- Iminosugars from Baphia nitida Lodd.
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Chromatographic separation of the 50% aqueous EtOH extract of the leaves of the African medicinal tree Baphia nitida resulted in isolation of 10 iminosugars. The plant contained 2R,5R-dihydroxymethyl-3R,4R-dihydroxypyrrolidine (DMDP) as a major alkaloid. The structure of a new alkaloid was also elucidated by spectroscopic methods as the 1-O-β-d-fructofuranoside of DMDP, and this plant produced 3-O-β-d-glucopyranosyl-DMDP as well. DMDP is a potent inhibitor of β-glucosidase and β-galactosidase, whereas the other two derivatives lowered inhibition toward both of these enzymes and improved inhibitory activities toward rice α-glucosidase and rat intestinal maltase.
- Kato, Atsushi,Kato, Noriko,Miyauchi, Saori,Minoshima, Yuka,Adachi, Isao,Ikeda, Kyoko,Asano, Naoki,Watson, Alison A.,Nash, Robert J.
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Read Online
- METHODS OF TREATING POMPE DISEASE
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Disclosed herein are novel uses of ADMDP stereoisomers or their derivatives for the manufacture of a medicament for treating Pompe disease. Accordingly, the present disclosure provides a method of treating Pompe disease in a subject. The method includes the step of, administering to the subject a therapeutically effective amount of a compound of formula (I), or a salt, an ester or a solvate thereof, wherein R1 and R2 are independently H or alkyl optionally substituted by -NH2 or -OH, so as to ameliorate, alleviate mitigate and/or prevent symptoms associated with the Pompe disease. According to certain embodiments of the present disclosure, the compound of formula (I) may serve a stabilizer of α-glucosidase via preventing its denaturalization of deactivation.
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Paragraph 0065-0066; 0069-0070
(2021/04/10)
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- 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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p. 657 - 661
(2015/08/03)
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- Diastereoselective concise syntheses of the polyhydroxylated alkaloids DMDP and DAB
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A diastereoselective concise synthesis of the iminosugars DMDP and DAB is presented starting from l-xylose and affording the two alkaloids in good yields of 35% and 22% over seven and eight steps, respectively. The Petasis borono-Mannich reaction of 3,5-di-O-benzyl-l-xylofuranose with benzylamine and (E)-styrylboronic acid served as the nitrogen-introducing key step furnishing the new C-N bond in an entirely diastereoselective manner. A chemo- and regioselective O-mesylation followed by an intramolecular SN2- cyclisation allowed the formation of the pyrrolidine ring. Ozonolysis of the styryl double bond and subsequent reduction to form the C-5 hydroxymethyl substituent followed by hydrogenolysis of the benzyl protecting groups concluded the DMDP synthesis. Furthermore, an unexpected fragmentation process during the ozonolysis reaction also gave access to the C-5 decarbinolated DMDP derivative DAB.
- Bouillon, Marc E.,Pyne, Stephen G.
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p. 475 - 478
(2014/01/06)
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- Stereoselective synthesis of (2S,3S,4R,5S)-3,4-dihydroxy-2,5- dihydroxymethyl pyrrolidine from l-sorbose
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One of the most frequently synthesized iminosugar derivatives is DMDP. Starting from l-sorbose, a practical method for the synthesis of derivatives of this five-membered iminocyclitol has been developed, involving straightforward steps and a convenient selective reduction of a ketoxime intermediate.
- Balieu, Sebastien,Guilleret, Arnaud,Reynaud, Romain,Martinez, Agathe,Haudrechy, Arnaud
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- C-branched iminosugars: α-glucosidase inhibition by enantiomers of isoDMDP, isoDGDP, and isoDAB- l -isoDMDP compared to miglitol and miglustat
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The Ho crossed aldol condensation provides access to a series of carbon branched iminosugars as exemplified by the synthesis of enantiomeric pairs of isoDMDP, isoDGDP, and isoDAB, allowing comparison of their biological activities with three linear isomeric natural products DMDP, DGDP, and DAB and their enantiomers. l-IsoDMDP [(2S,3S,4R)-2,4-bis(hydroxymethyl)pyrrolidine-3,4-diol], prepared in 11 steps in an overall yield of 45% from d-lyxonolactone, is a potent specific competitive inhibitor of gut disaccharidases [Ki 0.081 μM for rat intestinal maltase] and is more effective in the suppression of hyperglycaemia in a maltose loading test than miglitol, a drug presently used in the treatment of late onset diabetes. The partial rescue of the defective F508del-CFTR function in CF-KM4 cells by l-isoDMDP is compared with miglustat and isoLAB in an approach to the treatment of cystic fibrosis.
