- Synthesis and Anti-HBV Activity of Thiouracils Linked via S and N-1 to the 5-Position of Methyl β-D-Ribofuranoside
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Reverse nucleoside derivatives of 2-(methylsulfanyl)uracils 6a-d were prepared by treating of the sodium salt of 2-(methylsulfanyl)uracils (5a-d) with methyl 2,3-O-isopropylidene-5-O-p-toluenesulfonyl-β-D-ribofuranoside (2). The alkylation of 2-thiouracils 4a-d with methyl 5-deoxy-5-iodo-2,3-O-isopropylidene-D-ribofuranoside (3) afforded the corresponding S-ribofuranoside derivatives 8a-d. Deisopropylidenation of 6a-d and 8a-d afforded the corresponding deprotected derivatives 7a-d and 9a-d, respectively. The Anti-HBV activity of selected compounds was studied.
- Abdel-Rahman, Adel A.-H.,Abdel-Megied, Ahmed E.-S.,Goda, Adel E.-S.,Zeid, Ibrahim F.,El Ashry, El Sayed H.
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- Alkylcobalamins: formation by enantioselective alkylation of cob(I)alamin, 1H NMR spectra, and conformational analysis of the alkyl group
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The 1H NMR spectra of a series of alkylcobalamins, principally 2-oxy substituted, including adenosyl- and ribosylcobalamin, have been analysed with particular attention to the conformation of the alkyl moiety.The enantioselectivity of formation of some of these compounds from their chiral precursors has been determined (NMR analysis) and rationalized.
- Anderson, Rosaleen J.,Dixon, Ruth M.,Golding, Bernard T.
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- SYNTHESIS OF HIGHER-CARBON SUGARS BY TRIBUTYLTIN HYDRIDE - AZOBISISOBUTYRONITRILE INDUCED RADICAL ADDITIONS
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The Bu3SnH-AIBN induced radical additions of 3,5-di-O-acetyl-6-deoxy-6-iodo-1,2-O-isopropylidene-α-D-gluco- and -allofuranose (1 and 10), and methyl 5-deoxy-5-iodo-2,3-O-isopropylidene-β-D-ribofuranoside (19) to dimethyl maleate, methyl acrylate, acrylonitrile, methyl vinyl ketone, and vinylene carbonate gave various types of higher-carbon sugars.
- Araki, Younosuke,Endo, Tadatoshi,Tanji, Masaki,Arai, Yoshifusa,Ishido, Yoshiharu
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Read Online
- Structure-property relationships of ribose based ionic liquids
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The authors of this work have successfully synthesized a broad choice of new ribose based ionic liquids, using several varying protecting groups (methyl, ethyl, allyl and benzyl) at the various positions of the carbohydrate, as well as different quarternised N-heterocycles and different anions. These consistent variations of the carbohydrate based ionic liquids (CHILs) enabled an extensive structure-property relationship study of thermal properties, allowing the authors to prove existing trends and to find a correlation between the decomposition temperature and the structure of the CHILs.
- Jopp, Stefan,Komabayashi, Mirai,Stiller, Tanja
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- NOVEL SPIROBICYCLIC ANALOGUES
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The present invention relates to novel spirobicyclic analogues of Formula (I) wherein the variables have the meaning defined in the claims. The compounds according to the present invention are useful as PRMT5 inhibitors. The invention further relates to pharmaceutical compositions comprising said compounds as an active ingredient as well as the use of said compounds as a medicament.
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Page/Page column 60
(2019/06/23)
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- Synthesis of Nucleosides through Direct Glycosylation of Nucleobases with 5-O-Monoprotected or 5-Modified Ribose: Improved Protocol, Scope, and Mechanism
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Simplifying access to synthetic nucleosides is of interest due to their widespread use as biochemical or anticancer and antiviral agents. Herein, a direct stereoselective method to access an expansive range of both natural and synthetic nucleosides up to a gram scale, through direct glycosylation of nucleobases with 5-O-tritylribose and other C5-modified ribose derivatives, is discussed in detail. The reaction proceeds through nucleophilic epoxide ring opening of an in situ formed 1,2-anhydrosugar (termed “anhydrose”) under modified Mitsunobu reaction conditions. The scope of the reaction in the synthesis of diverse nucleosides and other 1-substituted riboside derivatives is described. In addition, a mechanistic insight into the formation of this key glycosyl donor intermediate is provided.
