- Concise and highly stereoselective syntheses of D-fagomine and 2-epi-fagomine
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Highly stereoselective total syntheses of polyhydroxylated piperidines D-fagomine and 2-epi-fagomine have been developed starting from 3,4,6-tri-O-benzyl-D-glucal which is a derivative of D-Glucose. Key steps in the synthesis of these azasugars involved N-Boc-protected amine preparation from oxime followed by stereo specific iodination of alcohol and cascade cyclization triggered by N-Boc deprotection.
- Kallam, Srinivasa Reddy,Datrika, Rajender,Khobare, Sandip R.,Gajare, Vikas S.,Rajana, Nagaraju,Mohan, H. Rama,Babu, J. Moses,Siddaiah,Pratap
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p. 1351 - 1353
(2018/03/23)
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- A PROCESS FOR SYNTHESIS OF PIPERIDINE ALKALOIDS
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The present invention discloses a process for synthesis of piperidine alkaloids selected from fagomine, 4-epi-fagomine and nojirimycin from tri-O-benzyl-D-glucal or tri-O-benzyl-D-galactal.
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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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- Applications and limitations of the I2-mediated carbamate annulation for the synthesis of piperidines: Five-versus six-membered ring formation
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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.
- Corkran, Hilary M.,Munneke, Stefan,Dangerfield, Emma M.,Stocker, Bridget L.,Timmer, Mattie S. M.
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p. 9791 - 9802
(2013/10/22)
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- Total synthesis of d-fagomine and 6-deoxyfagomine
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Total synthesis of d-fagomine and 6-deoxyfagomine from readily available d-lyxose is described. The key steps included regioselective and diastereoselective amination, hydroboration-oxidation, and Appel reaction. The reaction of 3,4-anti-tribenzyl ether with chlorosulfonyl isocyanate in toluene at 0 °C afforded 3,4-anti-amino alcohol, an essential compound for the preparation of d-fagomine and 6-deoxyfagomine, with a high diastereoselectivity (dr=26:1) in 74% yield. The origin of diastereoselectivity can be explained by the neighboring group effect, which leads to retention of the stereochemistry.
- Min, Im Sook,Kim, Seung In,Hong, Seungmin,Kim, In Su,Jung, Young Hoon
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p. 3901 - 3906
(2013/06/27)
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- Assessment of partially deoxygenated deoxynojirimycin derivatives as glucosylceramide synthase inhibitors
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Glucosylceramide synthase (GCS) is an approved drug target for the treatment of Gaucher disease and is considered as a valid target for combating other human pathologies, including type 2 diabetes. The clinical drug N-butyldeoxynojirimycin (Zavesca) is thought to inhibit through mimicry of its substrate, ceramide. In this work we demonstrate that, in contrast to what is proposed in this model, the C2-hydroxyl of the deoxynojirimycin core is important for GCS inhibition. Here we show that C6-OH appears of less important, which may set guidelines for the development of GCS inhibitors that have less affinity (in comparison with Zavesca) for other glycoprocessing enzymes, in particular those hydrolases that act on glucosylceramide.
- Van Den Berg, Richard J. B. H. N.,Wennekes, Tom,Ghisaidoobe, Amar,Donker-Koopman, Wilma E.,Strijland, Anneke,Boot, Rolf G.,Van Der Marel, Gijsbert A.,Aerts, Johannes M. F. G.,Overkleeft, Herman S.
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supporting information; experimental part
p. 519 - 522
(2011/09/15)
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- Efficient and stereoselective syntheses of DAB-1 and D-fagomine via chiral 1,3-oxazine
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The concise, stereocontrolled syntheses of DAB-1 and d-fagomine were achieved utilizing chiral oxazine. The key features in these strategies are the stereoselective intramolecular oxazine formation catalyzed by palladium(0), and pyrrolidine and piperidine formation by catalytic hydrogenation of oxazine.
- Kim, Ji-Yeon,Mu, Yu,Jin, Xiangdan,Park, Seok-Hwi,Pham, Van-Thoai,Song, Dong-Keun,Lee, Kee-Young,Ham, Won-Hun
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p. 9426 - 9432
(2011/12/14)
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- Synthesis of non-natural carbohydrates from glycerol and aldehydes in a one-pot four-enzyme cascade reaction
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A simple procedure has been developed for the synthesis of enantio- and diastereomerically pure carbohydrate analogues from glycerol and a variety of aldehydes in one pot using a four-enzyme cascade reaction. As a proof of concept of the usefulness of this enzymatic catalytic cascade the naturally occurring azasugar d-fagomine was synthesized. This work highlights the potential value of using enzymes in cascade reactions to selectively form complex products that by previous traditional organic chemistry could only be obtained via repeated isolation and purification of intermediates.