- Jenkinson, Sarah F.,Best, Daniel,Saville, A. Waldo,Mui, James,Martinez, R. Fernando,Nakagawa, Shinpei,Kunimatsu, Takahito,Alonzi, Dominic S.,Butters, Terry D.,Norez, Caroline,Becq, Frederic,Bleriot, Yves,Wilson, Francis X.,Weymouth-Wilson, Alexander C.,Kato, Atsushi,Fleet, George W. J.
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p. 7380 - 7397
(2013/09/02)
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- Enantioselective construction of a polyhydroxylated pyrrolidine skeleton from 3-vinylaziridine-2-carboxylates: Synthesis of (+)-DMDP and a potential common intermediate for (+)-hyacinthacine A1 and (+)-1-epi-australine
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We report an enantioselective synthesis of the polyhydroxylated pyrrolidine alkaloid (+)-DMDP. The key steps in the synthesis were guanidinium ylide mediated asymmetric aziridination, stereospecific ring opening of trans-3-vinylaziridine-2- carboxylate with an oxygen nucleophile, iodine-mediated 5-endo-trig amino cyclization, and Prevost displacement. In addition, a potential common intermediate for the polyhydroxylated pyrrolizidine alkaloids (+)-hyacinthacine A1 and (+)-1-epi-australine was synthesized from a diastereoisomeric cis-aziridine coformed in the asymmetric aziridination using the same strategy. A rationale for the diastereoselectivity observed for the iodine-mediated amino cyclization reactions is proposed on the basis of the heats of formation of the products.
- Kondo, Yukari,Suzuki, Noriyuki,Takahashi, Masato,Kumamoto, Takuya,Ishikawa, Tsutomu,Masu, Hyuma
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p. 7988 - 7999,12
(2020/10/15)
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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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- A convenient approach toward the synthesis of enantiopure isomers of DMDP and ADMDP
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A practical method for the synthesis of five-membered iminocyclitols, pyrrolidine alkaloids bearing multiple hydroxyl substituents, has been developed. All of the eight key intermediates, enantiopure tri-O-benzyl cyclic nitrones, are prepared from four cheap, readily available d-aldopentoses. The nucleophilic addition of cyclic nitrones with vinyl magnesium chloride and TMSCN shows high 2,3-trans stereoselectivity. To construct the 2,3-cis configurations, inversion of the C-2 nitrile group is achieved via an elimination-reduction sequence. Using this approach, five isomers of DMDP and six isomers of ADMDP are prepared efficiently. In the biological evaluation, iminocyclitol 27 is a new and potent inhibitor against β-hexosaminidase with an IC50 value of 0.2 μM.
- Tsou, En-Lun,Yeh, Yao-Ting,Liang, Pi-Hui,Cheng, Wei-Chieh
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experimental part
p. 93 - 100
(2009/04/07)
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- A concise synthesis of 2,5-dideoxy-2,5-imino-d-mannitol (DMDP) and HomoDMDP from l-xylose
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A short and practical procedure for the preparation of C-2 substituted polyhydroxypyrrolidines is described. The C-2 substituent is introduced by a stereoselective addition of a Grignard reagent to a 2,3,5-protected aldofuranose and the cyclization to the pyrrolidine ring system is performed through a bis-mesylation/double nucleophilic displacement sequence. The efficiency of the methodology was demonstrated by its application to the synthesis of HomoDMDP and DMDP.
- Behr, Jean-Bernard,Guillerm, Georges
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p. 2369 - 2372
(2007/10/03)
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- Palladium-catalyzed DYKAT of butadiene monoepoxide: Enantioselective total synthesis of (+)-DMDP, (-)-bulgecinine, and (+)-broussonetine G
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Palladium catalyzed asymmetric allylic alkylation reaction of an amine with two equivalents of butadiene monoxide allows for the expedient synthesis of trans- and cis-2,5-dihydropyrroles. The versatility of these chiral synthons towards the synthesis of a wide variety of iminosugar natural products was demonstrated with the short and high yielding asymmetric syntheses of (+)-DMDP, and (-)-bulgecinine. In addition, the first total synthesis of (+)-broussonetine G, a potent glycosidase inhibitor, is described along with the assignment of its relative and absolute stereochemical configuration.
