- Pithohirolide, an antimicrobial tetradepsipeptide from a fungus Pithomyces chartarum
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Pithohirolide (1), a new depsipeptide, was isolated from an ascomycetous fungus Pithomyces chartarum TAMA 581. The planar structure of 1 was elucidated on the basis of NMR and MS analyses and the absolute configuration was determined by the advanced Marfey’s analysis, chiral-phase HPLC analysis, and synthesis of degradation product. Compound 1 possesses a cyclic structure comprising (S)-2-hydroxy-3-phenylpropanoic acid, (S)-3-hydroxy-3-phenylpropanoic acid, (S)-2-hydroxyisovaleric acid, and N-methyl-l-alanine, connected via three ester and one amide linkages. Compound 1 exhibited antimicrobial activity against Staphylococcus aureus and Saccharomyces cerevisiae at MIC 3.1 μg ml?1.
- Zhang, Zhiwei,Zhou, Tao,Xing, Tian,Ishizaki, Takayuki,Okuda, Toru,Oku, Naoya,Igarashi, Yasuhiro
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- Medusamide a, a panamanian cyanobacterial depsipeptide with multiple β-amino acids
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From a collection of marine cyanobacteria made in the Coiba National Park along the Pacific coast of the Republic of Panama a novel cyclic depsipeptide, given the trivial name medusamide A, has been isolated and fully characterized. Medusamide A contains four contiguous β-amino acid (2R,3R)-3-amino-2-methylhexanoic acid (Amha) residues. This is the first report of multiple Amha residues and contiguous β-amino acid residues within a single cyclic peptide-type natural product. Stereochemical assignment of the Amha residues was completed following the synthesis of reference standards for this β-amino acid and the subsequent derivatization with Marfey's reagent and LC-MS analysis.
- Fenner, Amanda M.,Engene, Niclas,Spadafora, Carmenza,Gerwick, William H.,Balunas, Marcy J.
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- Rare Streptomyces N-formyl amino-salicylamides inhibit oncogenic K-Ras
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During a search for inhibitors of oncogenic K-Ras, we detected two known and two new examples of the rare neoantimycin structure class from a liquid cultivation of Streptomyces orinoci, and reassigned/assigned structures to all based on detailed spectroscopic analysis and microscale C3 Marfey's and C3 Mosher chemical degradation/derivatization/analysis. SAR investigations inclusive of the biosynthetically related antimycins and respirantin, and synthetic benzoxazolone, documented a unique N-formyl amino-salicylamide pharmacophore as a potent inhibitor of oncogenic K-Ras.
- Salim, Angela A.,Cho, Kwang-Jin,Tan, Lingxiao,Quezada, Michelle,Lacey, Ernest,Hancock, John F.,Capon, Robert J.
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- Structure revision of isocereulide A, an isoform of the food poisoning emetic Bacillus cereus toxin cereulide
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The emetic Bacillus cereus toxin cereulide presents an enormous safety hazard in the food industry, inducing emesis and nausea after the consumption of contaminated foods. Additional to cereulide itself, seven structurally related isoforms, namely the isocereulides A-G, have already been elucidated in their chemical structure and could further be identified in B. cereus contaminated food samples. The newly performed isolation of isocereulide A allowed, for the first time, 1D- and 2D-NMR spectroscopy of a biosynthetically produced isocereulide, revealing results that contradict previous assumptions of an L-O-Leu moiety within its chemical structure. By furthermore applying posthydrolytical dipeptide analysis, amino acid and α-hydroxy acid analysis by means of UPLC-ESITOF- MS, as well as MSn sequencing, the structure of previously reported isocereulide A could be corrected. Instead of the L-O-Leu as assumed to date, one L-O-Ile unit could be verified in the cyclic dodecadepsipeptide, revising the structure of isocereulide A to [(D-O-Leu-D-Ala-L-O-Val-L-Val)2(DO- Leu-D-Ala-L-O-Ile-L-Val)].
