- Identification of the Amipurimycin Gene Cluster Yields Insight into the Biosynthesis of C9 Sugar Nucleoside Antibiotics
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Feeding studies indicate a possible synthetic pattern for the N-terminal cis-aminocyclopentane carboxylic acid (ACPC) and suggest an unusual source of the high-carbon sugar skeleton of amipurimycin (APM). The biosynthetic gene cluster of APM was identified and confirmed by in vivo experiments. A C9 core intermediate was discovered from null mutants of ACPC pathway, and an ATP-grasp enzyme (ApmA8) was reconstituted in vitro for ACPC loading. Our observations allow a first proposal of the APM biosynthetic pathway.
- Kang, Wen-Jia,Pan, Hai-Xue,Wang, Shengyang,Yu, Biao,Hua, Huiming,Tang, Gong-Li
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supporting information
p. 3148 - 3152
(2019/05/10)
-
- The N-Hydroxymethyl Group as a Traceless Activating Group for the CAL-B-Catalysed Ring Cleavage of β-Lactams: A Type of Two-Step Cascade Reaction
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An efficient enzymatic two-step cascade procedure has been devised for rapid access to diverse amino acids from N-hydroxymethyl-β-lactams; representative amino acids include the antifungal agent cispentacin, intermediates for the taxol side-chain, and assorted cathepsin inhibitors. When CAL-B-catalysed hydrolyses of racemic N-hydroxymethyl-β-lactams were performed with H2O (0.5 equiv.) in iPr2O at 60 °C, relatively quick (vs. non-activated counterparts) and enantioselective (E > 200) ring cleavage reactions took place. As the ring-opened amino acids formed, the hydroxymethyl group, as a traceless activating group, underwent spontaneous in situ degradation. Consequently, the desired β-amino acid and unreacted N-hydroxymethyl-β-lactam enantiomers (ee > 95 %) were formed. The formation of polymers, induced by liberation of formaldehyde, was successfully restricted by the addition of benzylamine as a capture agent, to the enzymatic reactions. An efficient enzymatic two-step cascade procedure was devised for CAL-B-catalysed hydrolysis of racemic N-hydroxymethyl-β-lactams. Conditions in which the hydroxymethyl group serves as a traceless activating group (E > 200), giving desired β-amino acid along with unreacted starting lactam enantiomers (ee > 95 %) were identified; polymerization was controlled by addition benzylamine addition.
- Forró, Enik?,Galla, Zsolt,Fül?p, Ferenc
-
p. 2647 - 2652
(2016/06/09)
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- High-Performance Liquid Chromatographic Enantioseparation of Cyclic β-Amino Acids on Zwitterionic Chiral Stationary Phases Based on Cinchona Alkaloids
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Stereoselective high-performance liquid chromatographic separations of eight sterically constrained cyclic β-amino acid enantiomer pairs were carried out using the newly developed Cinchona alkaloid-based zwitterionic chiral stationary phases Chiralpak ZWIX(+) and ZWIX(-). The effects of the mobile phase composition, the nature and concentrations of the acid and base additives, the counterions and temperature on the separations were investigated. The changes in standard enthalpy, Δ(ΔH°), entropy, Δ(ΔS°), and free energy, Δ(ΔG°), were calculated from the linear van't Hoff plots derived from the ln α vs. 1/T curves in the studied temperature range (10-50°C). The values of the thermodynamic parameters depended on the nature of the selectors and the structures of the analytes. Unusual temperature behavior was observed on the ZWIX(-) column: decreased retention times were accompanied by increased separation factors with increasing temperature. On the ZWIX(+) column only enthalpically, whereas on the ZWIX(-) column both enthalpically and entropically driven separations were observed. The elution sequence was determined in all cases and was observed to be the opposite on ZWIX(+) and on ZWIX(-). Chirality 27:563-570, 2015.