- Trost, Barry M.,Horne, Daniel B.,Woltering, Michael J.
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p. 6607 - 6620
(2008/09/16)
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- Intramolecular benzyl protection delivery: A practical synthesis of DMDP and DGDP from D-fructose
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A two-step protection of 1,2-diols as the corresponding o-xylylene cyclic ethers, involving an intramolecular ring-closing O-benzylation reaction, has been developed to overcome the problems associated to regioselective benzylation reactions. The strategy has been applied to the high-yielding synthesis of the pyrrolidine glycosidase inhibitors DMDP and DGDP.
- Garcia-Moreno, M. Isabel,Aguilar, Matilde,Mellet, Carmen Ortiz,Garcia Fernandez, Jose M.
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p. 297 - 299
(2007/10/03)
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- Pseudoamide-Type Pyrrolidine and Pyrrolizidine Glycomimetics and Their Inhibitory Activities against Glycosidases
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Coupling reaction of (2R,3R,4R,5R)-2,5-hydroxy-methyl-3,4-dihydroxypyrrolidine (DMDP) with isothiocyanates afforded the corresponding thiourea adducts, which were transformed into isourea-type bicyclic oxapyrrolizidine glycomimetics by mercury(II) oxide-assisted intramolecular sulfur displacement. Cyclic carbamate and thiocarbamate analogues were also prepared by direct carbonylation or thiocarbonylation of DMDP. Evaluation of the glycosidase inhibitory properties demonstrated that remarkable specificities in enzyme inhibition can be achieved upon modifications on the pseudoaglyconic side chain and on the nature of the sp2-hybridized endocyclic ring nitrogen.
- Garcia-Moreno, M. Isabel,Rodriguez-Lucena, David,Ortiz Mellet, Carmen,Garcia Fernandez, Jose M.
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p. 3578 - 3581
(2007/10/03)
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- Synthesis of dihydroxylated prolines and iminocyclitols from five-membered endocyclic enecarbamates. Total synthesis of the potent glycosidase inhibitor (2R,3R,4R,5R)-2,5-dihydroxymethyl-3,4-dihydroxypyrrolidine (DMDP)
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cis- and trans-3,4-Dihydroxylated prolines and the iminocyclitol 1,4-dideoxy-1,4-imino ribitol were synthesized employing a strategy involving the Heck arylation of five-membered endocyclic enecarbamates with aryldiazonium salts followed by oxidative cleavage of the electron-rich aromatic ring. The total synthesis of the potent α- and β-glucosidase inhibitor (2R,3R,4R,5R)-2,5-hydroxymethyl-3,4-dihydroxypyrrolidine (DMDP) was also achieved by the same strategy in ten steps from a chiral five-membered enecarbamate in 12% overall yield.
- Garcia, Ariel Lázaro L.,Correia, Carlos Roque D.
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p. 1553 - 1557
(2007/10/03)
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- New synthesis of pyrrolidine homoazasugars via aminohomologation of furanoses and their use for the stereoselective synthesis of aza-C-disaccharides
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The introduction of a formyl group at the anomeric center of 2,3,5-tri-O-benzyl furanoses and substitution of the ring oxygen with a basic nitrogen atom (aminohomologation) was carried out via stereoselective addition of 2-lithiothiazole to N-benzyl, N-furanosylhydroxylamines (masked N-benzyl sugar nitrones), followed by reductive dehydroxylation of the resulting open-chain adducts, and then ring closure via intramolecular displacement of the free hydroxy group by the amino group and unmasking of the formyl group from the thiazole ring. The resulting formyl aza-C-glycosides were transformed into 2,5-dideoxy-2,5-imino-hexitols (pyrrolidine homoazasugars) by reduction of the formyl to the hydroxymethyl group and removal of the O- and N-benzyl groups by hydrogenolysis. This reaction sequence was applied to four furanoses (D-arabino, D-ribo, D-lyxo, L-xylo) to give the hydroxy- and amino-free homoazasugars, including the natural product 2,5-dideoxy-2,5-imino-D-mannitol, in 17% overall yields (six steps). The formyl aza-C-glycosides proved to be valuable intermediates for the synthesis of more complex derivatives. In fact, these sugar aldehydes were employed in Wittig-type coupling reactions with galactose and ribose phosphoranes to give bis-glycosylated alkenes, which upon reduction of the double bond were transformed into methylene isosteres of (1→6)- and (1→5)-linked disaccharides in which one of the two sugar moieties was an azasugar (aza-(1→x)-C-disaccharides).
