piperidines and fagomine

A range of enantiopure polyhydroxylated piperidines, including (2R,3S,4R)-dihydroxypipecolic acid, (-)-3-epi-fagomine, (2S,3S,4R)-dihydroxyhomopipecolic acid, (2S,3R,4R)-dihydroxyhomopipecolic acid, and two trihydroxy-substituted homopipecolic acids, have been prepared using diastereoselective olefinic oxidations of a range of enantiopure tetrahydropyridines as the key step. The requisite substrates were readily prepared from tert-butyl sorbate using our diastereoselective hydroamination or aminohydroxylation protocols followed by ring-closing metathesis. After diastereoselective olefinic oxidation of the resultant enantiopure tetrahydropyridines and deprotection, enantiopure polyhydroxylated piperidines were isolated as single diastereoisomers (>99:1 dr) in good overall yield.

Topics: Imino Pyranoses; Molecular Structure; Oxidation-Reduction; Pipecolic Acids; Piperidines; Stereoisomerism

A protecting-group-free synthetic strategy for the synthesis of piperidines has been explored. Key in the synthesis is an I2-mediated carbamate annulation, which allows for the cyclization of hydroxy-substituted alkenylamines into piperidines, pyrrolidines, and furans. In this work, four chiral scaffolds were compared and contrasted, and it was observed that with both d-galactose and 2-deoxy-d-galactose as starting materials, the transformations into the piperidines 1-deoxygalactonorjirimycin (DGJ) and 4-epi-fagomine, respectively, could be achieved in few steps and good overall yields. When d-glucose was used as a starting material, only the furan product was formed, whereas the use of 2-deoxy-d-glucose resulted in reduced chemo- and stereoselectivity and the formation of four products. A mechanistic explanation for the formation of each annulation product could be provided, which has improved our understanding of the scope and limitations of the carbamate annulation for piperidine synthesis.

Topics: 1-Deoxynojirimycin; Carbamates; Cyclization; Fucose; Imino Pyranoses; Molecular Structure; Piperidines; Stereoisomerism

To study the chemical constituents from the leaves of Morus multicaulis.. The compounds were isolated by ion exchange resin, silica gel and Sephadex LH -20 column chromatographies. Their structures were elucidated on the basis of physico-chemical properties and spectral data.. Twelve compounds were isolated from the leaves of this plant. Their structures were identified as 1-deoxynojirimycin (1), fagomine (2), 2-O-alpha-D-galactopyranosyl-1-deoxynojirimycin (3), quercetin-7-O-beta-D-glucoside (4), kaempferol (5), quercetin (6), scopoletin (7), D-aspartic acid (8), L-proline (9), D-alpha-alanine (10), myo-inositol (11) and dausterol (12).. All compounds were isolated from this plant for the first time.

Topics: 1-Deoxynojirimycin; Imino Pyranoses; Kaempferols; Morus; Piperidines; Plant Leaves; Plants, Medicinal; Spectrometry, Mass, Electrospray Ionization

[Structure: see text] D-fructose-6-phosphate aldolase (FSA) mediates a novel straightforward two-step chemo-enzymatic synthesis of D-fagomine and some of its N-alkylated derivatives in 51% isolated yield and 99% de. The key step is the FSA-catalyzed aldol addition of simple dihydroxyacetone (DHA) to N-Cbz-3-aminopropanal. The use of FSA greatly simplifies the enzymatic procedures that used dihydroxyacetonephosphate or DHA/esters. Some N-alkyl derivatives synthesized elicited antifungal and antibacterial activity as well as enhanced inhibitory activity, and selectivity against beta-galactosidase and alpha-glucosidase.

Topics: Alkylation; Anti-Bacterial Agents; Catalysis; Fructose-Bisphosphate Aldolase; Imino Pyranoses; Microbial Sensitivity Tests; Piperidines

A general synthesis of alpha-1-C-substituted derivatives of fagomine (2-deoxynojirimycin-alpha-C-glycosides) by ring-opening reactions of an aziridine with various heteroatomic nucleophiles, including thiol, amine, alcohol, carboxylate and phosphate, is described. The nine-step reaction sequence proceeded in an overall yield of 14-28% from tri-O-benzyl-D-glucal. Biological evaluation of alpha-1-C-substituted derivatives of fagomine, of the 2-deoxy analog of alpha-homonojirimycin 19 and its 1,N-anhydro derivative 22 as glycosidase inhibitors is reported. The glycosyl phosphate mimetic 15k was found to display no inhibitory activity towards glycogen phosphorylase b and phosphoglucomutase.

