- 1,3-Oxazine as a chiral building block used in the total synthesis of (+)-1-deoxynojirimycin and (2R,5R)-dihydroxymethyl-(3R,4R)-dihydroxypyrrolidine
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Concise and stereocontrolled syntheses of (+)-1-deoxynojirimycin and (2R,5R)-dihydroxymethyl-(3R,4R)-dihydroxypyrrolidine [(+)-DMDP] were achieved via a diastereomerically enriched oxazine intermediate. The key strategies include the use of 1,3-oxazine as a chiral building block and diastereoselective nucleophilic addition to an aldehyde. Starting from readily available (R)-methyl 2-benzamido-3-((tert-butyldimethylsilyl)oxy)propanoate, (+)-1-deoxynojirimycin was synthesized in 11 steps and 26.2% overall yield while (+)-DMDP was synthesized in 11 steps and 27.1% overall yield, respectively.
- Park, Seok-Hwi,Kim, Ji-Yeon,Kim, Jin-Seok,Jung, Changyoung,Song, Dong-Keun,Ham, Won-Hun
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Read Online
- A short and practical synthesis of 1-deoxynojirimycin
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The potent glucosidase inhibitor 1-deoxynojirimycin was synthesized from L-sorbose using a short synthesis and only one protecting group. The last step, which constituted the removal of an acetonide protecting group and an intramolecular reductive amination, was accomplished on an acidic ion-exchange resin. This provided a synthesis capable of being operated on a multi-kilogram scale.
- Behling,Farid,Medich,Scaros,Prunier,Weier,Khanna
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Read Online
- A fluorescence study of isofagomine protonation in β-glucosidase
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N-(10-Chloro-9-anthracenemethyl)isofagomine 5 and N-(10-chloro-9-anthracenemethyl)-1-deoxynojirimycin 6 were prepared, and their inhibition of almond β-glucosidase was measured. The isofagomine derivative 5 was found to be a potent inhibitor, while the 1-deoxynojirimycin derivative 6 displayed no inhibition at the concentrations investigated. Fluorescence spectroscopy of 5 with almond β-glucosidase at different pH values showed that the inhibitor nitrogen is not protonated when bound to the enzyme. Analysis of pH inhibition data confirmed that 5 binds as the amine to the enzyme's unprotonated dicarboxylate form. This is a radically different binding mode than has been observed with isofagomine and other iminosugars in the literature.
- Lindb?ck, Emil,Laursen, Bo Wegge,Poulsen, Jens Christian Navarro,Kils?, Kristine,Pedersen, Christian Marcus,Bols, Mikael
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Read Online
- Isotope edited NMR studies of glycosidases: Design and synthesis of a novel glycosidase inhibitor
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N-13C-methyl-deoxynojirimycin was synthesized and used in isotope- edited NMR studies to probe the binding site of an α-glucosidase. Results from this analysis led to the design and preparation of a novel α- glucosidase inhibitor, N-glycyl deoxynojirimycin.
- Hines, Jennifer V.,Chang, Heesun,Gerdeman, Melinda S.,Warn, Dana E.
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Read Online
- Design, synthesis, and activity evaluation of novel N-benzyl deoxynojirimycin derivatives for use as α-glucosidase inhibitors
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To obtain α-glucosidase inhibitors with high activity, 19 NB-DNJDs (N-benzyldeoxynojirimycin derivatives) were designed and synthesized. The results indicated that the 19 NBDNJDs displayed different inhibitory activities towards α-glucosidase in vitro. Compound 18a (1- (4-hydroxy-3-methoxybenzyl)-2-(hydroxymethyl) piperidine-3,4,5-triol) showed the highest activity, with an IC50 value of 0.207 ± 0.11 mM, followed by 18b (1-(3-bromo-4-hydroxy-5- methoxybenzyl)-2-(hydroxymethyl) piperidine-3,4,5-triol, IC50: 0.276 ± 0.13 mM). Both IC50 values of 18a and 18b were significantly lower than that of acarbose (IC50: 0.353 ± 0.09 mM). According to the structure-activity analysis, substitution of the benzyl and bromine groups on the benzene ring decreased the inhibition activity, while methoxy and hydroxyl group substitution increased the activity, especially with the hydroxyl group substitution. Molecular docking results showed that three hydrogen bonds were formed between compound 18a and amino acids in the active site of α- glucosidase. Additionally, an arene-arene interaction was also modelled between the phenyl ring of compound 18a and Arg 315. The three hydrogen bonds and the arene-arene interaction resulted in a low binding energy (-5.8 kcal/mol) and gave 18a a higher inhibition activity. Consequently, compound 18a is a promising candidate as a new α-glucosidase inhibitor for the treatment of type II diabetes.
- Zeng, Fanxin,Yin, Zhongping,Chen, Jiguang,Nie, Xuliang,Lin, Ping,Lu, Tao,Wang, Meng,Peng, Dayong
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- Asymmetric total syntheses of (+)-2,5-dideoxy-2,5-imino-D-glucitol [(+)-DGDP] and (?)-1-deoxymannojirimycin [(?)-DMJ] via an extended chiral 1,3-oxazine
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The asymmetric total syntheses of (+)-2,5-dideoxy-2,5-imino-D-glucitol [(+)-DGDP] 1 and (?)-1-deoxymannojirimycin [(?)-DMJ] 2 were achieved using an extended chiral 1,3-oxazine. The key synthetic strategies included extension of the chirality of anti,syn-oxazine 3 using diastereoselective dihydroxylation, and piperidine and pyrrolidine ring formation. Starting from readily available anti,syn-oxazine 3, (+)-DGDP 1 was synthesized in 5 steps with 31.6% overall yield and (?)-DMJ 2 was synthesized in 4 steps with 60.6% overall yield.
