- Oxyenamides as Versatile Building Blocks for a Highly Stereoselective One-Pot Synthesis of the 1,3-Diamino-2-ol-Scaffold Containing Three Continuous Stereocenters
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A highly diastereoselective one-pot synthesis of the 1,3-diamino-2-alcohol unit bearing three continuous stereocenters is described. This method utilizes 2-oxyenamides as a novel type of building block for the rapid assembly of the 1,3-diamine scaffold containing an additional stereogenic oxygen functionality at the C2 position. A stereoselective preparation of the required (Z)-oxyenamides is reported as well.
- Bolte, Michael,Grimmer, Jennifer,Kelm, Harald,Kramer, Philipp,Krieg, Sara-Cathrin,Manolikakes, Georg
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p. 23667 - 23671
(2021/09/30)
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- Two-way homologation of aliphatic aldehydes: Both one-carbon shortening and lengthening via the same intermediate
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Aliphatic aldehydes can be homologated to both one-carbon shorter and one-carbon longer homologous carbonyl compounds through the 2–4 steps of reactions via the same intermediates, β,γ-unsaturated α-nitrosulfones, prepared from the proline-catalyzed sequential reactions of several aliphatic aldehydes with phenylsulfonylnitromethane. While the oxidative cleavage of the key intermediates gave one-carbon less homologous carbonyl compounds, the reduction of the same key intermediates followed by an oxidation produced one-carbon more homologous carbonyl compounds.
- Yoo, Jae Won,Seo, Youngran,Park, Jong Beom,Kim, Young Gyu
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- Synthetic method of chiral piperazidone derivative
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The invention relates to a synthetic method of a chiral piperazidone derivative. The synthetic method comprises the following steps: performing an oxidation reaction on ethanolamine with a protectivegroup in a formula (I) to obtain aminoacetaldehyde with a protective group in a formula (II); in an alcohol solvent, performing a reduced amination reaction on the aminoacetaldehyde with the protective group in the formula (II) and amino acid ester in the presence of a reducing agent to obtain the chiral piperazidone derivative in the formula (II), wherein the reduced amination reaction temperature is -10 DEG C to 0 DEG C, and the amino acid ester is L-type amino acid ester or D-type amino acid ester; and in the alcohol solvent, performing a de-protection reaction on the chiral piperazidone derivative in the formula (II) and forming a ring to obtain a chiral piperazidone derivative in a formula (IV), wherein a reaction route is shown as follows: the protective group X is benzoxo carbonyl or tert-butyoxo carbonyl; R is methyl, ethyl, isopropyl, isobutyl, hydroxyethyl, benzyl, p-hydroxybenzyl and the like; and R' is methyl, ethyl and the like.
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- α-Amino Aldehydes as Readily Available Chiral Aldehydes for Rh-Catalyzed Alkyne Hydroacylation
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Readily available α-amino aldehydes, incorporating a methylthiomethyl (MTM) protecting group on nitrogen, are shown to be efficient substrates in Rh-catalyzed alkyne hydroacylation reactions. The reactions are performed under mild conditions, employing a small-bite-angle bis-phosphine ligand, allowing for good functional group tolerance with high stereospecificity. Amino aldehydes derived from glycine, alanine, valine, leucine, phenylalanine, isoleucine, serine, tryptophan, methionine, and cysteine were successfully employed, as was an enantiomerically enriched α-OMTM-aldehyde derived from phenyllactic acid. The synthetic utility of the α-amino enone products is demonstrated in a short enantioselective synthesis of the natural product sphingosine.
- Hooper, Joel F.,Seo, Sangwon,Truscott, Fiona R.,Neuhaus, James D.,Willis, Michael C.
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supporting information
p. 1630 - 1634
(2016/02/20)
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- Synthesis and evaluation of protein arginine N-methyltransferase inhibitors designed to simultaneously occupy both substrate binding sites
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The protein arginine N-methyltransferases (PRMTs) are a family of enzymes that function by specifically transferring a methyl group from the cofactor S-adenosyl-l-methionine (AdoMet) to the guanidine group of arginine residues in target proteins. The most notable is the PRMT-mediated methylation of arginine residues that are present in histone proteins which can lead to chromatin remodelling and influence gene transcription. A growing body of evidence now implicates dysregulated PRMT activity in a number of diseases including various forms of cancer. The development of PRMT inhibitors may therefore hold potential as a means of developing new therapeutics. We here report the synthesis and evaluation of a series of small molecule PRMT inhibitors designed to simultaneously occupy the binding sites of both the guanidino substrate and AdoMet cofactor. Potent inhibition and surprising selectivity were observed when testing these compounds against a panel of methyltransferases.