- Babich, Lara,Van Hemert, Lieke J. C.,Bury, Aleksandra,Hartog, Aloysius F.,Falcicchio, Pierpaolo,Van Der Oost, John,Van Herk, Teunie,Wever, Ron,Rutjes, Floris P. J. T.
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experimental part
p. 2895 - 2900
(2011/12/05)
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- Silicon-mediated asymmetric synthesis of fagomine and 3,4-di-epi-fagomine
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The synthesis of d-fagomine and its stereoisomer, d-3,4-di-epi-fagomine has been achieved from C2-symmetric 3,4-bis-silyl substituted adipic acid di-oxazolidin-2-one derivatives via stereocontrolled azidation and silicon to hydroxyl conversion as the key steps. The Evans oxazolidin-2-one controlled the stereochemical outcome of the azidation which supersedes the directing effects of the silyl substituent.
- Kundu, Pintu K.,Ghosh, Sunil K.
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p. 1090 - 1096
(2011/10/04)
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- Efficient and stereodivergent syntheses of D- and L-fagomines and their analogues
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The syntheses of D- and L-fagomines 1, 4, 5 and 6 and their isomers from starting D-glycals have been achieved. The syntheses involve elaboration of common amino alcohol precursors obtained from 2-deoxy-1-amino sugar derivatives. The key steps in the synt
- Kumari, Nitee,Reddy, B. Gopal,Vankar, Yashwant D.
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experimental part
p. 160 - 169
(2009/08/09)
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- Asymmetric synthesis of fagomine
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We report an asymmetric synthesis of the alkaloid fagomine, which is an inhibitor of mammalian α-glucosidase and β-galactosidase, by means of Sharpless asymmetric dihydroxylation and Pd(II)-catalyzed cyclization, starting from 3-(t-butoxylcarbonylamino)propanol.
- Yokoyama, Hajime,Ejiri, Hiromi,Miyazawa, Masahiro,Yamaguchi, Seiji,Hirai, Yoshiro
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p. 852 - 856
(2008/01/13)
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- D-fructose-6-phosphate aldolase-catalyzed one-pot synthesis of iminocyclitols
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A one-pot chemoenzymatic method for the synthesis of a variety of new iminocyclitols from readily available, non-phosphorylated donor substrates has been developed. The method utilizes the recently discovered fructose-6-phosphate aldolase (FSA), which is functionally distinct from known aldolases in its tolerance of different donor substrates as well as acceptor substrates. Kinetic studies were performed with dihydroxyacetone (DHA), the presumed endogenous substrate for FSA, as well as hydroxy acetone (HA) and 1-hydroxy-2-butanone (HB) as donor substrates, in each case using glyceraldehyde-3-phosphate as acceptor substrate. Remarkably, FSA used the three donor substrates with equal efficiency, with kcat/KM-values of 33, 75, and 20 M -1 s-1, respectively. This level of donor substrate tolerance is unprecedented for an aldolase. Furthermore, DHA, HA, and HB were accepted as donors in FSA-catalyzed aldol reactions with a variety of azido- and Cbz-amino aldehyde acceptors. The broad substrate tolerance of FSA and the ability to circumvent the need for phosphorylated substrates allowed for one-pot synthesis of a number of known and novel iminocyclitols in good yields, and in a very concise fashion. New iminocyclitols were assayed as inhibitors against a panel of glycosidases. Compounds 15 and 16 were specific α-mannosidase inhibitors, and 24 and 26 were potent and selective inhibitors of β-N-acetylglucosaminidases in the submicromolar range. Facile access to these compounds makes them attractive core structures for further inhibitor optimization.
- Sugiyama, Masakazu,Hong, Zhangyong,Liang, Pi-Hui,Dean, Stephen M.,Whalen, Lisa J.,Greenberg, William A.,Wong, Chi-Huey
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p. 14811 - 14817
(2008/09/19)
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- Fructose-6-phosphate aldolase in organic synthesis: Preparation of D-fagomine, N-alkylated derivatives, and preliminary biological assays
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(Chemical Equation Presented) 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 β-galactosidase and α-glucosidase.