- Dondoni, Alessandro,Giovannini, Pier Paolo,Perrone, Daniela
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p. 7203 - 7214
(2007/10/03)
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- Synthesis of azasugars as potent inhibitors of glycosidases
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A series of enantiomerically pure azasugars (2,5-dideoxy-2,5-imino-D-mannitol, 1-deoxynojirimycin, 1-deoxymannojirimycin, and related compounds) was synthesized from D-mannitol via aminoheterocyclization of C2-symmetric bis-epoxides and subsequently followed by ring isomerization in few cases. These compounds have been evaluated as inhibitors of several glycosidases (α- and β-D-glucosidases, α-D-mannosidase and α-L-fucosidase). Inhibition studies indicate notably that the polyhydroxylated azepanes are inhibitors of glycosidases, with K(i) in the micromolar range.
- Le Merrer, Yves,Poitout, Lydie,Depezay, Jean-Claude,Dosbaa, Isabelle,Geoffroy, Sabine,Foglietti, Marie-Jose
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p. 519 - 533
(2007/10/03)
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- Synthesis of azasugars. Part 1. Isomerization of polyhydroxylated piperidines
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N-Benzyl-3,4-di-O-benzyl-1,5-dideoxy-1,5-imino-D-glucitol and L-gulitol undergo easy isomerization, mainly either by ring contraction, or either by SN2 inversion at C2. This isomerization performed by bis-hydroxyl activation allows to access to 2,5-dideoxy-2,5-imino-L-iditol, 5-epi-DNJ, DMDP, and DMJ.
- Poitout,Le Merrer,Depezay
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p. 1609 - 1612
(2007/10/03)
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- SYNTHESIS OF (2R,3R,4R,5R)-3,4-DIHYDROXY-2,5-DIHYDROXYMETHYLPYRROLIDINE AND (-)-ANISOMYCIN DERIVATIVE FROM (S)-PYROGLUTAMIC ACID DERIVATIVE
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Double asymmetric dihydroxylation of (E)-α,β-unsaturated ester (2) with a catalitic amount of potassium osmate and chiral ligand gave dihydroxy compounds (3a and 4a) selectively.Polyhydroxylated pyrrolidines (10 and 14) were synthesized from corresponding methoxymethyl ether (3c) and tert-butyl-dimethylsilyl ether (4d), respectively.
- Ikota, Nobuo
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p. 983 - 994
(2007/10/02)
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- BIORATIONAL DESIGN OF HERBICIDES: SYNTHESIS OF INHIBITORS OF THE PFP ENZYME
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Transition state and reaction coordinate analog inhibitors of the PFP enzyme were synthesized for the biorational design of herbicides.Some of the promising ones were scaled up and tested on whole plants.Open chain, aza and phosphonated analogs of fructose showed significant PFP inhibitory activity.
- Chorghade, Mukund S.,Cseke, Csaba T.
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p. 213 - 222
(2007/10/02)
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- Expeditious synthesis of azasugars by the double reductive amination of dicarbonyl sugars
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Polyhydroxylated pyrrolidines and piperidines were prepared by the double reductive amination of dicarbonyl sugars with primary amines and NaCNBH3 in MeOH. Stereocontrol in these reactions depended on the nature of the amine and dicarbonyl sugar. For example, 5-keto-D-fructose (7) gave three pyrrolidine stereoisomers, with the N-alkylated 2,5-anhydro-2,5-imino-D-glucitol predominating. Under similar reaction conditions with benzhydrylamine, 5-keto-D-glucose (20) afforded a 96:4 mixture of piperidines favoring D-gluco 25A, whereas 5-keto-D-mannose (6) produced a 67:33 mixture enriched in D-manno isomer 40. This method allowed for the direct and relatively short synthesis of 1-deoxynojirimycin (DNJ, 1) and 1-deoxymannojirimycin (DMJ, 5) and N-alkylated derivatives thereof. Similar reactions with O-protected 5-keto-D-glucose derivatives 21 and 22 were less stereoselective and lower yielding.