- Ilisz, István,Gecse, Zsanett,Lajk?, Gyula,Forr?, Enik?,Fül?p, Ferenc,Lindner, Wolfgang,Péter, Antal
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p. 563 - 570
(2015/08/25)
-
- Stereoselective organocatalytic approach to α,β-disubstituted- β-amino acids: A short enantioselective synthesis of cispentacin
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α-Branched α,β-unsaturated aldehydes have been tested in the organocatalytic tandem Michael addition/cyclization with N-(benzyloxycarbonyl)hydroxylamine, a reaction which until now has been restricted to α-unsubstituted enals. Starting from cyclopentene-2- carbaldehyde, and using diphenylprolinol trimethylsilyl ether as a chiral amine catalyst, this approach has led to the development of a practical, high yielding (93-98 % overall yield, three steps), and highly enantioselective (up to 98:2 er) route to the cyclic β-amino acid cispentacin, which compares favourably with previously described asymmetric syntheses of this biologically active natural product. When using acyclic α-branched α,β-unsaturated aldehydes as substrates, the reaction yields depend on the substitution pattern of the aldehydes, and mixtures of cis- and trans-isomers are obtained. Nevertheless, this strategy has proved to be successful in some instances, and (3R,4R)-benzyl 3-ethyl-4-methyl-5-oxoisoxazolidin-2-carboxylate could be obtained in 70 % overall yield (two steps) from the reaction of 2-ethylcrotonaldehyde and N-(benzyloxycarbonyl)hydroxylamine under catalysis with diphenylprolinol trimethylsilyl ether, and with high enantiomeric purity (99:1 er). The organocatalytic tandem Michael addition/cyclization of cyclopentene-2-carbaldehyde with N-Cbz-hydroxylamine, using diphenylprolinol TMS ether as a chiral amine catalyst, gives a practical, high yielding, and highly enantioselective route to the cyclic β-amino acid cispentacin. Acyclic α-branched enals give variable results in the same reaction, depending on the substitution pattern. Copyright
- Pou, Ana,Moyano, Albert
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p. 3103 - 3111
(2013/06/26)
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- CYCLOALKYL-FUSED TETRAHYDROQUINOLINES AS CRTH2 RECEPTOR MODULATORS
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The invention provides certain cycloalkyl-fused tetrahydroquinolines of the Formula (I), and their pharmaceutically acceptable salts and esters, wherein R1, R2, R7, R8, R8a, E, Y, Z, n, u, and t are a
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Page/Page column 53
(2013/02/28)
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- Hairpin folding behavior of mixed α/β-peptides in aqueous solution
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The invention of new strategies for the design of protein-mimetic oligomers that manifest the folding encoded in natural amino acid sequences is a significant challenge. In contrast to the α-helix, mimicry of protein β-sheets is less understood. We report
- Lengyel, George A.,Frank, Rebecca C.,Horne, W. Seth
-
p. 4246 - 4249
(2011/06/21)
-
- PEPTIDES AND PEPTIDOMIMETIC COMPOUNDS, THE MANUFACTURING THEREOF AS WELL AS THEIR USE FOR PREPARING A THERAPEUTICALLY AND/OR PREVENTIVELY ACTIVE PHARMACEUTICAL COMPOSITION
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Peptides, peptidomimetics and derivatives thereof of the general formula I: H2N-GHRPX1-β-X4X5X6X7X8X9X10-X11 (I), in which X1-X10 denote one of the 20 genetically coded amino acids, wherein X8, X9 and X10 may also denote a single chemical bond;X11 denotes OR1 in which R1 equals hydrogen or (C1-C10) alkyl NR2R3 with R2 and R3 are equal or different and denote hydrogen, (C1-C10) alkyl, or a residue —W-PEG5-60K, in which the PEG residue is attached via a suitable spacer W to the N-atom, ora residue NH—Y-Z-PEG5-60K, in whichY denotes a chemical bond or a genetically coded amino acids from the group S, C, K or R andZ denotes a spacer, via which a polyethylene glycol (PEG)-residue can be attached, and their physiologically acceptable salts, andβ denotes an amino acid, or a peptidomimetic element, which induces a bend or turn in the peptide backbone.