- Castillo, Jose A.,Calveras, Jordi,Casas, Josefina,Mitjans, Montserrat,Vinardell, M. Pilar,Parella, Teodor,Inoue, Tomoyuki,Sprenger, Georg A.,Joglar, Jesus,Clapes, Pere
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p. 6067 - 6070
(2008/02/07)
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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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- Stereoselective Aldol Additions Catalyzed by Dihydroxyacetone Phosphate-Dependent Aldolases in Emulsion Systems: Preparation and Structural Characterization of Linear and Cyclic Iminopolyols from Aminoaldehydes
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The potential of dihydroxyacetone phosphate (DHAP)-dependent aldolases to catalyze stereoselective aldol additions is, in many instances, limited by the solubility of the acceptor aldehyde in aqueous/co-solvent mixtures. Herein, we demonstrate the efficiency of emulsion systems as reaction media for the class I fructose-1,6-b isphosphate aldolase (RAMA) and class II recombinant rhamnulose-1-phosphate aldolase from E. coli (RhuA)catalyzed aldol addition between DHAP and N-benzyloxycarbonyl (N-Cbz) aminoaldehydes. The use of emulsions improved the RAMA-catalyzed aldol conversions by three to tenfold relative to those in conventional DMF/ water mixtures. RhuA was more reactive than RAMA towards the N-Cbz aminoaldehydes regardless of the reaction medium. With (S)- or (R)-Cbz-alaninal, RAMA exhibited preference for the R enantiomer, while RhuA had no enantiomeric discrimination. The linear N-Cbz aminopolyols thus obtained were submitted to catalytic intramolecular reductive amination to afford the corresponding iminocyclitols. This reaction was diastereoselective in all cases examined; the face selectivity was controlled by the stereochemistry of the newly formed hydroxyl group originating from the aldehyde. Characterization of the resulting iminocyclitols allowed the assessment of the diastereoselectivity of the enzymatic aldol reactions with respect to the N-protected aminoaldehyde. RAMA formed single diastereoisomers from N-Cbz-glycinal and from both enantiomers of N-Cbz-alaninal, while 14% of the epimeric product was observed from N-Cbz-3-aminopropanal. Diastereoselectivity from RhuA was lower than that observed from RAMA. Interestingly, a single diastereoisomer was formed from (S)-Cbz-alaninal, whereas only a 34% diastereomeric excess was observed from its enantiomer (i.e., (R)-Cbz-alaninal).
- Espelt, Laia,Parella, Teodor,Bujons, Jordi,Solans, Conxita,Joglar, Jesus,Delgado, Antonio,Clapes, Pere
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p. 4887 - 4899
(2007/10/03)
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- Asymmetric synthesis of the four possible fagomine isomers
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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.
- Takahata, Hiroki,Banba, Yasunori,Ouchi, Hidekazu,Nemoto, Hideo,Kato, Atsushi,Adachi, Isao
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p. 3603 - 3607
(2007/10/03)
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- Asymmetric synthesis of fagomine and its congeners
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The total synthesis of fagomine and its congeners 1-3 has been achieved starting from D-serine-derived Garner aldehyde 5 by catalytic ring-closing metathesis (RCM) for the construction of the piperidine ring followed by dihydroxylation.
- Banba, Yasunori,Abe, Chiemi,Nemoto, Hideo,Kato, Atsushi,Adachi, Isao,Takahata, Hiroki
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p. 817 - 819
(2007/10/03)
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- Enzyme-Catalyzed Reactions, 13. - A New, Efficient Synthesis of Fagomine
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2-Deoxy-L-threo-5-hexulosonitrile (4) is obtained in excellent chemical yield by yeast transketolase (EC 2.2.1.1)-catalyzed reaction of racemic 3-hydroxy-4-oxobutyronitrile with lithium hydroxypyruvate (3).Catalytic hydrogenation of 4 exclusively gives fagomine (7).Key Words: Fagomine / Enzymes / Transketolase / Carbohydrates / Yeast transketolase
- Effenberger, Franz,Null, Volker
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p. 1211 - 1212
(2007/10/02)
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- Synthesis of homochiral β-hydroxy-α-aminoacids [2S,3R,4R)-3, 4-dihydroxyproline and (2S,3R,4R)-3,4-dihydroxypipecolic acid] and of 1,4-dideoxy-1,4-imino-D-arabinitol [DAB1] and fagomine [1,5-imino-1,2,5-trideoxy-D-arabino-hexitol]
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Efficient syntheses from diacetone glucose of 1,4-dideoxy-1, 4-imino-D-arabinitol, (2S,3R,4R)-3,4-dihydroxyproline, fagomine [1,5-imino-1,2,5-trideoxy-D arabino-hexitol], and (2S,3R,4R)-3,4)-3,4-dihydroxpipecolic acid by intramolecular nucleophilic displacement by an amino function of 2-O-trifluoromethanesulphonates of anomeric mixtures of methyl furanosides are reported.