- Van Haren, Matthijs,Van Ufford, Linda Quarles,Moret, Ed E.,Martin, Nathaniel I.
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p. 549 - 560
(2015/02/02)
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- The discovery of potent, selective, and reversible inhibitors of the house dust mite peptidase allergen der p 1: An innovative approach to the treatment of allergic asthma
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Blocking the bioactivity of allergens is conceptually attractive as a small-molecule therapy for allergic diseases but has not been attempted previously. Group 1 allergens of house dust mites (HDM) are meaningful targets in this quest because they are globally prevalent and clinically important triggers of allergic asthma. Group 1 HDM allergens are cysteine peptidases whose proteolytic activity triggers essential steps in the allergy cascade. Using the HDM allergen Der p 1 as an archetype for structure-based drug discovery, we have identified a series of novel, reversible inhibitors. Potency and selectivity were manipulated by optimizing drug interactions with enzyme binding pockets, while variation of terminal groups conferred the physicochemical and pharmacokinetic attributes required for inhaled delivery. Studies in animals challenged with the gamut of HDM allergens showed an attenuation of allergic responses by targeting just a single component, namely, Der p 1. Our findings suggest that these inhibitors may be used as novel therapies for allergic asthma.
- Newton, Gary K.,Perrior, Trevor R.,Jenkins, Kerry,Major, Meriel R.,Key, Rebekah E.,Stewart, Mark R.,Firth-Clark, Stuart,Lloyd, Steven M.,Zhang, Jihui,Francis-Newton, Nicola J.,Richardson, Jonathan P.,Chen, Jie,Lai, Pei,Garrod, David R.,Robinson, Clive
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p. 9447 - 9462
(2015/01/16)
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- NOVEL OXAZOLIDINONE DERIVATIVE AND MEDICAL COMPOSITION CONTAINING SAME
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Disclosed is a novel oxazolidinone derivative represented by Formula 1 above, in particular, a novel oxazolidinone compound having a cyclic amidoxime or cyclic amidrazone group. In Formula 1, R and Q are the same as defined in the detailed description. In addition, disclosed is a pharmaceutical composition for an antibiotic which includes the novel oxazolidinone derivative of Formula 1, a prodrug thereof, a hydrate thereof, a solvate thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. The novel oxazolidinone derivative, the prodrug thereof, the hydrate thereof, the solvate thereof, the isomer thereof, and the pharmaceutically acceptable salt thereof have broad antibacterial spectrum against resistant bacteria, low toxicity and strong antibacterial effects against Gram-positive and Gram-negative bacteria and thus may be effectively used as antibiotics.
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- NOVEL OXAZOLIDINONE DERIVATIVE AND MEDICAL COMPOSITION CONTAINING SAME
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Disclosed is a novel oxazolidinone derivative represented by Formula 1 above, in particular, a novel oxazolidinone compound having a cyclic amidoxime or cyclic amidrazone group. In Formula 1, R and Q are the same as defined in the detailed description. In addition, disclosed is a pharmaceutical composition for an antibiotic which includes the novel oxazolidinone derivative of Formula 1, a prodrug thereof, a hydrate thereof, a solvate thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. The novel oxazolidinone derivative, the prodrug thereof, the hydrate thereof, the solvate thereof, the isomer thereof, and the pharmaceutically acceptable salt thereof have broad antibacterial spectrum against resistant bacteria, low toxicity and strong antibacterial effects against Gram-positive and Gram-negative bacteria and thus may be effectively used as antibiotics.
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- A novel immobilized chloroperoxidase biocatalyst with improved stability for the oxidation of amino alcohols to amino aldehydes
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Chloroperoxidase from Caldariomyces fumago (CPO, EC 1.11.1.10) is one of the most promising of the heme peroxidase enzymes for synthetic applications. Since the synthetic use of CPO suffers severely from its rapid deactivation in the presence of peroxides, the immobilization of this enzyme was studied as a possibility for stability improvement. Three methods of immobilization were considered using monoaminoethyl-N-aminoethyl (MANA) agarose gels: ionic adsorption, covalent attachment via carbodiimide coupled activation and covalent attachment of oxidized CPO. The most successful results led to almost complete immobilization with retained activities of around 51% for the two methods of covalent attachment and 77% for the ionic adsorption of CPO on MANA. Besides, all of the immobilized enzyme systems showed drastically improved stability toward presence of peroxide; CPO immobilized on MANA through carbodiimide coupled method resulted to be the most stable one with an increase in apparent half-life time of more than 500-fold that of the soluble enzyme. CPO immobilized by this method was compared to the soluble enzyme as catalyst for Cbz-ethanolamine oxidation to Cbz-glycinal using tert-butyl hydroperoxide (t-BuOOH) as an oxidant. Despite the lower reaction rate, the reaction catalyzed by immobilized CPO reached higher Cbz-glycinal yield with almost three-fold lower activity loss.