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-
- Enantiomeric discrimination of cyclic β-amino acids using (18-crown-6)-2,3,11,12-tetracarboxylic acid as a chiral NMR solvating agent
-
(18-Crown-6)-2,3,11,12-tetracarboxylic acid is an excellent chiral NMR solvating agent for cyclic β-amino acids with cyclopentane, cyclohexane, cycloheptane, cyclopentene, cyclohexene, bicyclo[2.2.1]heptane, and bicyclo[2.2.1]heptene rings. The crown ether was added to the neutral β-amino acids in methanol-d4. A neutralization reaction between the crown ether and β-amino acid forms the ammonium ion needed for favorable association. Enantiomeric discrimination of the two hydrogen atoms α to the amine and carboxylic acid moieties of the β-amino acid was observed with every substrate studied. Trends in the order of the enantiomeric discrimination of certain hydrogen atoms for substrates of similar structures correlate with the absolute configuration.
- Chisholm, Cora D.,Fueloep, Ferenc,Forro, Eniko,Wenzel, Thomas J.
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experimental part
p. 2289 - 2294
(2010/11/05)
-
- Vapour-assisted enzymatic hydrolysis of β-lactams in a solvent-free system
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A new, solvent-free, vapour-assisted method, developed for the synthesis of carbocyclic cis β-amino acid enantiomers through the Candida antarctica lipase B-catalysed enantioselective (E >200) hydrolysis of β-lactams with 0.5 equiv of H2O at 70 °C, has been demonstrated to be applicable on a preparative scale to produce (±)-2 (the starting racemate for cispentacin), (±)-3 (the starting racemate for 4-tert-butylcispentacin, a new cispentacin analogue) and (±)-7 (the starting racemate for 1,4-ethylene-bridged cispentacin).
- Forro, Eniko,Fueloep, Ferenc
-
p. 1005 - 1009
(2008/09/21)
-
- The first direct enzymatic hydrolysis of alicyclic β-amino esters: A route to enantiopure cis and trans β-amino acids
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The first direct enzymatic method is reported for the synthesis of cis and trans βamino acid enantiomers through the lipase-catalyzed enantioselective hydrolysis of alicyclic β esters in organic media. High enantioselectivities (E usually > 001) were observed when the Candida antarctica lipase B catalyzed reactions were performed with H2O (0.5 equivalents) in iP iPr2O at 5°C. The resolved products, obtained in good yields (≥42%), could be easily separated.
- Forro, Eniko,Fueloep, Ferenc
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p. 6397 - 6401
(2008/02/13)
-
- 2,4-diamino-pyrimidines as aurora inhibitors
-
The present invention encompasses compounds of general formula (1) wherein R1 to R3 are defined as in claim 1, which are suitable for the treatment of diseases characterised by excessive or abnormal cell proliferation, and the use thereof for preparing a pharmaceutical composition having the above-mentioned properties.
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-
Page/Page column 18
(2008/06/13)
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- Chiral ligand-controlled asymmetric conjugate amination of enoates with lithium mesitylmethyl(trimethylsilyl)amide
-
Lithium mesitylmethyl(trimethylsilyl)amide behaved as a nice amination agent in a chiral ligand-controlled conjugate addition reaction of tert-butyl cinnamate to give the conjugate amination product with 99% ee in 90% yield. Other acyclic and cyclic enoat
- Sakai, Takeo,Doi, Hirohisa,Tomioka, Kiyoshi
-
p. 8351 - 8359
(2007/10/03)
-
- Catalytic enantioselective desymmetrization of meso-N-acylaziridines with TMSCN
-
A catalytic enantioselective desymmetrization of meso-N-p-nitrobenzoylaziridines with TMSCN was developed using a chiral gadolinium catalyst generated from Gd(OiPr)3 and d-glucose-derived ligand 1. In this reaction, the addition of a
- Mita, Tsuyoshi,Fujimori, Ikuo,Wada, Reiko,Wen, Jianfeng,Kanai, Motomu,Shibasaki, Masakatsu
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p. 11252 - 11253
(2007/10/03)
-
- (S,S)-trans-cyclopentane-constrained peptide nucleic acids. A general backbone modification that improves binding affinity and sequence specificity
-
Replacing the ethylenediamine portion of aminoethylglycine peptide nucleic acids (aegPNAs) with one or more (S,S)-trans-cyclopentane diamine units significantly increases binding affinity and sequence specificity to complementary DNA, making these modifie
- Pokorski, Jonathan K.,Witschi, Mark A.,Purnell, Bethany L.,Appella, Daniel H.