- Ehling-Schulz, Monika,Hofmann, Thomas F.,Kranzler, Markus,Stark, Timo D.,Walser, Veronika
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- Photocatalytic Asymmetric Reduction of 3-Methyl-2-oxobutanoic Acid with Chiral Rh(I) Complexes and Powdery Semiconductors
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Photocatalytic asymmetric reduction of 3-methyl-2-oxobutanoic acid giving 2-hydroxy-3-methylbutanoic acid has been carried out in up to 60percent ee in aqueous methanol with chiral BINAP-Rh(I) complexes and semiconductor photocatalysts, TiO2 or CdS.
- Wang, Hanhein,Sakata, Tadayoshi,Azuma, Masashi,Ohta, Tetsuo,Takaya, Hidemasa
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- Asymmetric Synthesis of Optically Active 3-Cyclohexene-1-carboxylic Acid Utilizing Lactic Ester as a Chiral Auxiliary in the Diastereoselective Diels–Alder Reaction
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The optically active 3-cyclohexene-1-carboxylic acid was synthesized through a TiCl4-catalyzed diastereoselective Diels–Alder reaction utilizing lactic acid ester as a chiral auxiliary, which can be removed by washing with H2O. The (S)- and (R)-isomers were both derived from easily available ethyl l-lactate.
- Ochiai, Hidenori,Hayashi, Wakana,Nishiyama, Akira,Fujita, Ryunosuke,Kubota, Shunichi,Sasagawa, Miwa,Nishi, Tatsuya
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supporting information
p. 1002 - 1009
(2022/02/09)
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- Dudawalamides A-D, Antiparasitic Cyclic Depsipeptides from the Marine Cyanobacterium Moorea producens
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A family of 2,2-dimethyl-3-hydroxy-7-octynoic acid (Dhoya)-containing cyclic depsipeptides, named dudawalamides A-D (1-4), was isolated from a Papua New Guinean field collection of the cyanobacterium Moorea producens using bioassay-guided and spectroscopic approaches. The planar structures of dudawalamides A-D were determined by a combination of 1D and 2D NMR experiments and MS analysis, whereas the absolute configurations were determined by X-ray crystallography, modified Marfey's analysis, chiral-phase GCMS, and chiral-phase HPLC. Dudawalamides A-D possess a broad spectrum of antiparasitic activity with minimal mammalian cell cytotoxicity. Comparative analysis of the Dhoya-containing class of lipopeptides reveals intriguing structure-activity relationship features of these NRPS-PKS-derived metabolites and their derivatives.
- Almaliti, Jehad,Malloy, Karla L.,Glukhov, Evgenia,Spadafora, Carmenza,Gutiérrez, Marcelino,Gerwick, William H.
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p. 1827 - 1836
(2017/06/28)
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- Odobromoamide, a terminal alkynyl bromide-containing cyclodepsipeptide from the marine cyanobacterium okeania sp.
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The bioassay-guided fractionation of the Okinawan marine cyanobacterium Okeania sp. led to the isolation of the novel cyclodepsipeptide odobromoamide (1). The gross structure of 1 was determined by spectroscopic analyses, and its absolute stereochemistry was determined using a variety of different methods, including chemical derivatization and degradation followed by HPLC analysis. In addition, odobromoamide (1) exhibited broad-spectrum cytotoxicity against a human cancer cell line panel.
- Sueyoshi, Kosuke,Kudo, Takafumi,Yamano, Aki,Sumimoto, Shimpei,Iwasaki, Arihiro,Suenaga, Kiyotake,Teruya, Toshiaki
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p. 436 - 440
(2017/06/14)
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- 2-Bromo-6-isocyanopyridine as a Universal Convertible Isocyanide for Multicomponent Chemistry
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The development of 2-isocyanopyridines as novel convertible isocyanides for multicomponent chemistry is reported. Comparison of 12 representatives of this class revealed 2-bromo-6-isocyanopyridine as the optimal reagent in terms of stability and synthetic efficiency. It combines sufficient nucleophilicity with good leaving group capacity of the resulting amide moiety under both basic and acidic conditions. To demonstrate the practical utility of this reagent, an efficient two-step synthesis of the potent opioid carfentanil is presented.
- Van Der Heijden, Gydo,Jong,Ruijter, Eelco,Orru, Romano V. A.