- Pesic, Milja,Lopez, Carmen,Alvaro, Gregorio,Lopez-Santin, Josep
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p. 144 - 151
(2012/10/30)
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- In situ aldehyde generation for aldol addition reactions catalyzed by d-fructose-6-phosphate aldolase
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In situ coupling of aldehyde generation, by a mild alcohol oxidation, with an enzymatic aldol addition reaction, mediated by d-fructose-6-phosphate aldolase (FSA) has been investigated as an approach to improve the performance of the process. Four sustainable oxidation methods compatible with the activity and stability of the enzymatic aldol addition have been assayed. Among them, the laccase/O2/2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) and alcohol oxidase gave the best results for the N-Cbz-aminoethanol to N-Cbz-glycinal (53%) and furfuryl alcohol to furfural (89%), respectively, followed by the aldol addition with hydroxyacetone catalyzed by FSA A129S mutant.
- Mifsud, Maria,Szekrenyi, Anna,Joglar, Jesus,Clapes, Pere
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p. 102 - 107
(2012/10/30)
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- Synthesis and evaluation of arylaminoethyl amides as noncovalent inhibitors of cathepsin S. Part 3: Heterocyclic P3
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A series of Nα-2-benzoxazolyl-α-amino acid-(arylaminoethyl)amides were identified as potent, selective, and noncovalent inhibitors of cathepsin S. Structure-activity relationships including strategies for modulating the selectivities among cathepsins S, K, and L, and in vivo pharmacokinetics are discussed. A X-ray structure of compound 3 bound to the active site of cathepsin S is also reported.
- Tully, David C.,Liu, Hong,Alper, Phil B.,Chatterjee, Arnab K.,Epple, Robert,Roberts, Michael J.,Williams, Jennifer A.,Nguyen, Khanhlinh T.,Woodmansee, David H.,Tumanut, Christine,Li, Jun,Spraggon, Glen,Chang, Jonathan,Tuntland, Tove,Harris, Jennifer L.,Karanewsky, Donald S.
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p. 1975 - 1980
(2007/10/03)
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- First stereoselective synthesis of potassium aeschynomate and its no-natural stereomers
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The synthesis of potassium aeshynomate and its non-natural stereomers was achieved using the Sharpless catalytic asymmetric dihydroxylation of (Z) or (E) vinylogous glycine as the key step. The resulting γ-amino α,β-dihydroxyester stereomer was deprotected and coupled with the caffeic acid to afford stereoselectively potassium aeshynomate or its stereomers. A detailed study of the NMR data of the different stereomers is reported that corrects the literature data.
- Claudel, Stéphanie,Olszewski, Tomasz Krzysztof,Mutzenardt, Pierre,Aroulanda, Christie,Coutrot, Philippe,Grison, Claude
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p. 1787 - 1798
(2007/10/03)
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- Synthesis and SAR of arylaminoethyl amides as noncovalent inhibitors of cathepsin S: P3 cyclic ethers
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The synthesis and structure-activity relationship of a series of arylaminoethyl amide cathepsin S inhibitors are reported. Optimization of P3 and P2 groups to improve overall physicochemical properties resulted in significant improvements in oral bioavail
- Tully, David C.,Liu, Hong,Chatterjee, Arnab K.,Alper, Phil B.,Epple, Robert,Williams, Jennifer A.,Roberts, Michael J.,Woodmansee, David H.,Masick, Brian T.,Tumanut, Christine,Li, Jun,Spraggon, Glen,Hornsby, Michael,Chang, Jonathan,Tuntland, Tove,Hollenbeck, Thomas,Gordon, Perry,Harris, Jennifer L.,Karanewsky, Donald S.