Topics: 1-Deoxynojirimycin; Animals; Aziridines; Cattle; Cyclization; Glucosamine; Glycoside Hydrolases; Glycosides; Humans; Imino Pyranoses; Inhibitory Concentration 50; Molecular Structure; Oxidation-Reduction; Piperidines; Rats; Structure-Activity Relationship

The asymmetric synthesis of fagomine and its congeners 1-4 has been achieved by catalytic ring-closing metathesis (RCM). The synthesis involved the construction of the piperidene-type chiral building block 5 followed by dihydroxylation, starting from the d-serine-derived Garner aldehyde 6.

Topics: Catalysis; Combinatorial Chemistry Techniques; Cyclization; Hydroxylation; Imino Pyranoses; Indicators and Reagents; Molecular Structure; Piperidines; Stereoisomerism

Natural azasugars have the ring oxygen substituted by nitrogen. They show potent inhibitory activity against glycosidases. The effect of substituting the ring carbon with nitrogen was examined with 1-azafagomine. 1-Azafagomine exhibited similar activity against processing glucosidase to that of fagomine.

Topics: 1-Deoxynojirimycin; Dose-Response Relationship, Drug; Enzyme Inhibitors; Glucosidases; Glucosides; Humans; Imino Pyranoses; Indolizines; Piperidines; Protein Processing, Post-Translational; Substrate Specificity

The mechanisms of potentiation by fagomine, an N-containing pseudo-sugar derived from mulberry leaves, of insulin secretion from isolated rat pancreatic islets in response to glucose was studied. Fagomine at more than 1 mmol/L significantly potentiated insulin secretion induced by 10 mmol/L glucose. The pseudo-sugar, however, did not affect the basal insulin secretion assessed at a glucose concentration of 3.5 mmol/L. The effects of fagomine on 10 mmol/L and 20 mmol/L glucose-induced insulin secretion were not significantly different. Fagomine (4 mmol/L) also potentiated glyceraldehyde-induced insulin secretion, but not the leucine-induced type. Glycolysis assessed by lactate production from glucose was significantly enhanced. The amounts of all intermediates (from glucose 6-phosphate to glyceraldehyde 3-phosphate) of the upper part of the glycolytic pathway in islets incubated with 20 mmol/L glucose were not affected by 4 mmol/L fagomine. The rise in the ATP/ADP ratio through both the glycolytic pathway and the citric acid cycle is believed to be pivotal in glucose- and glyceraldehyde-induced insulin secretion; whereas the ATP/ADP ratio rise through the citric acid cycle via the formation of acetyl-CoA is involved in leucine-induced insulin secretion. Our findings, together with these considerations, suggest that fagomine potentiates glucose-induced insulin secretion through acceleration of some step(s) after the formation of glyceraldehyde 3-phosphate in the glycolytic pathway.

Topics: Acetyl Coenzyme A; Adenosine Diphosphate; Adenosine Triphosphate; Animals; Drug Synergism; Enzyme Inhibitors; Female; Glucose; Glyceraldehyde; Glyceraldehyde 3-Phosphate; Glycolysis; Imino Pyranoses; Insulin; Insulin Secretion; Islets of Langerhans; Lactic Acid; Oligo-1,6-Glucosidase; Piperidines; Rats; Rats, Wistar

50% aqueous MeOH extracts from the leaves and roots of Xanthocercis zambesiaca (Leguminosae) were subjected to various ion-exchange column chromatographic steps to give fagomine (1), 3-epi-fagomine (2), 3,4-di-epi-fagomine (3), 3-O-beta-D-glucopyranosylfagomine (4), and 4-O-beta-D-glucopyranosylfagomine (5). Their structures were determined by spectroscopic analyses, particularly by extensive 1D and 2D NMR studies. Compounds 3 and 4 are new natural products. Compound 1 is a good inhibitor of isomaltase and certain alpha- and beta-galactosidases. Whereas 2 is a more potent inhibitor of isomaltase and beta-galactosidases than 1, it does not inhibit alpha-galactosidase. Compounds 3-5 exhibited no significant inhibition against the glycosidases used.

Topics: alpha-Galactosidase; Animals; beta-Galactosidase; beta-Glucosidase; Cattle; Enzyme Inhibitors; Glucosidases; Glucosides; Hydrolysis; Imino Pyranoses; Liver; Magnetic Resonance Spectroscopy; Piperidines; Plants, Medicinal; Rats; Seeds