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supporting information
p. 984 - 987
(2016/03/15)
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- Foxo3a Inhibitors of Microbial Origin, JBIR-141 and JBIR-142
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JBIR-141 (1) and JBIR-142 (2) were discovered as potent Foxo3a inhibitors that consist of three quite unique substructures, a 1-((dimethylamino)ethyl)-5-methyl-4,5-dihydrooxazole-4-carboxylic acid that is originated from Ala-Thr amino acid residues, a 3-acetoxy-4-amino-7-(hydroxy(nitroso)amino)-2,2-dimethylheptanoic acid, and an α-acyl tetramic acid fused with a 2-methylpropan-1-ol moiety. Their structures involving absolute configurations were determined by spectroscopic data, chemical degradation, anisotropy methods, and LC-MS analyses of diastereomeric derivatives. Compounds 1 and 2 exhibited specific inhibition against Foxo3a transcriptional activity with IC50 values of 23.1 and 166.2 nM, respectively.
- Kawahara, Teppei,Kagaya, Noritaka,Masuda, Yuichi,Doi, Takayuki,Izumikawa, Miho,Ohta, Kumiko,Hirao, Atsushi,Shin-Ya, Kazuo
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supporting information
p. 5476 - 5479
(2015/11/18)
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- Chiral propargylic cations as intermediates in SN1-type reactions: Substitution pattern, nuclear magnetic resonance studies, and origin of the diastereoselectivity
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Nine propargylic acetates, bearing a stereogenic center (-C*HXR 2) adjacent to the electrophilic carbon atom, were prepared and subjected to SN1-type substitution reactions with various silyl nucleophiles employing bismuth trifluoromethanesulfonate [Bi(OTf)3] as the Lewis acid. The diastereoselectivity of the reactions was high when the alkyl group R2 was tertiary (tert-butyl), irrespective of the substituent X. Products were formed consistently with a diastereomeric ratio larger than 95:5 in favor of the anti-diastereoisomer. If the alkyl substitutent R2 was secondary, the diastereoselectivity decreased to 80:20. The reaction was shown to proceed stereoconvergently, and the relative product configuration was elucidated. The reaction outcome is explained by invoking a chiral propargylic cation as an intermediate, which is preferentially attacked by the nucleophile from one of its two diastereotopic faces. Density functional theory (DFT) calculations suggest a preferred conformation in which the group R2 is almost perpendicular to the plane defined by the three substituents at the cationic center, with the nucleophile approaching the electrophilic center opposite to R2. Transition states calculated for the reaction of allyltrimethylsilane with two representative cations support this hypothesis. Tertiary propargylic cations with a stereogenic center (-C* HXR2) in the α position were generated by ionization of the respective alcohol precursors with FSO3H in SO2ClF at -80 C. Nuclear magnetic resonance (NMR) spectra were obtained for five cations, and the chemical shifts could be unambiguously assigned. The preferred conformation of the cations as extracted from nuclear Overhauser experiments is in line with the preferred conformation responsible for the reaction of the secondary propargylic cations.
- Nitsch, Dominik,Huber, Stefan M.,Poethig, Alexander,Narayanan, Arjun,Olah, George A.,Prakash, G. K. Surya,Bach, Thorsten
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supporting information
p. 2851 - 2857
(2014/03/21)
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- Maedamide, a novel chymotrypsin inhibitor from a marine cyanobacterial assemblage of Lyngbya sp.
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Maedamide, a novel chymotrypsin-inhibiting depsipeptide, was isolated from a cyanobacterial assemblage that mostly consisted of Lyngbya sp. Its structure was elucidated by spectroscopic analyses and chiral HPLC analyses of hydrolysis products. Maedamide selectively inhibited chymotrypsin but not elastase and trypsin. In addition, Maedamide strongly inhibited the growth of HeLa cells and HL60 cells.
- Iwasaki, Arihiro,Ohno, Osamu,Sumimoto, Shinpei,Suda, Shoichiro,Suenaga, Kiyotake
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supporting information
p. 4126 - 4128
(2015/02/19)
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- Maedamide, a novel chymotrypsin inhibitor from a marine cyanobacterial assemblage of Lyngbya sp.