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p. 5112 - 5117
(2007/10/03)
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- Highly efficient two-step synthesis of C-sp3-centered geminal diiodides
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(Chemical Equation Presented) Trisubstituted gem-diiodoalkenes of functionalized chains are efficiently reduced to the corresponding terminal geminal diiodides in high yields upon treatment with the diazene precursor, diethyl 4-(hydrazinosulfonyl)-benzyl phosphonate.
- Cloarec, Jean-Manuel,Charette, Andre B.
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p. 4731 - 4734
(2007/10/03)
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- Design and synthesis of bridged γ-lactams as analogues of β-lactam antibiotics
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Anti-Bredt bridged bicyclo[3.2.1] γ-lactams were designed as inhibitors of penicillin binding proteins (PBPs). The compounds were prepared by a carbenoid insertion into a lactam N-H bond. Their weak antibacterial activity could either be explained by a poor chemical stability or by unfavorable steric interactions of the methylene bridge of the γ-lactam with the targeted enzymes.
- Aszodi, Jozsef,Rowlands, David A.,Mauvais, Pascale,Collette, Pascal,Bonnefoy, Alain,Lampilas, Maxime
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p. 2489 - 2492
(2007/10/03)
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- Toward protein-cleaving catalytic drugs: Artificial protease selective for myoglobin
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A protein-cleaving catalyst highly selective for a disease-related protein can be used as a catalytic drug. As the first protein-cleaving catalyst selective for a protein substrate, a catalyst for myoglobin (Mb) was designed by attaching the Cu(II) or Co(
- Jeon, Joong Won,Son, Sang Jun,Yoo, Chang Eun,Hong, In Seok,Suh, Junghun
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p. 2901 - 2910
(2007/10/03)
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- Retroviral protease inhibiting compounds
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A compound comprising a substituent of the formula (II) is disclosed as an HIV protease inhibitor. Intermediates for making such compounds and processes for making such intermediates are also disclosed.
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- A novel concept in combinatorial chemistry in solution with the advantages of solid-phase synthesis: Formation of N-betaines by multicomponent domino reactions
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Advantages of solid-phase and liquid-phase synthesis are combined in a new concept of combinatorial chemistry: a domino sequence comprising Knoevenagel and hetero-Diels-Alder reactions, with subsequent hydrogenation starting from protected aminoaldehydes, 1.3-dicarbonyl compounds, and enol ethers leads to N-heterocycles of high diversity with a betaine structure, which are isolated in highly pure form by precipitation with diethyl ether (see scheme), Cbz = benzylocycarbonyl, Bn = benzyl.
- Tietze, Lutz F.
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p. 903 - 905
(2007/10/03)
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- A convenient synthesis of indole-substituted 2-pyrrolidones and their cyclized derivatives
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Condensation between indole, Meldrum's acid, and benzyloxycarbonylacetaldehyde or aminoacetaldehyde derivatives yielded trimolecular adducts 7a-c. The latter were cyclized to indole-substituted 2-pyrrolidones 15a-b or 3-aminopyrrolid-2-ones 18a-b, dependi
- Boisbrun, Michel,Jeannin, Laurent,Toupet, Loic,Laronze, Jean-Yves
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p. 3051 - 3057
(2007/10/03)
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- RETROVIRAL PROTEASE INHIBITING COMPOUNDS
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A compound of the formula: STR1 is disclosed as an HIV protease inhibitor. Methods and compositions for inhibiting an HIV infection are also disclosed.
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- Liquid phase synthesis of a peptidic nucleic acid dimer
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The first liquid phase synthesis of a peptidic nucleic acid (PNA) dimer containing guanine and adenine has been achieved in good yields. A new strategy was elaborated in order to circumvent difficult coupling of the protected PNA.
- Farese, Audrey,Patino, Nadia,Condom, Roger,Dalleu, Sandrine,Guedj, Roger
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p. 1413 - 1416
(2007/10/03)
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- Conjugate additions of E-alkenylphosphonates to lithiated Schollkopf's bislactim ether: Stereocontrolled access to anti 2-amino-3-substituted-4-phosphonobutanoic acids
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Highly face-selective Michael adition of lithiated Schollkopf's bislactim ether (derived from cyclo-[L-val-gly], 7) to E-alkenylphosphonates 2a-d and 1,3-butadienylphosphonate 2e allows a direct and stereocontrolled access to the excitatory amino acid analogues 2,3-anti-2-amino-3-substituted-4-phosphonobutanoic acids 14a-d and 2-amino-6-phosphono-4-hexenoic acid 15. The relative stereochemistry was assigned from a NMR study of cyclic derivatives 16, 17 and 19.
