Aza Sugars Research Articles

Identification, method development, validation, and characterization of Aza sugars by an ion-chromatography, high-resolution mass spectrometer, and LC-MS/MS

BackgroundAza sugars are organi c sugars having nitrogen containing polyhydroxyl sugar molecules. These molecules are active pharmaceutical ingredients; these are not well separated and eluted early in the HPLC and UPLC columns due to high polar nature. Aza sugars are having high conductivity hence the ion chromatography validated method has been established for the castanospermin and celgosivir along with its degradation studies (impurities).MethodsAn ion chromatography with conductivity detector-cation column was used to determine the assay of castanospermin and celgosivir as in the form of bulk active pharmaceutical ingredients. The degradation impurities were identified and characterized by using the UPLC-TOF and the LCMS/MS techniques.ResultsAn ion chromatography method was developed and determined the assay for castanospermin and celgosivir as in the form of bulk active pharmaceutical ingredients with the specificity of the miglitol and 1-deoxynojirimycin. Validation was performed for assay of the castanospermin and celgosivir. The method precision %RSD results at 0.25 mg/mL concentration of castanospermin and celgosivir were 1.1 and 0.7 respectively. The linearity was performed from 25 to 200% (w.r.t 0.25 mg/mL); the results were 1.000 and 0.999 coefficient for the castanospermin and celgosivir respectively. The recovery studies, robustness, ruggedness, and solution stability results were within the acceptance limits of the ICHQ2 (R1) guidelines. The stress study for the castanospermin and celgosivir active pharmaceutical ingredients was performed by using 0.5N HCl solution, 0.5N NaOH solution, 3.0% H202 solution, UV-visible and the thermal conditions. The castanospermin was degraded as 20.8% of n-oxide impurity, and celgosivir was degraded as 10.0% n-oxide impurity under 3.0% H202 solution. In base degradation, the celgosivir was back converted completely to castanospermin. These n-oxide impurities were identified and characterized by using UPLC-TOF and LCMS/MS techniques after collection from the ion chromatography. Castanospermin and celgosivir are stable in remaining stress conditions.ConclusionsFrom the present study, it was found that robust analytical ion chromatography technique is used for the determination of assay in Aza sugar, especially assay for the castanospermin and celgosivir with minimum usage of test sample 0.25 mg/mL and used green chemistry solvents. The study also explains that the unique degradation of castanospermin and celgosivir under oxidative and base hydrolysis, Oxidative degradation impurities were identified and characterized as n-oxides of its respective castanospermin and celgosivir active pharmaceutical ingredients by using HRMS and LC-MS/MS.An Ion chromatography-Mass spectrometry method for Aza sugars.

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).

Aza variant of intramolecular nucleophile-catalyzed aldol lactonization (NCAL): formal synthesis of (3 S,4 R) and (3 R,4 S) 4-(hydroxymethyl)pyrrolidin-3-ol

Aza variant of intramolecular catalytic, asymmetric nucleophile-catalyzed, aldol lactonization (NCAL) reaction has been explored to synthesize β-lactone fused nitrogen heterocycles as aza sugars’ precursors by employing achiral amino acids. The utility of these bicyclic β-lactones is presented by the formal synthesis of aza sugars, (3 S,4 R) and (3 R,4 S) 4-(hydroxymethyl)pyrrolidin-3-ol.

ChemInform Abstract: Hydrazine Derivatives of Carbohydrates and Related Compounds

Publisher Summary This chapter provides an overview of the hydrazine derivatives of carbohydrates and related compounds. Hydrazine, hydroxylamine, and hydrogen peroxide are highly reactive nucleophiles that add to carbonyl compounds to give N - and O -adducts, which are not usually isolated. The chapter presents an account of the rich chemistry of the hydrazine derivatives of sugars, the versatility of their structures, and their availability, which makes them valuable enantiomerically pure synthons for chiral products. For example, reduction of aldose hydrazones affords an important class of chiral amino- and iminodeoxy sugars that contain nitrogen in place of the oxygen present in the rings of natural sugars. These imino sugars exhibit a wide spectrum of biological activities, mainly attributable to their ability to act as enzyme inhibitors. Also of considerable interest are the carba-sugars—the carbocyclic analogs of monosaccharides—which are readily available from inosose phenylhydrazones. Members of both these classes of compounds—the carba-sugars and the imino sugars (“aza sugars”)—are capable of inhibiting enzymes because they mimic the enzyme's natural substrates (the sugars). This chapter provides an overview of saccharide hydrazones and glycosylhydrazines and also discusses about saccharide osazones and poly(hydrazones).