- Myeong, In-Soo,Jung, Changyoung,Kim, Ji-Yeon,Park, Seok-Hwi,Ham, Won-Hun
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supporting information
p. 2422 - 2425
(2018/05/25)
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- Synthesis of 1-deoxynojirimycin: Exploration of optimised conditions for reductive amidation and separation of epimers
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1-Deoxynojirimycin (DNJ), which has importance with respect to sugar processing enzymes, is a synthetic target for chemists. A key step in the synthesis of DNJ is the preparation of 2,3,4,6-tetra-O-benzyl-D-glucono-δ-lactam. By varying reaction parameters such as temperature, solvent and reducing reagent, improvements on previous methods are described. A novel approach for the synthesis of 2,3,4,6-tetra-O-benzyl-5-dehydro-5-deoxo-D-gluconamide has been developed by using PCC as an oxidising agent. Separation of epimers permitted DNJ to be obtained in 85% yield after reduction and hydrogenolysis steps.
- Iftikhar, Mehwish,Wang, Lin,Fang, Zhijie
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p. 460 - 464
(2017/08/18)
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- A Fluorescence Polarization Activity-Based Protein Profiling Assay in the Discovery of Potent, Selective Inhibitors for Human Nonlysosomal Glucosylceramidase
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Human nonlysosomal glucosylceramidase (GBA2) is one of several enzymes that controls levels of glycolipids and whose activity is linked to several human disease states. There is a major need to design or discover selective GBA2 inhibitors both as chemical tools and as potential therapeutic agents. Here, we describe the development of a fluorescence polarization activity-based protein profiling (FluoPol-ABPP) assay for the rapid identification, from a 350+ library of iminosugars, of GBA2 inhibitors. A focused library is generated based on leads from the FluoPol-ABPP screen and assessed on GBA2 selectivity offset against the other glucosylceramide metabolizing enzymes, glucosylceramide synthase (GCS), lysosomal glucosylceramidase (GBA), and the cytosolic retaining β-glucosidase, GBA3. Our work, yielding potent and selective GBA2 inhibitors, also provides a roadmap for the development of high-throughput assays for identifying retaining glycosidase inhibitors by FluoPol-ABPP on cell extracts containing recombinant, overexpressed glycosidase as the easily accessible enzyme source.
- Lahav, Dani?l,Liu, Bing,Van Den Berg, Richard J.B.H.N.,Van Den Nieuwendijk, Adrianus M. C. H.,Wennekes, Tom,Ghisaidoobe, Amar T.,Breen, Imogen,Ferraz, Maria J.,Kuo, Chi-Lin,Wu, Liang,Geurink, Paul P.,Ovaa, Huib,Van Der Marel, Gijsbert A.,Van Der Stelt, Mario,Boot, Rolf G.,Davies, Gideon J.,Aerts, Johannes M. F. G.,Overkleeft, Herman S.
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supporting information
p. 14192 - 14197
(2017/10/17)
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- Conformational Behaviour of Azasugars Based on Mannuronic Acid
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A set of mannuronic-acid-based iminosugars, consisting of the C-5-carboxylic acid, methyl ester and amide analogues of 1deoxymannorjirimicin (DMJ), was synthesised and their pH-dependent conformational behaviour was studied. Under acidic conditions the methyl ester and the carboxylic acid adopted an “inverted” 1C4 chair conformation as opposed to the “normal” 4C1 chair at basic pH. This conformational change is explained in terms of the stereoelectronic effects of the ring substituents and it parallels the behaviour of the mannuronic acid ester oxocarbenium ion. Because of this solution-phase behaviour, the mannuronic acid ester azasugar was examined as an inhibitor for a Caulobacter GH47 mannosidase that hydrolyses its substrates by way of a reaction itinerary that proceeds through a 3H4 transition state. No binding was observed for the mannuronic acid ester azasugar, but sub-atomic resolution data were obtained for the DMJ?CkGH47 complex, showing two conformations—3S1 and 1C4—for the DMJ inhibitor.
- van Rijssel, Erwin R.,Janssen, Antonius P. A.,Males, Alexandra,Davies, Gideon J.,van der Marel, Gijsbert A.,Overkleeft, Herman S.,Codée, Jeroen D. C.
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p. 1297 - 1304
(2017/07/07)
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- Selenoureido-iminosugars: A new family of multitarget drugs
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Herein we report the synthesis of N-alkylated deoxynojirimycin derivatives decorated with a selenoureido motif at the hydrocarbon tether as an example of unprecedented multitarget agents. Title compounds were designed as dual drugs for tackling simultaneously the Gaucher disease (by selective inhibition of β-glucosidase, Ki= 1.6–5.5 μM, with improved potency and selectivity compared to deoxynojirimycin) and its neurological complications (by inhibiting AChE, Kiup to 5.8 μM). Moreover, an excellent mimicry of the selenoenzyme glutathione peroxidase was also found for the catalytic scavenging of H2O2(Kcat/Kuncatup to 640) using PhSH as a cofactor, with improved activity compared to known positive controls, like (PhSe)2and ebselen; therefore, such compounds are also excellent scavengers of peroxides, an example of reactive oxygen species present at high concentrations in patients of Gaucher disease and neurological disorders.
- Olsen, Jacob Ingemar,Plata, Gabriela B.,Padrón, José M.,López, óscar,Bols, Mikael,Fernández-Bola?os, José G.
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p. 155 - 160
(2016/08/01)
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- High sugar composition for treatment and method
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The invention relates to the compounds of formula (I) or its pharmaceutical acceptable salts, as well as polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof The pharmaceutical compositions comprising an effective amount of compounds of formula (I), and methods for the treatment of hyperglycemia may be formulated for oral, buccal, rectal, topical, transdermal, transmucosal, intravenous, parenteral administration, syrup, or injection. Such compositions may be used to treatment of insulin resistance, diabetes mellitus, diabetes insipidus, type 1 diabetes, type 2 diabetes, microvascular complications, macrovascular complications, lipid disorders, prediabetes, obesity, arrhythmia, myocardial infarction, stroke, neuropathy, renal complications, hypertriglyceridemia, cardiovascular complications, and post prandial hyperglycemia.
