Azasugar Derivatives Research Articles

β-Silyl Acrylates in Asymmetric [3 + 2] Cycloadditions Affording Pyrrolidine Azasugar Derivatives.

A highly efficient copper(I)-catalyzed asymmetric 1,3-dipolar cycloaddition of azomethine ylides with 3-silyl unsaturated esters has been developed, providing elegant access to chiral 3-silylpyrrolidine derivatives bearing contiguous stereogenic centers in moderate-to-excellent yields (up to 99%) with high diastereo- and enantioselectivities (dr up to >99:1; ee up to 96%). Notably, the 3-silylpyrrolidines can easily be converted to pyrrolidine azasugar derivatives with potential biological activities by the reduction of two ester groups and carbon-silicon bond oxidation.

ChemInform Abstract: Chemoenzymatic Approach to Synthesis of Hydroxylated Pyrrolidines from Benzoic Acid.

Abstractipso‐Diol (II), prepared via a chemoenzymatic ipso‐dihydroxylation of benzoic acid, is used as a source of chirality in the synthesis of aza sugar derivative (XIV).

Chemoenzymatic Approach to Synthesis of Hydroxylated Pyrrolidines from Benzoic Acid

ipso-Diol (II), prepared via a chemoenzymatic ipso-dihydroxylation of benzoic acid, is used as a source of chirality in the synthesis of aza sugar derivative (XIV).

N-Benzyl-6-deoxy-3,6-iminomethylene-1,2,3,5-O-tetraacetyl-α-D-1(S)-epiallofuranose

The mol­ecule of the title compound, C22H27NO9, an azasugar derivative, consists of one benzene ring and two fused rings, which have the cis arrangement at the ring junctions, and gives a V-shaped geometry. The inter­planar angle between the five- and six-membered rings is 65.69 (11)°. The crystal structure is stablized by weak inter­molecular C—H⋯O hydrogen bonds.

ChemInform Abstract: Stereoselective Michael Addition of Thiophenols, Amino Acids, and Hydrazoic Acid to (2S)-Hydroxymethyl-dihydropyridone as a Convenient Route to Novel Azasugar Derivatives.

Abstract The outcome and stereochemical aspects of 1,4-conjugate addition of thiophenols, α-aminoacid derivatives and hydrazoic acid to chiral (2S)-hydroxymethyl-dihydropyridone 3 is presented. Subsequent reduction with NaBH4 provided predominantly the kinetically favored axial 3-piperidinol adducts. The stereochemistry of the products, which depends on electrostatic interaction and steric hindrance, was revealed by 1H NMR and 2D NOESY spectroscopic analysis.

CB-12181, a New Azasugar-Based Matrix Metalloproteinase/Tumor Necrosis Factor-α Converting Enzyme Inhibitor, Inhibits Vascular Endothelial Growth Factor-Induced Angiogenesis in Vitro and Retinal Neovascularization in Vivo

To evaluate the anti-angiogenic efficacy of CB-12181 [an azasugar derivative that has inhibitory actions against matrix metalloproteinases (MMPs) and tumor necrosis factor-alpha (TNF-alpha) converting enzyme (TACE)], we investigated the suppressing ability on in vitro (tube formation by endothelial cells) and in vivo (retinal neovascularization on murine ischemia-induced proliferative retinopathy) models of angiogenesis. For in vitro analysis, a capillary-like tube formation model using human umbilical vein endothelial cells (HUVECs) and fibroblasts co-culture assay was employed. Tube formation of HUVECs was stimulated by vascular endothelial growth factor (VEGF) and incubated with different concentrations of CB-12181 (0.1-100 microM) for 11 days. For in vivo analysis, mice were exposed to 75% oxygen between postnatal days 7 and 12 (P7 to P12). Then, the mice were removed from the oxygen treatment and treated with CB-12181 (1, 15, or 50 mg/kg) by daily subcutaneous injection from the time of reintroduction to room air at P12 until P16. At P17, pathological and physiological angiogenesis was quantified using retinal flat-mounts visualized by fluorescent angiography. In the in vitro angiogenesis model, CB-12181 significantly suppressed VEGF-induced HUVEC tube formation. Furthermore, in the in vivo angiogenesis model, administration of CB-12181 significantly suppressed retinal neovascularization without any apparent side effects on physiological revascularization to the oxygen-induced obliteration area. These results suggest that CB-12181 might be useful in the treatment of various diseases that depend on pathologic angiogenesis, and especially valuable for the treatment of diabetic retinopathy and retinopathy of prematurity.