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p. 15067 - 15073
(2007/10/03)
-
- Lipase-catalyzed enantioselective ring opening of unactivated alicyclic-fused beta-lactams in an organic solvent.
-
[reaction: see text] A highly efficient and very simple method was developed for the synthesis of enantiopure beta-amino acids (e.g. cispentacin) and beta-lactams through the enzyme-catalyzed enantioselective ring opening of unactivated alicyclic beta-lac
- Forro, Eniko,Fueloep, Ferenc
-
p. 1209 - 1212
(2007/10/03)
-
- An alkaloid-mediated desymmetrization of meso-anhydrides via a nucleophilic ring opening with benzyl alcohol and its application in the synthesis of highly enantiomerically enriched β-amino acids
-
The cinchona alkaloid-mediated opening of prochiral cyclic anhydrides in the presence of benzyl alcohol leading to optically active hemiesters is described. Structurally diverse anhydrides are converted into their corresponding benzyl monoesters with either enantiomer being obtained with up to 99 percent e.e. by using quinine or quinidine as the directing additive. A simple aqueous work-up protocol permits the isolation of the products in analytically pure form and the recovery of the alkaloids almost quantitatively. These hemiesters can be converted to N-protected β-amino esters by means of Curtius degradation of the corresponding acyl azides. Subsequent cleavage of both protecting groups by a single reaction step leads to the free β-amino acids in excellent yields. The efficiency of this procedure is demonstrated by the short asymmetric synthesis of the fungicide cis-pentacin delivering the amino acid with >99.7 percent enantiomeric excess.
- Zhang, Mingbao,Zhu, Lei,Ma, Xin
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p. 3455 - 3468
(2007/10/03)
-
- The use of enantiomerically pure ketene dithioacetal bis(sulfoxides) in highly diastereoselective intramolecular nitrone cycloadditions. Application in the total synthesis of the beta-amino acid (-)-cispentacin and the first asymmetric synthesis of cis-(3R,4R)-4-amino-pyrrolidine-3-carboxylic acid.
-
Intramolecular 1,3-dipolar nitrone cycloaddition onto an enantiomerically pure ketene dithioacetal dioxide using a three-carbon tether gave the corresponding 5,5-disubstituted isoxazolidine as a single diastereomer in good yield. This reaction has been used as the key step in an asymmetric synthesis of the naturally occurring antibiotic, (-)-cispentacin. An asymmetric synthesis of 4-amino-pyrrolidine-3-carboxylic acid has also been carried out using the intramolecular nitrone cycloaddition as the stereocontrolling step.
- Aggarwal, Varinder K,Roseblade, Stephen,Alexander, Rikki
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p. 684 - 691
(2007/10/03)
-
- Novel antifungal β-amino acids: Synthesis and activity against Candida albicans
-
A series of novel β-amino acids has been synthesized and tested for their in vitro antifungal activity against Candida albicans. A steep SAR was observed. β-Amino acid 21 (BAY 10-8888/PLD-118) revealed the most favourable activity-tolerability profile and was selected for clinical studies as a novel antifungal for the oral treatment of yeast infections.