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Paragraph 0095; 0096; 0102; 0103
(2017/03/25)
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- One pot oxidative dehydration - oxidation of polyhydroxyhexanal oxime to polyhydroxy oxohexanenitrile: A versatile methodology for the facile access of azasugar alkaloids
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A unique oxidative dehydration-oxidation of polyhydroxy-oxime (7) to the corresponding ketonitrile (8) in one pot is reported for the first time in carbohydrate literature. Key ketonitrile intermediate (8) upon palladium hydroxide mediated cascade reaction afforded 1-deoxynojirimycin (DNJ) 1b in moderate diastereoselectivity. The cascade reaction involves the conversion of nitrile to amine, heteroannulation, reduction of the imine and subsequent debenzylation to furnish the azasugars. This oxidative dehydration-oxidation and reductive heteroannulation methodology is successfully utilized for the total synthesis of 1-deoxynojirimycin (1b), miglitol (2) and miglustat (3).
- Khobare, Sandip R.,Gajare, Vikas,Reddy, E. Vishnuvardhan,Datrika, Rajender,Banda, Malavika,Siddaiah, Vidavalur,Pachore, Sharad S.,Timanna, Upadhya,Dahanukar, Vilas H.,Syam Kumar
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- Compositions and methods for the treatment of hyperglycemia
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The invention relates to the compounds of formula I or its pharmaceutical acceptable salts, as well as polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. The pharmaceutical compositions comprising an effective amount of compounds of formula I, and methods for the treatment of hyperglycemia may be formulated for oral, buccal, rectal, topical, transdermal, transmucosal, intravenous, parenteral administration, syrup, or injection. Such compositions may be used to treatment of insulin resistance, diabetes mellitus, diabetes insipidus, type 1 diabetes, type 2 diabetes, microvascular complications, macrovascular complications, lipid disorders, prediabetes, obesity, arrhythmia, myocardial infarction, stroke, neuropathy, renal complications, hypertriglyceridemia, cardiovascular complications, and post prandial hyperglycemia.
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Page/Page column 27; 28
(2015/10/28)
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- Transforming flask reaction into cell-based synthesis: Production of polyhydroxylated molecules via engineered Escherichia coli
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Dihydroxyacetone phosphate (DHAP)-dependent aldolases have been intensively studied and widely used in the synthesis of carbohydrates and complex polyhydroxylated molecules. However, strict specificity toward donor substrate DHAP greatly hampers their synthetic utility. Here, we transformed DHAP-dependent aldolases-mediated by in vitro reactions into bioengineered Escherichia coli (E. coli). Such flask-to-cell transformation addressed several key issues plaguing in vitro enzymatic synthesis: (1) it solves the problem of DHAP availability by in vivo-hijacking DHAP from the glycolysis pathway of the bacterial system, (2) it circumvents purification of recombinant aldolases and phosphatase, and (3) it dephosphorylates the resultant aldol adducts in vivo, thus eliminating the additional step for phosphate removal and achieving in vivo phosphate recycling. The engineered E. coli strains tolerate a wide variety of aldehydes as acceptor and provide a set of biologically relevant polyhydroxylated molecules in gram scale.
- Wei, Mohui,Li, Zijie,Li, Tiehai,Wu, Baolin,Liu, Yunpeng,Qu, Jingyao,Li, Xu,Li, Lei,Cai, Li,Wang, Peng George
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p. 4060 - 4065
(2015/11/11)
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- Synthetic 1-deoxynojirimycin N-substituted peptides offer prolonged disruption to N-linked glycan processing
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A panel of 1-deoxynojirimycin (DNJ) N-linked peptides were synthesized. Their IC50 values were measured in vitro against a-glucosidases I and II and were found to be in the micromolar range for both isozymes, and better than that of the iminosugar NB-DNJ (miglustat, 3) against a-glucosidase II. Cell-based studies revealed that although the free iminosugar 3 is most effective at disrupting N-linked glycan processing for shortterm incubations (one day), when the cell-based studies were extended to three days, the DNJ N-linked tetrapeptide KDEL, which is an endoplasmic reticulum (ER)-retaining sequence, performed far better than 3. In low inhibitor washout studies, NB-DNJ inhibition was decreased to zero after 24 h, but DNJ- KDEL retained 13% activity. This method offers a general approach for targeting drugs to the ER and prolonging their activity. Moreover, it is modular, so as new iminosugars of increased potency are discovered, they can be added to this template for targeting.
- Aguilar, Aim Lpez,Escribano, Jaime,Wentworth, Paul,Butters, Terry D.
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p. 2809 - 2813
(2015/02/02)
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- Gluconobacter mediated synthesis of amino sugars
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An easy and convenient chemo-enzymatic method for preparation of 1-deoxygalactonojirimycin and 1-deoxynojirimycin hydrochlorides has been demonstrated. All the compounds prepared have been characterized by MASS, 1H NMR, 13C NMR and SOR.
- Sethi, Madhuresh K.,Kumar, Anish,Maddur, Nagaraj,Shukla, Rohit,Vemula, Lakshmi Narayana
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- Asymmetric syntheses of (-)-1-deoxymannojirimycin and (+)-1- deoxyallonojirimycin via a ring-expansion approach
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The asymmetric syntheses of (-)-1-deoxymannojirimycin and (+)-1-deoxyallonojirimycin are described herein. The ring-closing iodoamination of two epimeric bishomoallylic amines to give the corresponding 5-iodomethylpyrrolidines was followed by in situ ring-expansion to give two diastereoisomerically pure (>99:1 dr) cyclic carbonates. Subsequent deprotection gave (-)-1-deoxymannojirimycin and (+)-1-deoxyallonojirimycin as single diastereoisomers in 7.4 and 3.3% overall yield, respectively, from commercially available starting materials.