A short and common stereoselective approach to 5/6, 6/6, 6/7 bicyclic aza sugars

An efficient and highly stereoselective approach to bicyclic aza sugars is described using Grignard reaction on an N-benzyl imine derived from 3- O-benzyl-1,2- O-isopropylidine-α- d- xylo-pentodialdofuranose, ring closing metathesis, and reductive cyclization as key steps.

Amino Acid‐Catalyzed Asymmetric Carbohydrate Formation: Organocatalytic One‐Step De Novo Synthesis of Keto and Amino Sugars

AbstractA direct de novo synthesis of ketoses and amino sugars by amino acid‐catalyzed asymmetric aldol, Mannich and Michael reactions with dihydroxyacetone phosphate mimics as donors is presented. Proline, proline derivatives and thiazolidine‐4‐carboxylic acids catalyzed the asymmetric assembly of keto sugars and amino sugars in high yield with up to >99% ee. The organocatalytic C3+Cn methodology presented herein is a direct entry to the de novo synthesis of orthogonally protected C4, C5, and C6 ketoses, carbohydrate derivatives, amino and aza sugars and the total synthesis of polyoxamic acids. The addition of water significantly accelerated and improved the enantioselectivity of the proline‐mediated biomimetic asymmetric CC bond‐forming reactions.

A Study of the Epoxidation of 6‐Deoxyhex‐5‐enopyranosides. 1,5‐Dicarbonyl Derivatives and Novel Synthetic Routes to D‐xylo‐Hexos‐5‐ulose and D‐lyxo‐Hexos‐5‐ulose.

AbstractFor Abstract see ChemInform Abstract in Full Text.

A Study of the Epoxidation of 6-Deoxyhex-5-enopyranosides. 1,5-Dicarbonyl Derivatives and Novel Synthetic Routes to d-xylo-Hexos-5-ulose and d-lyxo-Hexos-5-ulose

The work described deals with the isolation and characterization of epoxides from 6-deoxyhex-5-enopyranosides and preliminary exploration of their synthetic potential. Prolonged epoxidation reaction times led to their hydrolysis in situ and gave novel protected D-hexos-5-ulose derivatives (sugar 1,5-dicarbonyls). Some reactions of the hexos-5-uloses were studied, and in some cases septanoside (seven-membered-ring saccharide) derivatives were isolated. Novel routes to D-xylo-hexos-5-ulose and D-lyxo-hexos-5-ulose, of interest as intermediates in the synthesis and biosynthesis of inositols and aza sugars, are also described. The structures of the epoxides and novel hexos-5-uloses were established by NMR and X-ray crystallographic methods.

Enantioselective synthesis of aza sugars from amino acids. 2. The 3-hydroxy-2-hydroxymethylpyrrolidines.

Enantioselective synthesis of aza sugars from amino acids. 2. The 3-hydroxy-2-hydroxymethylpyrrolidines.

Polyalkoxy Nitrones as Chiral Building Blocks in Asymmetric Synthesis

Optically active nitrones derived from both aldoses and dialdoses add metallated heterocycles in a stereocontrolled way depending on the nature of the Lewis acid used as a precomplexing agent of the nitrone. Further elaborations of the resulting hydroxylamines lead to the development of new synthetic methodologies for the preparation of polyalkoxy α-amino aldehydes and α-amino acids. These compounds can be used as key advanced intermediates in the synthesis of a wide range of natural products and derivatives including amino sugars, aza sugars, and complex nucleosides.

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).