- Downey, A. Michael,Pohl, Radek,Roithová, Jana,Hocek, Michal
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supporting information
p. 3910 - 3917
(2017/03/27)
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- Method for preparing ticagrelor key intermediate
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The invention relates to a chemical synthesis method of ticagrelor key intermediate 2-[[(3aR, 4S, 6R, 6aS)-6-aminotetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxolane-4-yl] oxy]ethanol (a key intermediate A). The method comprises the following steps: taking D-ribose as a raw material, and carrying out ten chemical reaction steps of 1-locus methylation and 2,3-loci isopropylidene protection, 4-locus derivatization, iodination, furan ring-opening, hydroxylamine reaction, palladium on carbon catalytic hydrogenation, amino Cbz protection, hydroxy protection, sodium borohydride reduction ester, Cbz removal protection and the like, thereby obtaining the key intermediate A. The raw materials are cheap and readily available, the preparation process is high in operability, steps of optical resolution, chiral induction and the like are avoided, the total yield is relatively high, and the product quality is better; particularly due to the use of sodium borohydride reduction ester, the preparation cost of ticagrelor is greatly reduced; and the method is suitable for large-scale industrial production.
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- Highly Substituted Cyclopentane-CMP Conjugates as Potent Sialyltransferase Inhibitors
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Sialylconjugates on cell surfaces are involved in many biological events such as cellular recognition, signal transduction, and immune response. It has been reported that aberrant sialylation at the nonreducing end of glycoconjugates and overexpression of sialyltransferases (STs) in cells are correlated with the malignance, invasion, and metastasis of tumors. Therefore, inhibitors of STs would provide valuable leads for the discovery of antitumor drugs. On the basis of the transition state of the enzyme-catalyzed sialylation reaction, we proposed that the cyclopentane skeleton in its two puckered conformations might mimic the planar structure of the donor (CMP-Neu5Ac) in the transition state. A series of cyclopentane-containing compounds were designed and synthesized by coupling different cyclopentane α-hydroxyphosphonates with cytidine phosphoramidite. Their inhibitory activities against recombinant human ST6Gal-I were assayed, and a potent inhibitor 48l with a Ki of 0.028 ± 0.006 μM was identified. The results show that the cyclopentanoid-type compounds could become a new type of sialyltransferase inhibitors as biological probes or drug leads.
- Li, Wenming,Niu, Youhong,Xiong, De-Cai,Cao, Xiaoping,Ye, Xin-Shan
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supporting information
p. 7972 - 7990
(2015/11/09)
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- Iodoetherification of conformationally restricted dienyl alcohols: Unexpected formation of oxocenes by 8-endo-mode oxacyclizations
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Iodine-promoted oxacyclizations of a family of conformationally restricted dienyl alcohols consistently afford oxocenes, arising from 8-endo-mode cyclizations.
- Stoltz, Kristen L.,Alba, Andrea-Nekane R.,McDonald, Frank E.,Wieliczko, Marika B.,Bacsa, John
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p. 1519 - 1526
(2016/10/12)
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- Analogues of the natural product sinefungin as inhibitors of EHMT1 and EHMT2
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A series of analogues of the natural product sinefungin lacking the amino acid moiety was synthesized and probed for their ability to inhibit EHMT1 and EHMT2. This study led to inhibitors 3b and 4d of methyltransferase activity of EHMT1 and EHMT2 and it demonstrates that such analogues constitute an interesting scaffold to develop selective methyltransferase inhibitors. Surprisingly, the inhibition was not competitive toward AdoMet.