- Davies, Stephen G.,Figuccia, Aude L. A.,Fletcher, Ai M.,Roberts, Paul M.,Thomson, James E.
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p. 2042 - 2045
(2013/06/05)
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- Stereoselective synthesis of 1-deoxynojirimycin, D-glucono-δ-lactam and D-altrono-δ-lactam from a common chiral intermediate derived from D-mannitol
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A stereoselective synthesis of 1-deoxynojirimycin, D-glucono-δ-lactam and D-altrono-δ-lactam were accomplished from a common chiral intermediate derived from D-mannitol. The key transformations in the synthesis include Miyashita C-2 selective endo-mode azide opening of epoxy alcohol and Sharpless asymmetric dihydroxylation. ARKAT-USA, Inc.
- Ravinder, Mettu,Reddy, Thatikonda Narendar,Mahendar, Budde,Rao, Vaidya Jayathirtha
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p. 287 - 302
(2013/02/26)
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- Asymmetric synthesis of 1-deoxyazasugars from chiral aziridines
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A general and facile synthesis of enantiopure 1-deoxyazasugars was achieved from stereoselective dihydroxylation of a common synthetic intermediate, piperidine ring fused oxazolidin-2-one, originating from a commercially available starting substrate, chiral aziridine-2-carboxylate, in high yields. The Royal Society of Chemistry 2011.
- Singh, Alok,Kim, Bongchan,Lee, Won Koo,Ha, Hyun-Joon
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p. 1372 - 1380
(2011/04/16)
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- Facile and stereo-controlled synthesis of 2-deoxynojirimycin, Miglustat and Miglitol
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A novel and facile synthesis of a series of the biologically significant iminosugar derivatives including 2-deoxynojirimycin, Miglustat and Miglitol is reported. The synthesis features a strategic double inversion mechanism for securing the desired stereochemistry at C5 position of such glucose-type carbohydrate mimetics, representing a practical and remarkable improvement on the previously reported method that suffers from the loss of the stereo-control during the reaction process. Crown Copyright
- Zhang, Zhen-Xing,Wu, Baolin,Wang, Bin,Li, Tie-Hai,Zhang, Peng-Fei,Guo, Li-Na,Wang, Wen-Jun,Zhao, Wei,Wang, Peng George
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supporting information; experimental part
p. 3802 - 3804
(2011/08/09)
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- Dual-action lipophilic iminosugar improves glycemic control in obese rodents by reduction of visceral glycosphingolipids and buffering of carbohydrate assimilation
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The lipophilic iminosugar N-[5-(adamantan-1-ylmethoxy)pentyl]-1- deoxynojirimycin (2, AMP-DNM) potently controls hyperglycemia in obese rodent models of insulin resistance. The reduction of visceral glycosphingolipids by 2 is thought to underlie its beneficial action. It cannot, however, be excluded that concomitant inhibition of intestinal glycosidases and associated buffering of carbohydrate assimilation add to this. To firmly establish the mode of action of 2, we developed a panel of lipophilic iminosugars varying in configuration at C-4/C-5 and N-substitution of the iminosugar. From these we identified the L-ido derivative of 2, L-ido-AMP-DNM (4), as a selective inhibitor of glycosphingolipid synthesis. Compound 4 lowered visceral glycosphingolipids in ob/ob mice and ZDF rats on a par with 2. In contrast to 2, 4 did not inhibit sucrase activity or sucrose assimilation. Treatment with 4 was significantly less effective in reducing blood glucose and HbA1c. We conclude that the combination of reduction of glycosphingolipids in tissue and buffering of carbohydrate assimilation by 2 produces a superior glucose homeostasis.
- Wennekes, Tom,Meijer, Alfred J.,Groen, Albert K.,Boot, Rolf G.,Groener, Johanna E.,Van Eijk, Marco,Ottenhoff, Roelof,Bijl, Nora,Ghauharali, Karen,Song, Hang,O'Shea, Tom J.,Liu, Hanlan,Yew, Nelson,Copeland, Diane,Van Den Berg, Richard J.,Van Der Marel, Gijsbert A.,Overkleeft, Herman S.,Aerts, Johannes M.
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supporting information; experimental part
p. 689 - 698
(2010/07/06)
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- Straightforward synthesis of diverse 1-deoxyazapyranosides via stereocontrolled nucleophilic additions to six-membered cyclic nitrones
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A systematic study of diastereoselective nucleophilic addition of Grignard reagents to six-membered chiral tri-O-benzyl cyclic nitrones is described. With all eight chiral cyclic nitrones and asymmetric reaction conditions in hand, a practical methodology is established for the preparation of diverse 1-deoxyazapyranosides bearing various stereogenic centers. We have developed practical methods to prepare all eight six-membered chiral cyclic nitrones. Using these cyclic nitrones and diastereoselective nucleophilic additions, 12 examples of diverse 1-deoxyazapyranosides including enantiomers were synthesized to demonstrate the generality and flexibility of this new approach.