Synthesis of both enantiomers of hydroxypipecolic acid derivatives equivalent to 5-azapyranuronic acids and evaluation of their inhibitory activities against glycosidases

We have synthesized 3-hydroxy- and 3,4,5-trihydroxypipecolic acid derivatives corresponding to 5-aza derivatives of uronic acids and evaluated their inhibitory activities against various glycosidases including β-glucuronidase. Compounds 4 and 5 were chosen as common intermediates for the synthesis of 3,4,5-trihydroxypipecolic acids and 3-hydroxypipecolic acids as well as for 3-hydroxybaikiain, a unique natural product isolated from a toxic mushroom. Cross aldol reaction of N-Boc-allylglycine derivative with acrolein followed by the ring-closing metathesis gave 4 and 5 as a mixture of diastereomers which could be separated by silica gel column chromatography. By employing lipase-catalyzed kinetic resolution, the synthesis of both l- and d-isomers of 3,4,5-trihydroxy- and 3-hydroxypipecolic acids was achieved. None of the compounds tested showed inhibitory activity against α- and β-glucosidases. On the other hand, l- 23 and l- 29 were found to have potent inhibitory activity against β-glucuronidase. In addition, it is interesting that some uronic-type azasugar derivatives showed moderate inhibitory activities against β- N-acetylglucosaminidase.

A practical and efficient synthesis of five-membered azasugar derivatives

A practical and efficient synthesis of 1,4-dideoxy-1,4-imino-D-arabinol and its partially protected derivatives has been described via the key intermediate with a norbornane-like structure using D-glucose as a starting material.

Stereoselective synthesis of partially protected azasugar derivatives

Five-membered azasugar derivatives with partially protected hydroxyl groups, and their fluorinated derivatives were synthesized via the key intermediates of norbornyl-like bicyclic acetals using d-xylose and d-glucose as starting materials. The glycosylation of the azasugar intermediate and 1-methylenesugar was also explored.

A new approach for the asymmetric syntheses of 2- epi-deoxoprosopinine and azasugar derivatives

A new approach to 2- epi-deoxoprosopinine 11 , 1-deoxygulonojirimycin 7 , and l-gulono-1,5-lactam 9 was described. The C-2 hydroxymethyl group was introduced regioselectively using SmI 2 mediated coupling of ( S)-3-silyloxyglutarimide 13b with either chloromethyl benzyl ether 16a or the Beau–Skrydstrup reagent 16b , followed by debenzylation and highly cis-diastereoselective reductive deoxygenation. Adoption of the Savoi's chemoselective ring-opening alkylation method allowed a highly diastereoselective introduction of the lipid side chain of 2- epi-deoxoprosopinine 11 in a straightforward manner. Dehydration followed by highly trans-diastereoselective dihydroxylation led to polyoxygenated lactam derivative 27 as a key intermediate for the syntheses of 7 and 9 .

Stereoselective Synthesis of Azasugar Thioglycosides.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Stereoselective synthesis of azasugar thioglycosides

Bicyclic (2-oxapyrrolizidines) and monocyclic (piperidine) azasugar ethyl thioglycosides, a new type of azasugar derivative, are stereoselectively prepared from suitable glycosylenamines, through anhydroazasugar derivatives.

Electrogenerated Chiral 4-Methoxy-2-oxazolidinones as Diastereoselective Amidoalkylation Reagents for the Synthesis of β-Amino Alcohol Precursors

A flexible and efficient synthesis of enantiomerically pure 4,5-substituted 2-oxazolidinones − important target molecules as precursors of pharmacologically active 2-oxazolidinones, β-amino alcohols, β-blockers and azasugar derivatives − is described. As starting materials, the enantiopure storage forms of chiral N-acyliminium ions (4RS,5S)-5-chloromethyl-4-methoxy-1,3-oxazolidin-2-one (2) and (4RS,5R)-4-methoxy-5-methyl-1,3-oxazolidin-2-one (3) were used; these are readily available from the chiral pool with the aid of electrochemical transformations. Substitution of the 4-methoxy group in building blocks 2 and 3 with a large variety of organometallic nucleophiles resulted in the trans-diastereoselective formation of enantiopure 4,5-disubstituted 2-oxazolidinones, with a high degree of flexibility in the substituent at the 4-position.