- Ojea, Vicente,Fernandez, Ma. Carmen,Ruiz, Maria,Quintela, Jose Ma.
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p. 5801 - 5804
(2007/10/03)
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- 3-azido compound
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A new and practical method for synthesizing heterocyclic polyhydroxylated alkaloids using enzymatic aldol condensation and catalytic intramolecular reductive amination is disclosed.
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- Simple Three-Step Synthesis of (R)- and (S)-4-Amino-3-hydroxybutanoic Acid (GABOB) by Stereoselective Aldol Addition
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A simple synthesis of both (R)- and (S)-GABOB (5) is reported.In the key step, doubly deprotonated (R)- or (S)-2-Hydroxy-1,2,2-triphenylethyl acetate (HYTRA) (1) is added to Cbz-protected glycinal (2).
- Braun, Manfred,Waldmueller, Delia
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p. 856 - 858
(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 Analogues of 1,3-Dihydroxyacetone Phosphate and Glyceraldehyde 3-Phosphate for Use in Studies of Fructose-1,6-diphosphate Aldolase
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This paper describes the synthesis of five analogues of dihydroxyacetone phosphate (3-azidohydroxyacetone 1-phosphate (5), 3-(acetylamino)hydroxyacetone 1-phosphate (12), (R)-1,3-dihydroxy-2-butanone 1-phosphate (18), (+/-)-1,3-dihydroxy-2-butanone 3-phosphate (26), and phosphonomethyl glycolate (31)).The syntheses of 18 and 26 are based on a new reaction: that is, the introduction of the phosphate group by the reaction of a diazo ketone with dibenzyl phosphate.These methods provide easy access to a number of compounds that are potential substrates for the synthetically useful enzyme aldolase (fructose-1,6-diphosphate aldolase from rabbit muscle, EC 4.1.2.13, RAMA) and perhaps for other enzymes of glycolysis.This paper also describes syntheses of 14 aldehydes for examination as substrates for aldolase.When the precursor was available, ozonolysis of vinyl groups proved to be the best route to the corresponding aldehydes.
- Bischofberger, Norbert,Waldmann, Herbert,Saito, Tohru,Simon, Ethan S.,Lees, Watson,et al.
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p. 3457 - 3465
(2007/10/02)
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- A CONVENIENT SYNTHESIS OF &α',&β-DIAMINO- &α,&α-DIFLUOROKETONES, NEW DIPEPTIDE ISOSTERES
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A convenient and versatile synthesis of α',β-diamino-α,α-difluoroketones is described.These compounds represent a new class of true dipeptide isosteres useful for the design of serine protease inhibitors.
- Schirlin, D.,Baltzer, S.,Altenburger, J. M.
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p. 3687 - 3690
(2007/10/02)
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- New Methods and Reagents in Organic Synthesis. 67. A General Synthesis of Derivatives of Optically Pure 2-(1-Aminoalkyl)thiazole-4-carboxylic Acids
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Preparations of 2-(1-aminoalkyl)thiazole-4-carboxylic acids (thiazole amino acids), important constituents of a series of cytotoxic cyclic peptides from marine organisms, have been conveniently and efficiently achieved as their N- and C-protected derivatives 6 from N-Boc or N-Z α-amino acids 1 in five steps.Esterification of 1 with methyl iodide followed by reduction with lithium chloride-sodium borohydride afforded N-protected amino alcohols 3.Selective reduction of the α-ester functions of the glutamic acid derivatives (Z-D- and Z-L-Glu(O-t-Bu)-OMe and O-t-Bu) was also achieved under the above reduction conditions.Dimethyl sulfoxide oxidation, followed by condensation with cysteine methyl ester afforded the thiazolidine derivatives 5, which were conveniently dehydrogenated with manganese dioxide, called chemical manganese dioxide (CMD) and produced for batteries, to give the desired thiazole amino acid derivetives 6.The glutamine derivatives (Z-D- and Z-L-(gln)Thz-OMe) were prepared from the corresponding glutamic acid derivatives (Z-D- and Z-L-6f).No appreciable racemization was observed in the above conversion, which was proven by HPLC of the 3,5-dinitrobenzoyl derivatives of thiazole amino acids 6 using a chiral column.
- Hamada, Yasumasa,Shibata, Makoto,Sugiura, Tsuneyuki,Kato, Shinji,Shioiri, Takayuki
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p. 1252 - 1255
(2007/10/02)
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