- Chan, Ting-Hao,Chang, Yi-Fan,Hsu, Jung-Jung,Cheng, Wei-Chieh
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supporting information; experimental part
p. 5555 - 5559
(2011/01/05)
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- Looking glass inhibitors: scalable syntheses of DNJ, DMDP, and (3R)-3-hydroxy-l-bulgecinine from d-glucuronolactone and of l-DNJ, l-DMDP, and (3S)-3-hydroxy-d-bulgecinine from l-glucuronolactone. DMDP inhibits β-glucosidases and β-galactosidases whereas l-DMDP is a potent and specific inhibitor of α-glucosidases
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A convenient large-scale synthesis of 1-deoxynojirimyin (DNJ) from d-glucuronolactone involves introduction of azide at C-5 with retention of configuration to give 5-azido-5-deoxy-1,2-O-isopropylidene-α-d-glucofuranose as a key intermediate in an overall yield of up to 72%; the same intermediate can be transformed into DMDP [(2R,3R,4R,5R)-2,5-bis(hydroxymethyl)pyrrolidine-3,4-diol] and (3R)-3-hydroxy-l-bulgecinine [(2S,3R,4R,5R)-3,4-dihydroxy-5-hydroxymethyl-l-proline]. l-Glucuronolactone, a readily available l-sugar chiron, may similarly be used to access the enantiomers l-DNJ, l-DMDP, and (3S)-3-hydroxy-d-bulgecinine. A comparison of glycosidase inhibition by DMDP (an inhibitor of β-glucosidases and β-galactosidases) and l-DMDP (a potent and specific α-glucosidase inhibitor) with the corresponding enantiomeric hydroxybulgecinines is reported; DMDP and (3R)-3-hydroxy-l-bulgecinine show weak inhibition of glycogen phosphorylase.
- Best, Daniel,Wang, Chen,Weymouth-Wilson, Alexander C.,Clarkson, Robert A.,Wilson, Francis X.,Nash, Robert J.,Miyauchi, Saori,Kato, Atsushi,Fleet, George W.J.
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experimental part
p. 311 - 319
(2010/05/18)
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- An expeditious synthesis of iminosugars
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A short and expedient synthesis of the potent glycosidase inhibitors, 1-deoxynojirimycin, miglitol, miglustat, 1-deoxymannojirimycin, and 1-deoxygalactonojirimycin is presented.
- Gandy, Michael N.,Piggott, Matthew J.,Stubbs, Keith A.
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experimental part
p. 1409 - 1412
(2011/05/14)
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- Unambiguous syntheses of 3-o-benzyl-1,5-dideoxy-1,5-imino-d-glucitol and-l-iditol
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Short and unambiguous syntheses of 3-O-benzyl-1,5-dideoxy-1,5-imino-d- glucitol and -l-iditol are described. The compound previously reported as 3-O-benzyl-1,5-dideoxy-1,5-imino-d-glucitol (Roy, A.; Achari, B.; Mandal, S. B. Synthesis 2006, 1035) is shown to be actually 3-O-benzyl-1,5-dideoxy-1,5-imino- l-iditol. Georg Thieme Verlag Stuttgart New York.
- Csiki, Zsuzsanna,Fuegedi, Peter
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experimental part
p. 2626 - 2630
(2010/09/11)
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- D-fructose-6-phosphate aldolase in organic synthesis: Cascade chemical-enzymatic preparation of sugar-relafed polyhydroxylated compounds
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Novel aldol addition reactions of dihydroxyacetone (DHA) and hydroxyacetone (HA) to a variety of aldehydes catalyzed by D-fructose-6-phosphate aldolase (FSA) are presented. In a chemical-enzymatic cascade reaction approach, 1-deoxynojirimycin and 1-deoxymannojirimycin were synthesized starting from (R)- and (S)-3-(N-Cbz-amino)-2-hydroxypropanal, respectively. Furthermore, 1,4-dideoxy1,4-imino-D-arabinitol and 1,4,5-trideoxy-1,4-imino-D-arabinitol were prepared from N-Cbz-glycinal, 1 -Deoxy-D-xylulose was also synthesized by using HA as the donor and either 2-benzyloxyethanal or 2-hydroxyethanal as acceptors. In both cases the enzymatic aldol addition reaction was fully stereoselective, but with 2-hydroxyethanal 17% of the epimeric product at C2, 1-deoxy-D-erythro-2-pentulose, was observed due to enolization/epimerization during the isolation steps. It was also observed that D-(-)-threose is a good acceptor substrate for FSA, opening new synthetic possibilities for the preparation of important novel complex carbohydrate-related compounds from aldoses. To illustrate this, 1-deoxy-D-ido-hept-2-ulose was obtained stereoselectively by the addition of HA to D-(-)-threose, catalyzed by FSA. It was found that the reaction performance depended strongly on the donor substrate, HA being the one that gave the best conversions to the aldol adduct. The examples presented in this work show the valuable synthetic potential of FSA for the construction of chiral complex polyhydroxylated sugar-type structures.
- Concia, Alda Lisa,Lozano, Caries,Castillo, Jose A.,Parella, Teodor,Joglar, Jesus,Clapes, Pere
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experimental part
p. 3808 - 3816
(2010/01/16)
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- Syntheses and evaluation as glycosidase inhibitor of 1,5-dideoxy-1,5-imino-D-glucitol analogs of salacinol, a potent α-glucosidase inhibitor isolated from ayurvedic medicine, Salacia reticulata
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N-Alkylated deoxynojirimycin (10) bearing the same alkyl chain as salacinol (1), a potent α-glucosidase inhibitor isolated from Ayurvedic traditional medicine, Salacia reticulata, was found to inhibit both rat intestinal maltase and sucrase as strong as 1, while 10 has been reported to be inactive against glucoamylase G2 from Aspergillus niger. Its O-desulfate (12) was also found active against these enzymes, and characteristic sulfate anion moiety of 1 was found not essential for the α-glucosidase inhibitory activity.
- Tanabe, Genzoh,Hatanaka, Takanori,Minematsu, Toshie,Matsuda, Hisashi,Yoshikawa, Masayuki,Muraoka, Osamu
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experimental part
p. 1093 - 1100
(2009/12/26)
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- Stereocontrolled total synthesis of (+)-1-deoxynojirimycin
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A highly efficient non-chiral-pool synthesis of (+)-1-deoxynojirimycin has been realized (24% overall yield, 11 steps, complete stereocontrol). A novel one-pot enol ether metathesis/hydroboration/oxidation sequence is used for the selective formation of the all-trans cyclic triol.
