Expeditious Synthesis of Aza sugars by the Double Reductive Amination of Dicarbonyl Sugars

Baxter, Ellen W.; Reitz, Allen B.

doi:10.1021/jo00090a040

Cited by 203 publications

(142 citation statements)

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“…Following published procedures, 1-deoxynojirimycin (DNJ) was prepared from 2,3,4,6-tetra-O-benzyl-␣-glucopyranose (23). 2,5-Anhydro-imino-D-glucitol was prepared from 5-keto-D-fructose according to Baxter and Reitz's method (24,25). N-nonyl compounds (2, 3, 4, 5, and diethyl nonylamine) were prepared via reductive amination of nonyl aldehyde with 2,5-anhydro-imino-D-glucitol, morpholine, 1-(hydroxyethyl)piperazine, trans-4-hydroxy-L-proline, and diethylamine, respectively.…”

Section: ␤-Glu Inhibitors and Related Molecules To Probe The Requiremmentioning

confidence: 99%

Chemical chaperones increase the cellular activity of N370S β-glucosidase: A therapeutic strategy for Gaucher disease

Sawkar

Cheng

Beutler

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

486

455

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Gaucher disease is a lysosomal storage disorder caused by deficient lysosomal ␤-glucosidase (␤-Glu) activity. A marked decrease in enzyme activity results in progressive accumulation of the substrate (glucosylceramide) in macrophages, leading to hepatosplenomegaly, anemia, skeletal lesions, and sometimes CNS involvement. Enzyme replacement therapy for Gaucher disease is costly and relatively ineffective for CNS involvement. Chemical chaperones have been shown to stabilize various proteins against misfolding, increasing proper trafficking from the endoplasmic reticulum. We report herein that the addition of subinhibitory concentrations (10 M) of N-(n-nonyl)deoxynojirimycin (NN-DNJ) to a fibroblast culture medium for 9 days leads to a 2-fold increase in the activity of N370S ␤-Glu, the most common mutation causing Gaucher disease. Moreover, the increased activity persists for at least 6 days after the withdrawal of the putative chaperone. The NN-DNJ chaperone also increases WT ␤-Glu activity, but not that of L444P, a less prevalent Gaucher disease variant. Incubation of isolated soluble WT enzyme with NN-DNJ reveals that ␤-Glu is stabilized against heat denaturation in a dose-dependent fashion. We propose that NN-DNJ chaperones ␤-Glu folding at neutral pH, thus allowing the stabilized enzyme to transit from the endoplasmic reticulum to the Golgi, enabling proper trafficking to the lysosome. Clinical data suggest that a modest increase in ␤-Glu activity may be sufficient to achieve a therapeutic effect.

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Section: ␤-Glu Inhibitors and Related Molecules To Probe The Requiremmentioning

confidence: 99%

Chemical chaperones increase the cellular activity of N370S β-glucosidase: A therapeutic strategy for Gaucher disease

Sawkar

Cheng

Beutler

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

486

455

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“…-lyxo-Hexos-5-ulose (10), [34] which is the key intermediate used in the synthesis of DMJ by Baxter and Reitz, [35] was also prepared. An epoxidation hydrolysis of 7 gave the hemiketal 8.…”

Section: Synthesis Of Non-peptide Peptidomimeticsmentioning

confidence: 99%

Peptidomimetics, Glycomimetics and Scaffolds from Carbohydrate Building Blocks

Murphy

2007

Eur J Org Chem

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Saccharides, due to their high density of functional groups and availability as chiral building blocks are scaffolds for bioactive compound discovery. Pyranosides and iminosugar‐based peptidomimetics have been synthesised as ligands for somatostatin receptors and HIV protease. The synthesis of polyhydroxylated macrolides related to natural products and cyclophanes has been achieved from carbohydrate fragments with a view to investigation of their potential as scaffolds. In addition, the trajectory of aromatic systems grafted to saccharides have been studied and this has led to the synthesis of probes for the study of carbohydrate protein interactions. These compounds include geometrically diverse bivalent glycomimetics derived from scaffolds that are hybrids of sugars and aromatic groups. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

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“…The sequential N-alkylation of 30a and 30b with ethyl bromoacetate, reduction with LAH, acetylation, hydrogenation and selective protection with -Cbz group afforded 31a and 31b, respectively. Separate removal of 1,2-acetonide functionality, hydrogenation and deacetylation of 30a and 30b afforded N-hydroxyethyl-D-gluco-1-deoxyhomonojirimycin (27) and Nhydroxyethyl-L-ido-1-deoxyhomo-nojirimycin (28), respectively. The glycosidase inhibition activity of compounds 27 and 28 was evaluated using sweet almond seed as a rich source of different glycosidases.…”

Section: Figurementioning

confidence: 99%

“…The high degree of stereoselectivity observed in this double reductive amination reaction, probably involves cyclic intermediate and the stereoselective hydride addition (axial attack) appeared due to torsional effects. 27,28 In the subsequent step, removal of the benzyl and MOM protecting groups provided In the second approach (Scheme 7), 26 one carbon extension by Wittig reaction of perbenzylated α-D-glucopyranose 14 followed by dihydroxylation afforded 49a and 49b (10:1, the major isomer was predicted from Kishi's empirical rule 29 ) in which the primary hydroxyl group was protected as silyl ether. Oxidation of secondary alcohol functionality in 50a/50b afforded 1,5-diketone.…”

Section: Figurementioning

confidence: 99%

“…The synthesis of monosaccharides and related compounds via enzymatic aldol addition reaction, catalyzed by aldolases, has been proven to be very useful and several successful examples have been described in recent years. 38 In addition, the use of enzyme aldolases with azido substrate followed by hydrogenation of the azido-sugar produces various five-, six-and seven-membered azasugars 27,39,40 ( Figure 4). The same strategy is also extended for homoazasugars.…”

Section: (Vi) Enzyme Catalyzed Intramolecular Reductive Amination Strmentioning

confidence: 99%

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Piperidine homoazasugars: Natural occurrence, synthetic aspects and biological activity study

Dhavale¹,

Matin²

2004

Arkivoc

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A number of natural and synthetic analogues of homoazasugars, known in the literature, are promising glycosidase inhibitors. The methodologies used for the synthesis of piperidine homoazasugars are: (i) intramolecular reductive amination, (ii) intermolecular double reductive amination, (iii) amino/amido mercuration, (iv) intramolecular nucleophilic substitution, (v) synthesis from non-carbohydrate building block and aza-heterocycles and (vi) enzyme catalyzed intramolecular reductive amination. Homoazasugars showed higher selectivity and potency in the glycosidase inhibitory activity. In this report, natural occurrence, synthetic methodologies and potential application to glycosidase inhibitory activity of homoazasugars will be reviewed.

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Expeditious Synthesis of Aza sugars by the Double Reductive Amination of Dicarbonyl Sugars

Cited by 203 publications

References 0 publications

Chemical chaperones increase the cellular activity of N370S β-glucosidase: A therapeutic strategy for Gaucher disease

Chemical chaperones increase the cellular activity of N370S β-glucosidase: A therapeutic strategy for Gaucher disease

Peptidomimetics, Glycomimetics and Scaffolds from Carbohydrate Building Blocks

Piperidine homoazasugars: Natural occurrence, synthetic aspects and biological activity study

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