analogues 18 and 20 were prepared similarly from 16. Alternatively, beta-D-Galf(1-->4)-4-thio-3-deoxy-alpha-L-Xylp-OiPr was synthesized by Michael addition to a sugar enone of 1-thio-beta-d-Galf derivative, generated in situ from the glycosyl isothiourea derivative of 1. The free S-linked disaccharides were evaluated as inhibitors of the beta-galactofuranosidase from Penicillium fellutanum, being 15 and 20 the more active inhibitors against this enzyme.

Synthesis, spectroscopic and biological properties of bis(3-arylimidazolidinyl-1)methanes. A novel family of antimicrobial agents.

Synthesis, spectroscopic and biological properties of new bis(3-arylimidazolidinyl-1)methanes are described. These compounds were synthesized by condensation reaction between N-arylethylenediamines and formaldehyde. Chemical structures were confirmed by means of their (1)H- and (13)C-NMR and mass spectroscopic data. Investigation of in vitro antimicrobial activity was performed using Gram-negative and Gram-positive bacteria as well as antifungal studies against Aspergillus niger and Candida albicans. Minimal inhibitory concentrations of active compounds were determined.