- Danoun, Gregory,Ceccon, Julien,Greene, Andrew E.,Poisson, Jean-Francois
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experimental part
p. 4221 - 4224
(2011/02/24)
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- Large-scale synthesis of the glucosylceramide synthase inhibitor N-[5-(adamantan-1-yl-methoxy)-pentyl]-1-deoxynojirimycin
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A synthetic route for the preparation of glucosylceramide synthase inhibitor N-[5-(adamantan-1-yl-methoxy)-pentyl]-1-deoxynojirimycin methanesulfonic acid salt (AMP-DNM) has been developed. Herein we report the development and optimization of this synthetic route from its initial version in an academic research laboratory at milligram-scale to the final optimized route that was implemented in a cGMP miniplant on kilogram-scale. The definitive route starts with the separate synthesis of building blocks 2,3,4,6-tetra-O- benzyl-1-deoxynojirimycin and 5-(adamantan-1-ylmethoxy)-pentanal. The aldehyde was synthesized from 1,5-pentanediol in five steps and 45% overall yield. Protected 1-deoxynojirimycin was prepared by a successive hemiacetal reduction/Swern oxidation/double reductive amination sequence of 2,3,4,5-tetra-O-benzyl-D-glucopyranose in 52% overall yield. Reductive amination of the two building blocks produced the benzylprotected penultimate that was isolated as its crystalline (+)DTTA salt in 68% yield. Hydrogenolysis of the penultimate and crystallization of the end product as its methanesulfonic acid salt produced AMP-DNM in 76% yield with a purity of >99.5%. The described route enables the production of multikilogram amounts of inhibitor AMP-DNM as a stable crystalline solid with high purity under cGMP control.
- Wennekes, Tom,Lang, Bemhard,Leeman, Michel,Van Der Marel, Gijsbert A.,Smits, Elly,Weber, Matthias,Van Wiltenburg, Jim,Wolberg, Michael,Aerts, Johannes M.F.G.,Overkleeft, Herman S.
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p. 414 - 423
(2013/01/03)
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- New access to 1-deoxynojirimycin derivatives via azide-alkene cycloaddition
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(Chemical Equation Presented) The synthesis of 1-deoxynojirimycin (DNJ) derivatives is described from D-glucono-δ-lactone. The DNJ derivatives were obtained via a sequence that included a stereoselective intramolecular Huisgen reaction, decomposition to an aziridine, and its subsequent reaction with a nucleophile. Minimization of allylic strain in the transition state accounts for the stereoselectivity of the cycloaddition reaction.
- Zhou, Ying,Murphy, Paul V.
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supporting information; experimental part
p. 3777 - 3780
(2009/07/09)
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- Regioselective intramolecular ring closure of 2-amino-6-bromo-2,6- dideoxyhexono-1,4-lactones to 5- or 6-membered iminuronic acid analogues: Synthesis of 1-deoxymannojirimycin and 2,5-dideoxy-2,5-imino-d-glucitol
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1-Deoxymannojirimycin (8c) was synthesised from 2-amino-6-bromo-2,6- dideoxy-d-mannono-1,4-lactone (7) by intramolecular direct displacement of the C-6 bromine employing non-aqueous base treatment followed by reduction of the intermediate methyl ester. Li
- Malle, Birgitte M.,Lundt, Inge,Wrodnigg, Tanja M.
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experimental part
p. 1779 - 1786
(2008/10/09)
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- Stereoselective synthesis of D-1-deoxynojirimycin and its stereoisomers
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A stereoselective synthesis of D-l-deoxynojirimycin (1), D-1-deoxymannojirimycin (2), and D-1-deoxyallonojirimycin (3) was achieved via the regioselective and diastereoselective amination of anti-l,2-dibenzyl ether using chlorosulfonyl isocyanate (CSI), ring-closing metathesis, diastereoselective dihydroxylation, and the regioselective stereochemical inversion of the resulting diol.
- Kim, In Su,Lee, Ho Young,Jung, Young Hoon
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p. 1787 - 1800
(2008/03/14)
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- Selective protecting group manipulations on the 1-deoxynojirimycin scaffold
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Iminosugars are inhibitors of glycoprocessing and are of interest as scaffolds for medicinal chemistry, as their successful application as peptide mimetics has shown. The synthesis of novel peptidomimetics based on 1-deoxynojirimycin (DNJ) requires practical strategies that allow introduction of amino acid side chains or pharmacophore groups at each of its hydroxyl groups or to the nitrogen atom. This paper describes one approach towards achieving selective protection and deprotection at the hydroxyl and amino groups of?DNJ and a novel synthesis of DNJ from l-sorbose is included.
- Danieli, Elisa,Lalot, Jér?me,Murphy, Paul V.
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p. 6827 - 6834
(2008/02/07)
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- Palladium(II)-catalyzed cyclization of urethanes and its application to a total synthesis of 1-deoxynojirimycin
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We have employed a palladium(II)-catalyzed cyclization of allylic alcohol as a key reaction to achieve a total synthesis of the azasugar 1-deoxynojirimycin from o-mannitol. This reaction should be useful for the stereoselective construction of natural poly-substituted piperidine derivatives.
- Yokoyama, Hajime,Kobayashi, Hisatake,Miyazawa, Masahiro,Yamaguchi, Seiji,Hirai, Yoshiro
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p. 283 - 292
(2008/09/17)
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- Imino and amino sugar purification
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Novel processes for the purification of an imino or amino sugar, such as D-1-deoxygalactonojirimycin (DGJ). Particularly, there are described processes for the purification of multi-kilogram scale sugars using hydrochloric acid.