- Mittendorf, Joachim,Kunisch, Franz,Matzke, Michael,Militzer, Hans-Christian,Schmidt, Axel,Schoenfeld, Wolfgang
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p. 433 - 436
(2007/10/03)
-
- Synthesis of novel sila-substituted β-amino acids
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A highly efficient and stereoselective synthesis of unnatural cyclic sila-substituted β-amino acids has been developed from simple starting materials. The key step is nucleophilic ring opening of an intermediate aziridine with an umpolung synthon for the
- Matthews, Jennifer L,McArthur, Duncan R,Muir, Kenneth W
-
p. 5401 - 5404
(2007/10/03)
-
- Radical cyclization in heterocycle synthesis. Part 13: Sulfanyl radical addition-cyclization of oxime ethers and hydrazones connected with alkenes for synthesis of cyclic β-amino acids
-
A combination of sulfanyl radical addition-cyclization of the oxime ethers and hydrazones connected with alkenes and subsequent conversion of a phenylsulfanylmethyl group to a carboxyl group provides a novel method for the construction of the cyclic β-amino acids. Upon treatment with thiophenol in the presence of AIBN, the oxime ethers and hydrazones smoothly underwent sulfanyl radical addition-cyclization to give the 2-(phenylsulfanylmethyl)cycloalkylamine. This method was successfully applied to the practical synthesis of 2-aminocyclopentanecarboxylic acid and 4-amino-3-pyrrolidinecarboxylic acid.
- Miyata, Okiko,Muroya, Kanami,Kobayashi, Tomoko,Yamanaka, Rina,Kajisa, Seiko,Koide, Junko,Naito, Takeaki
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p. 4459 - 4479
(2007/10/03)
-
- Highly Diastereoselective Nitrone Cycloaddition onto a Chiral Ketene Equivalent: Asymmetric Synthesis of Cispentacin
-
matrix presented A highly diastereoselective intramolecular nitrone cycloaddition onto a chiral ketene equivalent, obtained by Horner-Wadsworth-Emmons olefination of either enantiomer of bis-sulfinyl phosphonate 6, is described. Cycloaddition gave 5,5-disubstituted isoxazolidine 10 in good yield as a single diastereomer. Catalytic hydrogenolysis of 10 furnished either enantiomer of optically pure cis-2-aminocyclopentane-1-carboxylic acid.
- Aggarwal, Varinder K.,Roseblade, Stephen J.,Barrell, Juliet K.,Alexander, Rikki
-
p. 1227 - 1229
(2007/10/03)
-
- A novel preparation of 2-aminocyclopentanecarboxamides
-
Different syntheses of cis- and trans-2-aminocyclopentanecarboxamides were studied. A convenient and effective method was devised for the preparation of cis-2-aminocyclopentanecarboxamide derivatives starting from the readily available 6-tert-butoxycarbon
- Csomos, Peter,Bernath, Gabor,Fueloep, Ferenc
-
p. 1077 - 1084
(2007/10/03)
-
- An improved synthesis of enantiopure β-amino acids
-
An improved method for the preparation of both the enantiopure β-amino acids is presented. The diastereomer benzyl β-amino esters, obtained by stereoselective reduction of β-enamino esters, were separated and hydrogenolyzed to the free enantiopure β-amino acids.
- Cimarelli,Palmieri,Volpini
-
p. 2943 - 2953
(2007/10/03)
-
- Efficient and highly enantioselective process for the preparation of enantiomerically pure cyclopentane-β-amino acids
-
The process according to the invention for the preparation of enantiomerically pure cyclopentane-β-amino acids of the general formula (I) STR1 in which A and D have the meanings given in the description, is characterized in that meso-dicarboxylic acid anhydrides are first converted by asymmetric alcoholysis with allyl alcohols and in the presence of a chiral amine base present in enantiomerically pure form, in inert solvents, via the intermediate enantiomerically pure salt stage, into the enantiomerically pure dicarboxylic acid monoesters, in a further step these dicarboxylic acid monoesters are intermediately converted, in the sense of a Curtius rearrangement by reaction with azides, into the corresponding acid azides, and are subsequently converted into the corresponding rearranged isocyanates and the isocyanates are then reacted with allyl alcohols to give the compounds of the general formula (VII), and finally the cyclopentane-β-amino acids of the general formula (I) are obtained by splitting off the urethane and ester function.