- Devkota, Kanchan,Lohse, Brian,Liu, Qing,Wang, Ming-Wei,Staerk, Dan,Berthelsen, Jens,Clausen, Rasmus Praetorius
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p. 293 - 297
(2014/05/06)
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- Revisiting synthetic preparation of the quorum sensing substrate S-d-ribosyl-l-homocysteine (SRH)
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Cleavage of the thioether bond of S-d-ribosyl-l-homocysteine (SRH) by the enzyme S-ribosylhomocysteinase (LuxS) serves as the final biosynthetic step in the generation of the quorum sensing autoinducer AI-2 by bacteria. Herein, a revised chemical synthesis of SRH is presented at convenient scale and purity for in vitro studies of LuxS. Potassium bis(trimethylsilyl)amide (KHMDS) is identified as a judicious base for the formation of the thioether of the target compound from readily-accessible precursors: a thiol nucleophile derived from l-homocystine and a sulfonate-activated d-ribosyl electrophile. The exclusive use of acid-labile protecting groups allows for facile deprotection to the final product, producing the TFA salt of SRH in five synthetic steps and 26% overall yield. The chemically-synthesized material is isolated at high purity and demonstrated to serve as the LuxS substrate by an in vitro assay.
- Bolitho, Megan E.,Corcoran, Brendan J.,Showell-Rouse, Emily I.,Wang, Keeshia Q.
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- A carbohydrate-based julia-kocienski reagent for syntheses of chain-extended and C-linked saccharides
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The carbohydrate-derived Julia-Kocienski reagent 2-{[(3aS,4S,6R,6aR)-6- methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methylsulfonyl}-1, 3-benzothiazole (6) was prepared from d-ribose and investigated in the eponymous olefination. The base-promoted generation of the Julia anion induced a rearrangement to the corresponding l-lyxose epimer 2-{[(3aS,4R,6R,6aR)-6- methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methylsulfonyl}-1, 3-benzothiazole (12), which reacted readily with aldehydes and with a gluconolactone. The latter reaction furnished an exo-glycal-linked C-diglycoside. Georg Thieme Verlag Stuttgart, New York.
- Bull, James A.,Kunz, Horst
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p. 1185 - 1190
(2014/05/20)
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- Doubly diastereoselective conjugate additions of the antipodes of lithium N-benzyl-N-(α-methylbenzyl)amide to enantiopure ε-O-protected α,β-unsaturated esters derived from d-ribose
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Enantiopure ε-O-silyloxy- and ε-O-benzyloxy-α,β- unsaturated esters derived from d-ribose, each containing a cis-dioxolane unit, display excellent (≥95:5 dr) levels of diastereofacial directing ability upon conjugate addition of achiral lithium N-benzyl-N-isopropylamide. In contrast to the corresponding enantiopure ε-O-silyloxy-α,β-unsaturated ester derived from l-tartaric acid, which contains a trans-dioxolane unit, the conjugate additions of the antipodes of lithium N-benzyl-N-(α- methylbenzyl)amide to its cis-configured counterpart result in doubly diastereoselective 'matched' and 'mismatched' reaction pairings in which the inherent reagent control serves to augment or oppose, respectively, the established substrate diastereocontrol.
- Davies, Stephen G.,Foster, Emma M.,Lee, James A.,Roberts, Paul M.,Thomson, James E.
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p. 534 - 546
(2014/05/06)
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- Synthesis of diastereomeric, deoxy and ring-expanded sulfone analogues of aigialomycin D
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Several analogues of the fungal natural product aigialomycin D (AmD) have been synthesised. These include the stereoisomer 5′R,6′S-AmD, 2,4-di-deoxyAmD, 1′,2′,7′,8′-tetrahydroAmD and a 15-membered macrocyclic sulfone. Growth inhibitory activities of these compounds against the HL-60 leukaemic cell line were measured. The ring-expanded sulfone and tetrahydro-analogue were found to have similar IC50 values to the natural product, whereas the 5′R,6′S-stereoisomer was inactive. Energy minimisation of AmD and the synthesised analogues resulted in a range of lowest energy conformers, from planar, open arrangements of the macrocycle in AmD and tetrahydroAmD to bent, L-shaped structures for the sulfone. The synthesis of methyl orsellinate was investigated and optimised as part of this work. A stereodivergent route to both enantiomers of the diol fragment from d-ribose was also achieved.
- Ting, Samuel Z.Y.,Baird, Lynton J.,Dunn, Elyse,Hanna, Reem,Leahy, Dora,Chan, Ariane,Miller, John H.,Teesdale-Spittle, Paul H.,Harvey, Joanne E.