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Page/Page column 5
(2008/06/13)
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- 1,5-Anhydro-D-fructose as chiral building block: A novel approach to 1-deoxymannojirimycin
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A novel six-step synthesis of 1-deoxymannojirimycin from 1,5-anhydro-D-fructose in 35% overall yield is reported. The key steps are nucleophilic piperidine ring formation and subsequent Lewis acid induced pyran ether cleavage. Georg Thieme Verlag Stuttgart.
- Maier, Peter,Andersen, Soren Moller,Lundt, Inge
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p. 827 - 830
(2007/10/03)
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- A short and simple synthesis of 1-deoxynojirimycin derivatives from D-glucose
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Insertion of an amino functionality at C-5 of D-glucose with inversion of configuration, followed by imine formation with the latent aldehyde at C-1 and concomitant reduction furnished the 1-deoxynojirimycin skeleton. Georg Thieme Verlag Stuttgart.
- Roy, Ashim,Achari, Basudeb,Mandal, Sukhendu B.
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p. 1035 - 1039
(2007/10/03)
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- Efficient and stereodivergent synthesis of deoxyimino sugars
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Both cis- and trans-2-substituted-1,2,3,6-tetrahydro-pyridin-3-ols have been prepared via an aldol condensation-ring-closing metathesis sequence. A stereodivergent synthesis of optionally functionalized deoxyimino sugars was achieved via asymmetric dihydroxylation or epoxidation/nucleophilic substitution of these tetrahydropyridines.
- Hong, Bor-Cherng,Chen, Zhong-Yi,Nagarajan, Arumugam,Kottani, Rudresha,Chavan, Vishal,Chen, Wei-Hung,Jiang, Yea-Fen,Zhang, Shuo-Cang,Liao, Ju-Hsiou,Sarshar, Sepehr
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p. 2457 - 2468
(2007/10/03)
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- Asymmetric synthesis of 1-deoxynojirimycin and its congeners from a common chiral building block
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A new, promising chiral building block 9 for the synthesis of 1-deoxy-4,5-trans-oriented azasugars such as 1-deoxynojirimycin (1) was prepared in only four steps from the Garner aldehyde 10 using catalytic ring-closing metathesis (RCM) for the construction of the piperidine ring. In practical test, the first synthesis of all four isomers (1 and 6-8) of trans-4,5-orientated 1-deoxyiminosugars using 9 as a common chiral building block was demonstrated. Graphical Abstract
- Takahata, Hiroki,Banba, Yasunori,Sasatani, Mayumi,Nemoto, Hideo,Kato, Atsushi,Adachi, Isao
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p. 8199 - 8205
(2007/10/03)
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- A General Synthesis of Iminosugars
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1-Deoxynojirimycin, 1-deoxymannojirimycin, and 1-deoxygalactostatin have been synthesized by epoxidation of tri-O-acetyl-6-deoxyhex-5-enopyranosyl azides followed by methanolysis, deacetylation, and catalytic hydrogenation. 1,6-Dideoxygalactostatin was obtained by the reaction of 2,3,4-tri-O-acetyl-6-deoxy-β-L-arabino-hex-5-enopyranosyl azide with NIS in methanol followed by deacetylation and catalytic hydrogenation. The overall yields were 4.4-23.5% over seven to nine steps.
- McDonnell, Ciaran,Cronin, Linda,O'Brien, Julie L.,Murphy, Paul V.
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p. 3565 - 3568
(2007/10/03)
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- A simple access to the D-mannosidase inhibitor, 1-deoxymannojirimycin
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Crystalline 1,3,4,5-tetra-O-acetyl-6-bromo-6-deoxy-keto-D-fructose was prepared by reaction of 1,3,4,5-tetra-O-acetyl-D-fructopyranose with triphenylphosphane dibromide in dichloromethane. Subsequent deprotection followed by reaction of the free 6-bromodeoxyfructofuranose with sodium azide in N,N-dimethylformamide furnished the corresponding 6-azidodeoxyketose. Catalytic hydrogenation led to 1-deoxymannojirimycin in 27% overall yield from 1,3,4,5-tetra-O-acetyl-D-fructopyranose. This access is simple, inexpensive, high-yielding and clearly suitable for multigram preparations.
- Spreitz, Josef,Stuetz, Arnold E.,Wrodnigg, Tanja M.
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p. 183 - 186
(2007/10/03)
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- Enantiopure 2,3-dihydro-4-pyridones as synthetic intermediates: Asymmetric synthesis of 1-deoxynojirimycin
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An asymmetric synthesis of 1-deoxynojirimycin (2) mediated by a chiral auxiliary is reported. The dihydropyridone 4 was converted to diol 11 in three steps by acetoxylation, hydrolysis, and stereoselective reduction. Dihydroxylation of 11 followed by catalytic reduction afforded 2.
- Comins, Daniel L,Fulp, Alan B
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p. 6839 - 6841
(2007/10/03)
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- Synthesis of D- and L-Deoxymannojirimycin via an Asymmetric Aminohydroxylation of Vinylfuran
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(Equation Presented) The Sharpless catalytic asymmetric aminohydroxylation has been applied to 2-vinylfuran, producing β-hydroxyfurfurylamine 5a with enantioexcess of >86% and 21% yield from furfural. The Cbz and TBS protected amino alcohol 5a was converted into both the D- and L-isomers of deoxymannojirimycin (DMJ) and deoxygulonojirimycin in five to seven steps and 48% and 66% overall yields. The key steps include the use of an aza-Achmatowicz reaction, a diastereoselective Luche reduction, diastereoselective dihydroxylation, and a tandem Cbz deprotection/reductive amination.
- Haukaas, Michael H.,O'Doherty, George A.