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Maedamide, a novel chymotrypsin-inhibiting depsipeptide, was isolated from a cyanobacterial assemblage that mostly consisted of Lyngbya sp. Its structure was elucidated by spectroscopic analyses and chiral HPLC analyses of hydrolysis products. Maedamide selectively inhibited chymotrypsin but not elastase and trypsin. In addition, Maedamide strongly inhibited the growth of HeLa cells and HL60 cells.
- Iwasaki, Arihiro,Ohno, Osamu,Sumimoto, Shinpei,Suda, Shoichiro,Suenaga, Kiyotake
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supporting information
p. 4126 - 4128
(2014/07/22)
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- Lipopeptides from the tropical marine cyanobacterium symploca sp.
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A collection of the tropical marine cyanobacterium Symploca sp., collected near Kimbe Bay, Papua New Guinea, previously yielded several new metabolites including kimbeamides A-C, kimbelactone A, and tasihalide C. Investigations into a more polar cytotoxic fraction yielded three new lipopeptides, tasiamides C-E (1-3). The planar structures were deduced by 2D NMR spectroscopy and tandem mass spectrometry, and their absolute configurations were determined by a combination of Marfeys and chiral-phase GC-MS analysis. These new metabolites are similar to several previously isolated compounds, including tasiamide (4), grassystatins (5, 6), and symplocin A, all of which were isolated from similar filamentous marine cyanobacteria.
- Mevers, Emily,Haeckl, F. P. Jake,Boudreau, Paul D.,Byrum, Tara,Dorrestein, Pieter C.,Valeriote, Frederick A.,Gerwick, William H.
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p. 969 - 975
(2014/05/20)
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- Pitipeptolides C-F, antimycobacterial cyclodepsipeptides from the marine cyanobacterium Lyngbya majuscula from Guam
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Pitipeptolides A (1) and B (2) are cyclic depsipeptides isolated from the marine cyanobacterium Lyngbya majuscula from Piti Bomb Holes, Guam. Additional analogues have now been isolated by revisiting larger collections of the same cyanobacterium. The four identified analogues, pitipeptolides C-F (3-6), are the tetrahydro analogue (3), an analogue with a lower degree of methylation (4) as well as two homologues (5 and 6) of pitipeptolide A. Their structures were elucidated using 2D NMR experiments, chiral HPLC analysis and comparison with pitipeptolide A. The identified analogues showed weaker cytotoxic activities compared to the two major parent compounds, pitipeptolides A (1) and B (2), against HT-29 colon adenocarcinoma and MCF7 breast cancer cells. On the other hand, pitipeptolide F (6) was the most potent pitipeptolide in a disc diffusion assay against Mycobacterium tuberculosis. The latter finding suggests that the structure of pitipeptolides could be optimized for selective antibacterial activity.
- Montaser, Rana,Paul, Valerie J.,Luesch, Hendrik
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experimental part
p. 2068 - 2074
(2012/01/13)
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- Cyclodepsipeptides, sesquiterpenoids, and other cytotoxic metabolites from the filamentous fungus Trichothecium sp. (MSX 51320)
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Two new cyclodepsipeptides (1 and 2), two new sesquiterpenoids (3 and 4), and the known compounds guangomide A (5), roseotoxin S, and three simple trichothecenes were isolated from the cytotoxic organic extract of a terrestrial filamentous fungus, Trichothecium sp. The structures were determined using NMR spectroscopy and mass spectrometry. Absolute configurations of the cyclodepsipeptides were established by employing chiral HPLC, while the relative configurations of 3 and 4 were determined via NOESY data. The isolation of guangomide A was of particular interest, since it was reported previously from a marine-derived fungus.
- Sy-Cordero, Arlene A.,Graf, Tyler N.,Adcock, Audrey F.,Kroll, David J.,Shen, Qi,Swanson, Steven M.,Wani, Mansukh C.,Pearce, Cedric J.,Oberlies, Nicholas H.