Diastereoselective iodoamidation of 3-acetyloxybut-1-enylamines: simple synthesis of a precursor of aza sugars involving a pyrrolidine ring

3-Acetyloxybut-1-enylamines 3–9 were easily transformed using iodine to pyrrolidine derivatives 3a–9a, precursors for aza sugars, via a diastereoselective iodoamidation.

ChemInform Abstract: The Efficient, Enantioselective Synthesis of Aza Sugars from Amino Acids. Part 1. The Polyhydroxylated Pyrrolidines.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

The Efficient, Enantioselective Synthesis of Aza Sugars from Amino Acids. 1. The Polyhydroxylated Pyrrolidines.

Beginning with (+)-serine or (-)-serine, as appropriate, convenient, high-yield, enantioselective synthesis of all eight stereoisomeric 2-hydroxymethyl-3,4-dihydroxypyrrolidines (the enantiomeric pairs of iminoribitol, -arabinitol, -xylitol, and -lyxitol) can be effected. The absolute configuration of the starting amino acid defines the set of azasugars produced.

ChemInform Abstract: A Rapid and Efficient Approach to Chiral, Nonracemic Aza Sugars from Nonsugars. A Formal Synthesis of 1,4‐Dideoxy‐1,4‐imino‐D‐lyxitol.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Mechanism and specificity of human alpha-1,3-fucosyltransferase V.

Human alpha-1,3-fucosyltransferase catalyzes the transfer of the L-fucose moiety from guanosine diphosphate-beta-L-fucose (GDP-Fuc) to acceptor sugars to form biologically important fucoglycoconjugates, including sialyl Lewis x (SLex). Evidence for a general base mechanism is supported by a pH-rate profile that revealed a catalytic residue with a pKa of 4.1. The characterized solvent kinetic isotope effect (Dv = 2.9, Dv/k = 2.1) in a proton inventory study indicates that only one-proton transfer is involved in the catalytic step leading to the formation of the transition state. Evidence for Mn2+ as an electrophilic catalyst was supported by the observation that the nonenzymatic transfer of L-fucose from GDP-Fuc to the hydroxyl group of water in the presence of 10 mM MnCl2 at 20 degrees C was accelerated from K(obs)= 3.5 x 10(-6) to 3.8 x 10(-5) min-1. Using the GDP-Fuc hydrolysis as the nonenzymatic rate, the enzymatic proficiency of FucT V, (Kcat/Ki,GDP-fuc. K(m),1.acNAc)/K(non), was estimated to be 1.2 x 10(10) M-1 with a transition-state affinity of 8.6 x 10(-11) M. The Km for Mn2+ was determined to be 6.1 mM, and alternative divalent metal cofactors were identified as Ca2+, Co2+, and Mg2+. Detailed kinetic characterization of the acceptor sugar specificity indicated that incorporation of hydrophobic functionality [e.g. -O-(CH2)5CO2CH3] to the reducing end of the acceptor sugar substantially decreased the K(m),acceptor by over 100-fold. The role of the nucleotide was investigated by studying the inhibition of nucleotides, including the guanosine series. The inhibitory potency trend (GTP approximately GDP > GMP > > guanosine) is consistent with bidentate chelation of Mn2+ by GDP-Fuc. The role of charge and distance in the synergistic inhibitory effect by the combination of GDP, an aza sugar, and the acceptor sugar was probed. A mechanism for fucosyl transfer incorporating these findings is proposed and discussed.

A Rapid and Efficient Approach to Chiral, Nonracemic Aza Sugars from Nonsugars. A Formal Synthesis of 1,4-Dideoxy-1,4-imino-D-lyxitol.

A Rapid and Efficient Approach to Chiral, Nonracemic Aza Sugars from Nonsugars. A Formal Synthesis of 1,4-Dideoxy-1,4-imino-D-lyxitol.

ChemInform Abstract: Microbial Oxidation of Aromatics in Enantiocontrolled Synthesis. Part 2. Rational Design of Aza Sugars (endo‐Nitrogenous). Total Synthesis of (+)‐Kifunensine, Mannojirimycin, and Other Glycosidase Inhibitors.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

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