Stereoselective Michael Addition of Thiophenols, Amino Acids and Hydrazoic Acid to (2 S)-Hydroxymethyl-dihydropyridone as a Convenient Route to Novel Azasugar Derivatives

The outcome and stereochemical aspects of 1,4-conjugate addition of thiophenols, α-aminoacid derivatives and hydrazoic acid to chiral (2 S)-hydroxymethyl-dihydropyridone 3 is presented. Subsequent reduction with NaBH 4 provided predominantly the kinetically favored axial 3-piperidinol adducts. The stereochemistry of the products, which depends on electrostatic interaction and steric hindrance, was revealed by 1H NMR and 2D NOESY spectroscopic analysis.

The Synthesis of Imidazol Sugars Which Mimic Cyclic Carboxonium Ions Formed During the Glycosidase‐Catalysed Hydrolysis of Oligo and Polysaccharides

Some naturally occurring carbohydrates, of which several hydroxy groups had been selectively protected, were condensed with formamidine to give the expected imidazole derivatives in the D-arabino (9), D-lyxo (12), L-xylo (17), D-threo (21), and in the L- and D-erythro (24) series. Introduction of a strong leaving group at the remaining free alcohol function of these products led at once to intramolecular SN2 cyclisation to the corresponding bicyclic aza sugar derivatives. This was followed by total deprotection to give the target aza sugars in the L-xylo (7), L-ribo (14), D-arabino (19), as well as in the D-threo (22) and the L- and D-erythro (26) series. Inhibitory assays with four glycosidases showed that the D-arabino aza sugar 19 is the only potent inhibitor (for an α-mannosidase of jack bean).

Azasugar Syntheses and Multistep Cascade Rearrangements via Hetero Diels-Alder Cycloadditions with Nitroso Dienophiles

Hetero Diels-Alder (HDA) reactions with nitroso dienophiles R-N=0 are shown to represent the key step in the stereospecific total synthesis of azasugar derivatives. A series of amino-deoxysugars, both racemic and chiral, have been prepared from the primary cycloadducts of such HDA-reactions. Asymmetric induction during these cycloadditions were achieved either with chiral dienes, or with chiral nitroso dienophiles. In some instances the primary HDA cycloadducts underwent spontaneous cascading rearrangements to thermodynamically more stable entities. These rearrangements were triggered off by the breaking at r.t. of the weak N-O single bond.

Preparation of the N‐Acetylglucosaminidase Inhibitor 1‐Acetamido‐1,2,5‐trideoxy‐2,5‐imino‐D‐glucitol from Methyl α‐D‐Mannopyranoside

AbstractFragmentation of methyl 3‐O‐benzyl‐6‐bromo‐2‐O‐(tert‐butyldimethylsilyl)‐6‐deoxy‐4‐O‐(4‐methoxybenzyl)‐α‐D‐mannopyranoside (2) and in situ reductive amination give (3R,4S,5R)‐6‐benzylamino‐4‐benzyloxy‐5‐(tert‐butyldimethylsilyloxy)‐3‐(4‐methoxybenzyloxy)hexene (3) which is converted by intramolecular aminomercuration into an epimeric mixture of the bromomercuriopiperidine derivatives 4 and 5. The minor D‐manno epimer 4 is transformed into mesylate 10 which, upon reaction with LiN3 in DMF, suffers a piperidine‐pyrrolidine ring contraction to give azidomethylpyrrolidine 11. Reductive acetylation by means of thioacetic acid affords the fully protected pyrrolidine aza sugar derivative 12. The major L‐gulo epimer 5 is transformed into the mesylate 15 which, again, upon reaction with LiN3 in DMF undergoes piperidine‐pyrrolidine ring contraction to give the 1‐azido‐3‐O‐benzyl‐2,5‐benzylimino‐6‐bromomercurio‐1,2,5,6‐tetradeoxy‐4‐O‐(4‐methoxybenzyl)‐L‐iditol (16). Eliminative dehalomercuration by means of Zn powder is accompanied by in situ reduction of the azido group to give amino alkene 17. Intramolecular aminomercuration of 17 followed by N‐acetylation yields the protected 1,2,5,6‐tetradeoxy‐2,5‐imino‐D‐glucitol derivative 20 as the major epimer. Reductive oxygenation of 20 leads to pyrrolidine 22 which is deprotected to give title compound 1. Selective cleavage of the PMB group of 22 leads to 24. Benzylation of 22 affords again 12 from which the OH group at C‐4 is liberated by selective cleavage of the PMB ether to give pyrrolidine 13. Compound 1 inhibits NAGase from bovine kidney. magnified image