- Fleet,Witty
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p. 119 - 136
(2007/10/02)
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- Use of a recombinant bacterial fructose-1,6-diphosphate aldolase in aldol reactions: Preparative syntheses of 1-deoxynojirimycin, 1-deoxymannojirimycin, 1,4-dideoxy-1,4-imuno-D-arabinitol, and fagomine
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A combined enzymatic aldol condensation and catalytic intramolecular reductive amination has been used in the high-yield asymmetric synthesis of polyhydroxylated alkaloids including 1-deoxynojirimycin, 1-deoxymannojirimycin, 1,4-dideoxy-1,4-imino-D-arabinitol, and fagomine. The Escherichia coli Zn2+-containing fructose-1,6-diphosphate aldolase overexpressed in E. coli was used for the syntheses. The enzyme in aqueous solution containing 0.3 mM ZnCl2 has excellent stability with a half-life of 60 days, compared to 2 days for the enzyme from rabbit muscle. The reactions were carried out under mild conditions without protection of functional groups. Either dihydroxyacetone phosphate or a mixture of dihydroxyacetone and inorganic arsenate can be used as donor in the aldol reactions. The aldol acceptors (R)- and (S)-3-azido-2-hydroxypropanal were prepared via lipase-catalyzed resolution of the racemic acetal precursor.
- Von Der Osten,Sinskey,Barbas III,Pederson,Wang,Wong
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p. 3924 - 3927
(2007/10/02)
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- ENZYMATIC ALDOL CONDENSATION AS A ROUTE TO HETEROCYCLES: SYNTHESIS OF 1,4-DIDEOXY-1,4-IMINO-D-ARABINITOL, FAGOMINE, 1-DEOXYNOJIRIMYCIN AND 1-DEOXYMANNOJIRIMYCIN
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1,4-Dideoxy-1,4-imino-D-arabinitol, fagomine (1,2,5-trideoxy-1,5-imino-D-arabinohexitol), 1-deoxynojirimycin (1,5-dideoxy-1,5-imino-D-glucitol) and 1-deoxymannojirimycin (1,5-dideoxy-1,5-imino-D-mannitol) have been prepared via fructose-1,6-diphosphate aldolase catalyzed condensation followed by catalytic intramolecular reductive amination.
- Pederson, Richard L.,Wong, Chi-Huey
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p. 477 - 480
(2007/10/02)
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- SYNTHESIS OF DEOXYMANNOJIRIMYCIN FAGOMINE DEOXYNOJIRIMYCIN 2-ACETAMIDO-1,5-IMINO-1,2,5-TRIDEOXY-D-MANNITOL 2-ACETAMIDO-1,5-IMINO-1,2,5-TRIDEOXY-D-GLUCITOL 2S,3R,4R,5R-TRIHYDROXYPIPECOLIC ACID AND 2S,3R,4R,5S-TRIHYDROXYPIPECOLIC ACID FROM METHYL 3-O-BENZYL-2,6-DIDEOXY-2,6-IMINO-α-D-...
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The value of methyl 3-O-benzyl-2,6-dideoxy-2,6-imino-α-D-mannofuranoside as a divergent intermediate for the preparation of polyhydroxylated piperidines is illustrated by the synthesis of deoxymannojirimycin (1,5-dideoxy-1,5-imino-D-mannitol), fagomine (1,5-imino-1,2,5-trideoxy-D-arabino-hexitol), deoxynojirimycin (1,5-dideoxy-1,5-imino-D-glucitol), 2-acetamido-1,5-imino-1,2,5-trideoxy-D-mannitol, 2-acetamido-1,5-imino-1,2,5-trideoxy-D-glucitol, 2S,3R,4R,5R-trihydroxypipecolic acid and 2S,3R,4R,5S-trihydroxypipecolic acid.
- Fleet, George W. J.,Fellows, L. E.,Smith, Paul W.
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p. 979 - 990
(2007/10/02)
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- LACK OF GLYCOSIDASE INHIBITION BY, AND ISOLATION FROM XANTHOCERCIS ZAMBESIACA (LEGUMINOSAE) OF, 4-O-(&β-D-GLUCOPYRANOSYL)-FAGOMINE , A NOVEL GLUCOSIDE OF POLYHYDROXYLATED PIPERIDINE ALKALOID
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A COSY spectrum has been used to determine the position of inter-residue linkage in 4-O-(β-D-glucopyranosyl) fagomine (1) an example of a new class of glycosides of polyhydroxylated piperidine alkaloids isolated from seed of the legume Xanthocercis zambesiaca. (Bak.) Dunn.Unlike a number of polyhydroxylated piperidines, neither the glucoside (1) nor the fagomine (3) showed any inhibitory activity towards glycosidase enzymes from a variety of sources.
- Evans, Stephen V.,Hayman, Alison R.,Fellows, Linda E.,Shing, Tony K. M.,Derome, Andrew E.,Fleet, George W. J.
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p. 1465 - 1468
(2007/10/02)
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