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supporting information
p. 10581 - 10592
(2013/11/19)
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- On the origins of diastereoselectivity in the conjugate additions of the antipodes of lithium N-benzyl-(N-α-methylbenzyl)amide to enantiopure cis- and trans-dioxolane containing α,β-unsaturated esters
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"Matching" and "mismatching" effects in the doubly diastereoselective conjugate additions of the antipodes of lithium N-benzyl-(N-α-methylbenzyl)amide to enantiopure cis- and trans-dioxolane containing α,β-unsaturated esters have been investigated. High levels of substrate control were established first upon conjugate addition of achiral lithium N-benzyl-N-isopropylamide to both tert-butyl (S,S,E)-4,5-O- isopropylidene-4,5-dihydroxyhex-2-enoate and tert-butyl (4R,5S,E)-4,5-O- isopropylidene-4,5-dihydroxyhex-2-enoate. However, upon conjugate addition of lithium (R)-N-benzyl-(N-α-methylbenzyl)amide and lithium (S)-N-benzyl-(N-α-methylbenzyl)amide to these substrates, neither reaction pairing reinforced the apparent sense of substrate control. These reactions do not, therefore, conform to the classical doubly diastereoselective "matching" or "mismatching" pattern usually exhibited by this class of reaction. A comparison of these reactions with the previously reported doubly diastereoselective conjugate addition reactions of lithium amide reagents to analogous substrates is also discussed.
- Davies, Stephen G.,Foster, Emma M.,Frost, Aileen B.,Lee, James A.,Roberts, Paul M.,Thomson, James E.
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supporting information; experimental part
p. 6186 - 6200
(2012/09/05)
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- Asymmetric synthesis of polyhydroxylated pyrrolizidines via transannular iodoamination with concomitant N-debenzylation
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The doubly diastereoselective "matched" conjugate addition of lithium (R)-N-but-3-enyl-N-(α-methyl-p-methoxybenzyl)amide to tert-butyl (4S,5R,E)-4,5-O-isopropylidene-2,7-dienoate (derived from d-ribose in 3 steps) and in situ enolate oxidation with (-)-camphorsulfonyloxaziridine was followed by ring-closing metathesis with Grubbs I to give a hexahydroazocine scaffold. Subsequent treatment with I2 resulted in transannular iodoamination accompanied by loss of the α-methyl-p-methoxybenzyl group to give the corresponding pyrrolizidine scaffold as a single diastereoisomer upon direct crystallization from the crude reaction mixture. Further functional group manipulations enabled the preparation of (-)-7a-epi-hyacinthacine A1.
- Brock, E. Anne,Davies, Stephen G.,Lee, James A.,Roberts, Paul M.,Thomson, James E.
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supporting information; experimental part
p. 1594 - 1597
(2011/05/03)
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- Stereoselective total synthesis of (-)-Ovalicin
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A new synthetic route for epoxyketone 3 is described, which is a key intermediate in Bartons synthesis of ovalicin (1), a powerful anti-angiogenetic inhibitor, from commercially available d-ribose. The key reactions involved in this synthesis are ring-closing metathesis, Rubottom oxidation and Corey-Chaykovsky epoxidation. The subsequent transformations are carried out according to Bartons strategy to complete the total synthesis of (-)-ovalicin. Georg Thieme Verlag Stuttgart New York.
- Yadav,Reddy, P. Narayana,Reddy, B.V. Subba
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scheme or table
p. 457 - 461
(2010/04/05)
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- A chiron approach to the total synthesis of cytotoxic (+)-muricatacin and (+)-5-epi-muricatacin from d-ribose
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A chiron approach strategy toward the total synthesis of (+)-muricatacin and (+)-5-epi-muricatacin starting from commercially available and inexpensive d-ribose through the key intermediate (S)-5-((R)-1-hydroxyallyl)furan-2(5H)-one has been disclosed.
- Ghosal, Partha,Kumar, Vikas,Shaw, Arun K.