- Baxter,Reitz
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p. 3175 - 3185
(2007/10/02)
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- The Utility of 2,5-Dideoxy-2,5-imino-D-mannitol as a PFP Enzyme Inhibitor
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2,5-Dideoxy-2,5-imino-D-mannitol was synthesized from an arabinofuranose derivative.Mercuric acetate cyclization of an ene-carbamate was the key step.The compound proved to be an inhibitor of the pyrophosphate-fructose-6-phosphate-1-phosphotransferase (PFP) enzyme and has potential utility in the biorational design of herbicides.
- Chorghade, Mukund S.,Cseke, Csaba T.,Liu, Paul S.
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p. 2251 - 2254
(2007/10/02)
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- Efficient cleavage of terminal acetonide group: Chirospecific synthesis of 2,5-Dideoxy-2,5-Imino-D-Mannitol
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Dowex 50W-X8 was efficient catalyst for selective cleavage of terminal actonide including acid-sensitive multifunctional groups. A facile and economically synthesis of DMDP (2,5-dideoxy-2,5-imino-D-mannitol) is described via selective hydrolysis and intramolecular nucleophilic amination.
- Park, Ki Hun,Yoon, Yong Jin,Lee, Sang Gyeong
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p. 9737 - 9740
(2007/10/02)
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- 2,5-Dideoxy-2,5-imino-D-mannitol and -D-glucitol. Two-step bio-organic syntheses from 5-azido-5-deoxy-D-glucofuranose and -L-idofuranose; evaluation as glucosidase inhibitors and application in affinity purification and characterisation of invertase from yeast
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Glucose isomerase (EC 5.3.1.5) catalyzes the quantitative isomerisation of 5-azido-5-deoxy-D-gluco- (7) and -L-idofuranose (9), respectively, into the corresponding ketoses, 5-azido-5-deoxy-D-fructopyranose (8) and -L-sorbopyranose (10), respectively. Upon catalytic hydrogenation over palladium-on-charcoal, the fructose derivative 8 gives the natural product and the efficient glycosidase inhibitor 2,5-dideoxy-2,5-imino-D-mannitol (4), while the sorbose derivative 10 affords 2,5-dideoxy-2,5-imino-D-glucitol (5). This represents a preparatively very simple and efficient two-step synthesis of these biologically active compounds. Both are strong inhibitors of α- and β-glucosidases from various sources, the D-manno-isomer 4 being distinctly more active. Because of its structural relationship with β-D-fructofuranose, compound 4 is also a vary good inhibitor of invertase from yeast and, as such, was for the first time employed, after immobilized and aminohexyl-sepharose, for the purification of this enzyme. Glucose isomerase (EC 5.3.1.5) catalyses the quantitative isomerization of 5-azido-5-deoxy-D-gluco (7) and -L-idofuranose (9), respectively, into the corresponding ketoses, 5-azido-5-deoxy-D-fructopyranose (8) and -L-sorbopyranose (10) respectively. Upon catalytic hydrogenation over palladium on 2,5-dideoxy-2,5-imino-D-mannitol (4), while the sorbose derivative 10 affords 2,5-dideoxy-2,5-imino-D-glucitol (5). This represents a preparatively very simple and efficient two-step synthesis of these biologically active compounds. Both are strong inhibitors of α- and β-glucosidases from various sources, the D-manno-isomer 4 being distinctly more active. Because of its structural relationship with β-D-fructofuranose, compound 4 is also a very good inhibitor of invertase from yeast and, as such, was for the first time employed, after immobilization on aminohexyl-sepharose, for the purification of this enzyme.
- Legler,Korth,Berger,Ekhart,Gradnig,Stutz
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- Methyl 2-azido-3-O-benzyl-2-deoxy-α-D-mamnofuranoside as a divergent intermediate for the synthesis of polyhydroxylated piperidines and pyrrolidines: synthesis of 2,5-dideoxy-2,5-imino-D-mannitol [2R,5R-dihydroxymethyl-3R,4R-dihydroxypyrrolidine]
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The synthesis of methyl 2-azido-3-O-benzyl-2-deoxy-α-D-mannofuranoside (1) from D-glucose is reported; the conversions of (1) into derivatives of methyl 3-O-benzyl-2,6-dideoxy-2,6-imino-α-D-mannofuranoside (as precursors for the synthesis of polyhydroxylated piperidines) and into the hydroxylated pyrrrolidine, 2,5-dideoxy-2,5-imino-D-mannitol [2R,5R-dihydroxymethyl-3R,4R-dihydroxypyrrolidine] are described.
- Fleet, George W.J.,Smith, Paul W.
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p. 971 - 978
(2007/10/02)
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