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p. 401 - 404
(2007/10/03)
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- Novel synthesis of the glycosidase inhibitor deoxymannojirimycin and of a synthetic precursor D-lyxo-hexos-5-ulose
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Equation presented The synthesis of D-lyxo-hexos-5-ulose (5-ketomannose, 1,5-dicarbonyl sugar), a synthetic precursor to the glycoprocessing inhibitor deoxymannojirimycin, was carried out by an in situ epoxidation and hydrolysis of a trimethylsilyl-protected 6-deoxyhex-5-enopyranoside followed by facile removal of the protecting groups. A novel nine-step synthesis of deoxymannojirimycin has also been achieved from methyl α-D-mannopyranoside; this involved methanolysis of epoxides derived from an acetylated 1-azido-6-deoxyhex-5-enopyranoside followed by deprotection and catalytic hydrogenation.
- O'Brien, Julie L.,Tosin, Manuela,Murphy, Paul V.
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p. 3353 - 3356
(2007/10/03)
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- A general approach to the synthesis of dideoxy and trideoxyiminoalditols from β-D-glycosides
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Imino sugars (also called azasugars), a class of compounds of which the 1,5-dideoxy and 1,5,6-trideoxyiminoalditols are members, are important glycosidase inhibitors with very high potential as drugs. Their potential therapeutic applications range from the treatment of diabetes to cancer and AIDS. We present here a general method for the preparation of such compounds with the D-gluco and D-galacto configurations starting from β-D-glycosides. The procedure is especially appealing because of its high stereoselectivity and straightforwardness. The key steps are the selective oxidation of the glycosides to hexulosonic acids and reduction of the oxime derivatives to lactams, which are further reduced to the target compounds. The C-6 position can be deoxygenated during the reduction if it bears an acetoxy group. Trideoxy imino sugars are then produced. Deacetylation prior to oxime reduction gives dideoxy compounds. (C) 2000 Elsevier Science Ltd.
- Pistia, Gabriela,Hollingsworth, Rawle I.
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p. 467 - 472
(2007/10/03)
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- Synthesis of 1-deoxynojirimycin and N-butyl-1-deoxynojirimycin
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1-Deoxynojirimycin (1) is a natural alkaloid with several biological activities; the analog N-butyl-1-deoxynojirimycin (4), for example has shown potent anti HIV-1 and HIV-2 activity without cytotoxicity. As part of a program to synthesize compounds with biological activity against retroviruses, we developed an efficient route for the preparation of 1 and 4 employing as raw material glucose and others inexpensive reagents.
- Matos, Carlos R. R.,Lopes, Rosangela S. C.,Lopes, Claudio C.
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p. 571 - 573
(2007/10/03)
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- New entry for asymmetric deoxyazasugar synthesis: Syntheses of deoxymannojirimycin, deoxyaltrojirimycin and deoxygalactostatin
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Deoxyazasugars such as deoxymannojirimycin, deoxyaltrojirimycin and deoxygalactostatin were stereoselectively synthesized starting from (R)-(+)-4-methoxycarbonyloxazolidinoe via a bicyclic oxazolidinylpiperidine as a common synthetic intermediate.
- Asano, Koji,Hakogi, Toshikazu,Iwama, Seiji,Katsumura, Shigeo
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- Simple synthetic route to polyhydroxylated pyrrolidines and piperidines
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A short and simple synthetic route to polyhydroxylated piperidines and pyrrolidines were described with D-glucurono-δ-lactone as chiral educt. Key reaction steps included selective cleavage of terminal isopropylidene group of compound 12 with Dowex 50W-X8 resin (H+ form), regioselective ring opening of epoxide 16 and intramolecular nucleophilic amination of compound 14 and 18.
- Lee, Sang Gyeong,Park, Ki Hun,Yoon, Yong-Jin
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p. 711 - 715
(2007/10/03)
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- Total syntheses of (+)- and (-)-1-deoxynojirimycin (1,5-dideoxy-1,5-imino-D- and L-glucitol) and of (+)- and (-)-1-deoxyidonojirimycin (1,5-dideoxy-1,5-imino-D- and L-iditol) via furoisoxazoline-3-aldehydes
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The isoxazoline obtained by 1,3-dipolar cycloaddition of 2,2-diethoxyacetonitrile N-oxide to furan was converted into enantiomerically pure (-)-(3aS,5S,6S,6aR)- and (+)-(3aR,5R,6R,6aS)-3a,5,6,6a-tetrahydro-5,6-isopropylidenedioxyfuro[2,3-d]isoxazole-3-carbaldehyde, (-)-5 and (+)-5, respectively, through resolution with (1S,2S)-1,2-diphenylethylenediamine. The aldehydes 5 are required as latent 1,5-iminohexitol moieties in cross-aldolizations towards imino-C-disaccharides. In order to establish absolute configurations of 5, and to probe the projected uses, (+)-5 was converted into (+)-1-deoxynojirimycin [(+)-1, 3 steps, 58%] and into (-)-1,5-dideoxy-1,5-imino-l-iditol [(-)-2, 4 steps, 40%] adopting stereoselective routes. Similarly, (-)-1,5-dideoxy-1,5-imino-l-glucitol ((-)-1) and (+)-1,5-dideoxy-1,5-imino-D-iditol ((+)-2) were obtained with the same ease. Copyright (C) 1998 Elsevier Science Ltd.
- Schaller, Christophe,Vogel, Pierre,Jaeger, Volker
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- Asymmetric synthesis of (+)-1-deoxynojirimycin
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An asymmetric synthesis of (+)-1-deoxynojirimycin (1) in 14 steps starting from diene (5) is described. The key transformations in the sequence are a sharpless dihydroxylation and epoxidation followed by a regio- and stereoselective aminolysis of vinyl epoxide 11 to give piperidine 12.
- Lindstroem, Ulf M.,Somfai, Peter
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p. 7173 - 7176
(2007/10/03)
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