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scheme or table
p. 41 - 44
(2011/02/28)
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- Doubly diastereoselective conjugate addition of homochiral lithium amides to homochiral α,β-unsaturated esters containing cis- and trans-dioxolane units
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As part of a long-term goal directed towards the ab initio asymmetric synthesis of unnatural amino sugars, the doubly diastereoselective conjugate addition reactions of the antipodes of lithium N-benzyl-N-(α-methylbenzyl) amide to a range of homochiral α,β-unsaturated esters containing cis- and trans-dioxolane units was investigated. These reactions resulted in "matching" and "mismatching" effects. In the "matched" cases a single diastereoisomer of the corresponding β-amino ester (containing three contiguous stereocentres) is produced. Upon conjugate addition to a homochiral α,β-unsaturated ester containing a cis-dioxolane unit, in the "mismatched" case it is the stereocontrol of the substrate which is dominant over that of the lithium amide, whilst upon addition to homochiral α,β-unsaturated esters containing a trans-dioxolane unit the stereocontrol of the homochiral lithium amide is dominant. Hydrogenolytic N-deprotection of the β-amino ester products of conjugate addition gives access to polyoxygenated β-amino acid derivatives.
- Davies, Stephen G.,Durbin, Matthew J.,Goddard, Euan C.,Kelly, Peter M.,Kurosawa, Wataru,Lee, James A.,Nicholson, Rebecca L.,Price, Paul D.,Roberts, Paul M.,Russell, Angela J.,Scott, Philip M.,Smith, Andrew D.
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supporting information; experimental part
p. 761 - 776
(2009/06/19)
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- Synthesis and biological evaluation of some 6-substituted purines
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We report herein the synthesis and the in vitro antileishmanial evaluation of a series of 6-substituted purines. The most active compounds against Leishmania amazonensis promastigotes were 6-(3′-chloropropylthio)purine 2 (D.A. Benson, I. Karsch-Mizrachi, D.J. Lipman, J. Ostell, B.A. Rapp, D.L. Wheeler, Genbank. Nucleic Acids Res. 28 (2000) 15-18; E.V. Aleksandrova, P.M.I.E. Valashek, J. Med. Pharm. Chem. 35 (2001) 172-173), 6-(3′-(thioethylamine)propylthio)purine 5, 6-(α-aceticacidthio)purine 7 and 6-(6′-deoxy-1′-O-methyl-β-d-ribofuranose)purine 14 with an IC50 = 50, 50, 39 and 29 μM, respectively.
- Braga, Fernanda Gambogi,Coimbra, Elaine Soares,de Oliveira Matos, Magnum,Lino Carmo, Arturene Maria,Cancio, Marisa Damato,da Silva, Adilson David
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p. 530 - 537
(2008/02/10)
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- Reaction of methyl-4-methylene-2,3-O-isopropylidene-β-D-ribofuranoside with N-bromosuccinimide in aqueous tetrahydrofurane
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Methyl-4-methylene-2,3-O-isopropylidene-β-D-ribofuranoside prepared from D-ribose reacted in a system NBS-THF-H2O to give a mixture of stereoisomeric products of regioselective bromohydroxylation of a double bond. The reaction involved a hydrolysis of the glycoside bond, but the acetonide protective group was retained. The mechanism of the selective hydrolysis originating from the ring-chain tautomerism of bromohydrins obtained was proved by the 1H NMR spectra of the steroisomeric methyl-5-deoxy-5-bromo-4- hydroxy-2,3-O-isopropylidene-β-D-ribofuranosides. By crotonic cyclization of the formed masked 1,4-dicarbonyl compounds at heating in benzene in the presence of neutral Al2O3 a new chiral cyclopentenone block, 2-bromo-4,5-isopropylideneoxycyclopent-2-en-1-one, was obtained in a low yield. Nauka/Interperiodica 2007.
- Ivanova,Valiullina,Shitikova,Miftakhov
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p. 742 - 746
(2008/02/08)
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- Pyrrolidine N-oxides by stereoselective addition of Grignard and lithium compounds to 4,5-dideoxy-2,3-O-isopropylidene-D-erythro-4-pentenose N-benzyl nitrone and subsequent Cope-House cyclization
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The addition of Grignard reagents to D-erythro-4-pentenose N-benzyl nitrone 5, which is easily accessible from D-ribose, furnishes ω-unsaturated hydroxylamines that readily undergo Cope-House cyclization to afford pyrrolidine N-oxides. The stereoselectivity of the addition step is altered by either employing organolithium compounds or Lewis acids as complexing agents. The pyrrolidine N-oxides obtained by this sequence serve as key intermediates in the synthesis of 2,5-disubstituted pyrrolidine-3,4-diols (to be discussed in detail separately), both constituting new potential inhibitors of glycosidases.