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-
-
- Dolastatin 15 derivatives
-
Compounds of the present invention include cell growth inhibitors which are peptides of Formula I and acid salts thereof, wherein A, D, and E are α-amino acid residues, B is an α-amino acid residue or an α-hydroxy acid residue, F is an aminobenzoic acid r
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-
-
- Chemoenzymatic synthesis of both enantiomers of cispentacin
-
Based on the lipase-catalysed kinetic resolution of the silyloxyalcohol (1RS,2SR)-5 by transesterification with vinyl acetate in the presence of lipase from Pseudomonas cepacia a synthesis of both enantiomers of the β-amino acid cispentacin (1R,2S)-1 and (1S,2R)-1 using simple functional group interconversions is described.
- Theil, Fritz,Ballschuh, Sibylle
-
p. 3565 - 3572
(2007/10/03)
-
- Stereoselective reduction of enantiopure β-enamino esters by hydride: A convenient synthesis of both enantiopure β-amino esters
-
The reduction of enantiopure β-enamino esters 1 with sodium triacetoxyborohydride in acetic acid is described. This occurs with good diastereo- and enantioselectivity to yield β-amino esters 2 and 3 (after hydrogenolysis of the N-chiral group). A model is
- Cimarelli, Cristina,Palmieri, Gianni
-
p. 5557 - 5563
(2007/10/03)
-
- Asymmetric Synthesis of (-)-(1R,2S)-Cispentacin and Related cis- and trans-2-Amino Cyclopentane- and Cyclohexane-1-carboxylic Acids
-
The antifungal antibiotic (-)-(1R,2S)-2-aminocyclopentane-1-carboxylic acid (cispentacin) 8 and its cyclohexane homologue 14 have been prepared utilizing the highly stereoselective conjugate addition of homochiral lithium N-benzyl-N-α-methylbenzylamide 5.
- Davies, Stephen G.,Ichihara, Osamu,Lenoir, Isabelle,Walters, Iain A. S.
-
p. 1411 - 1416
(2007/10/02)
-
- Diastereo and Enantioselective Entry to β-Amino Esters by Hydride Reduction of Homochiral β-Enamino Esters.
-
The reduction of homochiral β-enamino esters 1 with sodium triacetoxyborohydride, which occurs with good diastereo- and enantioselectivity in the β-amino esters 2, is described.The procedure allows a straightforward preparation of compounds with known bio
- Cimarelli, Cristina,Palmieri, Gianni,Bartoli, Giuseppe
-
p. 1455 - 1458
(2007/10/02)
-
- Synthesis of racemic and optically active cispentacin (FR109615) using intramolecular nitrone-olefin cycloaddition
-
Synthesis of racemic and optically active cispentacin ((-)-1) is described. Intramolecular nitrone-olefin cycloaddition of the alkenyl nitrone 7 gave cis-isoxazolidine (±)-8, which was transformed into (±)-1 by sequential reactions involving catalytic hyd
- Konosu,Oida
-
p. 1012 - 1018
(2007/10/02)
-
- Probing a Molecular Model of Taste Utilizing Peptidomimetic Stereoisomers of 2-Aminocyclopentanecarboxylic Acid Methyl Ester
-
On the basis of the preferred conformations of L-aspartyl dipeptide derivatives containing α-amino acids at the second position and their retro-inverso analogues deduced by a combination of X-ray crystallography, 1H NMR spectroscopy, and molecular mechani
- Yamazaki, Toshimasa,Zhu, Yun-Fei,Probstl, Albert,Chadha, Raj K.,Goodman, Murray
-
p. 6644 - 6655
(2007/10/02)
-
- Whole Cell Catalysed Kinetic Resolution of 6-Azabicyclohept-3-en-7-one: Synthesis of (-)-Cispentacin (FR 109615)
-
Enantioselective hydrolysis of the β-lactam (+/-)2 using Rhodococcus equi provided (1R,5S)-6-azabicyclohept-3-en-7-one (+)-2, a precursor of the antifungal agent cispentacin.
- Evans, Chris,McCague, Ray,Roberts, Stanley M.,Sutherland Alan G.,Wisdom, Richard
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p. 2276 - 2277
(2007/10/02)
-