- Palmer, Andreas M.,Jaeger, Volker
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p. 1293 - 1308
(2007/10/03)
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- Expeditoious Synthesis of Aminocyclopentitols from D-Ribose via Intramolecular Nitrone Cycloaddition
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The synthesis of 4α-aminocyclopentane-1α,2β,3β-triol (a key-intermediate in the preparation of carbocyclic nucleosides) and its N-substituted derivatives, has been achieved by the intarmolecular nitrone cycloadditions of a γ-unsaturated aldehyde, easily accessible from D-ribose, followed by reductive N-O bond cleavage in the resulting bicyclic oxazanes.
- Gallos, John K.,Goga, Efthymia G.,Koumbis, Alexandros E.
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p. 613 - 614
(2007/10/02)
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- Preparation of Neplanocin-A from D-Ribose and by a Chemoenzymic Method
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The carboxylic acid 6 was converted into the amine 13 en route to neplanocin-A 9.The same enantiomer of the amine 13 was made from D-ribose ina 13-step synthesis.
- Hill, Jason M.,Hutchinson, Edward J.,Grand, Darren M. Le,Roberts, Stanley M.,Thorpe, Andrew J.,Turner, Nicholas J.
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p. 1483 - 1488
(2007/10/02)
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- Substrate Specificity and Carbohydrate Synthesis Using Transketolase
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This paper describes the use of the enzyme transketolase as a catalyst in organic synthesis.The properties of transketolase from both yeast and spinach were investigated.The yeast enzyme was found to be more convenient for routine use.Examination of the substrate specificity of yeast tansketolase demonstrated that the enzyme accepts a wide variety of 2-hydroxy aldehydes as substrates.A practical protocol for tansketolase-catalyzed condensation of hydroxypyruvic acid with these aldehydes has been developed and used for the synthesis of four carbohydrates: L-idose, L-gulose, 2-deoxy-L-xylohexose, and L-xylose.
- Kobori, Yoshihiro,Myles, David C.,Whitesides, George M.
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p. 5899 - 5907
(2007/10/02)
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- DESIGN AND REACTIVITY OF ORGANIC FUNCTIONAL GROUPS: THE HIGHLY CRYSTALLINE 2-ALKOXY N,N'-DIPHENYL-1,3,2-DIAZAPHOSPHOLANES AND THEIR FACILE CONVERSION INTO ALKYL HALIDES
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Functionalization of alcohols as 2-alkoxy N,N'-diphenyl-1,3,2-diazaphospholanes affords highly crystalline derivatives useful for characterization purposes.These tervalent phosphorus derivatives undergo facile and mild conversion into the corresponding alkyl halides with inversion of configuration.
- Hanessian, Stephen,Leblanc, Yves,Lavallee, Pierre
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p. 4411 - 4414
(2007/10/02)
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- Reaction of Carbohydrate Halides with Magnesium. Novel C-C Coupling of Sugar Derivatives via Organometallic Intermediates
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The reaction of 3-deoxy-3-C-(iodomethyl)-1,2:5,6-di-O-isopropylidene-α-D-allofuranose (1c) with sublimed magnesium in refluxing tetrahydrofuran gave dimer 2 and only traces of the 3-deoxy-3-methyl derivative 1d.Similarly methyl 5-deoxy-5-iodo-2,3-O-isopro
- Ariatti, Mario,Zemlicka, Jiri
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p. 5204 - 5212
(2007/10/02)
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- Novel Reagent System for converting a Hydroxy-group into an Iodo-group in Carbohydrates with Inversion of Configuration. Part 2
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Isolated primary and secondary hydroxy-groups in carbohydrate derivatives are transformed into iodo-groups with inversion of configuration on treatment with either triphenylphosphine, iodine, and imidazole or triphenylphosphine and 2,4,5-tri-iodoimidazole
- Garegg, Per J.,Samuelsson, Bertil
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p. 2866 - 2869
(2007/10/02)
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