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experimental part
p. 2137 - 2142
(2011/12/14)
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- PROTEASE INHIBITORS, COMPOSITIONS AND METHODS OF USE
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This invention relates to grassystatins A, B and C, and their isolated or purified forms. The compounds of the invention are useful as aspartic protease, gamma secretase, or metalloprotease inhibitors. Methods of using the compounds and compositions thereof are also disclosed.
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Page/Page column 33-34
(2011/01/12)
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- Grassystatins A-C from marine cyanobacteria, potent cathepsin E inhibitors that reduce antigen presentation
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In our efforts to exploremarine cyanobacteria as a source of novel bioactive compounds, we discovered a statine unit-containing linear decadepsipeptide, grassystatin A (1), which we screened against a diverse set of 59 proteases. We describe the structure
- Kwan, Jason C.,Eksioglu, Erika A.,Liu, Chen,Paul, Valerie J.,Luesch, Hendrik
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experimental part
p. 5732 - 5747
(2010/03/24)
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- Natural products chemistry and taxonomy of the marine cyanobacterium Blennothrix cantharidosmum
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A Papua New Guinea field collection of the marine cyanobacterium Blennothrix cantharidosmum was investigated for its cytotoxic constituents. Bioassay-guided isolation defined the cytotoxic components as the known compounds lyngbyastatins 1 and 3. However, six new acyl proline derivatives, tumonoic acids D-I, plus the known tumonoic acid A were also isolated. Their planar structures were defined from NMR and MS data, while their stereostructures followed from a series of chiral chromatographies, degradation sequences, and synthetic approaches. The new compounds were tested in an array of assays, but showed only modest antimalarial and inhibition of quorum sensing activities. Nevertheless, these are the first natural products to be reported from this genus, and this inspired a detailed morphologic and 16S rDNA-based phylogenetic analysis of the producing organism.
- Clark, Benjamin R.,Engene, Niclas,Teasdale, Margaret E.,Rowley, David C.,Matainaho, Teatulohi,Valeriote, Frederick A.,Gerwick, William H.
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experimental part
p. 1530 - 1537
(2009/09/06)
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- A stable, convertible isonitrile as a formic acid carbanion [ -COOH] equivalent and its application in multicomponent reactions
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The application of 2-(2,2-dimethoxyethyl) phenyl isonitrile in Ugi, Passerini, and Ugi-Smiles reactions is described. The simple transformation to highly activated indolyl amides allows functional-group conversion of the isonitrile moiety into a variety of carboxylic acid derivatives, overall acting as a neutral, nucleophilic COOH equivalent. Georg Thieme Verlag Stuttgart.
- Kreye, Oliver,Westermann, Bernhard,Wessjohann, Ludger A.
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p. 3188 - 3192
(2008/09/20)
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- Synthetic methods for aplidine and new antitumoral derivatives, methods of making and using them
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The invention provides aplidine derivatives and synthetic methods.
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- PROCESS FOR PRODUCTION OF OPTICALLY ACTIVE 2-HALOGENO- CARBOXYLIC ACIDS
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The invention provides processes for producing efficiently optically active 2-halogenocarboxylic acids useful in the preparation of drugs or the like and salts thereof with amines. Specifically, an optically active 2-halogenocarboxylic acid is produced by halogenating an optically active amino acid in water in the presence of a hydrophobic organic solvent and nitrous acid with the configuration retained and with the racemization inhibited through the removal of 2-hydroxy- bromocarboxylic acid formed as a by-product; the obtained optically active 2-halogenocarboxylic acid is transferred to an aqueous phase by converting it into a salt thereof with a base, followed by the removal of the organic phase; and the optically active 2-halogenocarboxylic acid is transferred again to an organic solvent phase, followed by the removal of the aqueous phase, whereby an optically active 2-halogenocarboxylic acid is obtained through the removal of a halogen component. Further, a high-quality salt of an optically active 2-halogenocarboxylic acid with an amine can be obtained by a crystallization method wherein the amine is added over the period of 1/2 hour or longer either continuously or in portions and/or wherein the crystallization solvent consists of a hydrophobic organic solvent and a hydrophilic organic solvent.
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- pH-Dependent Chemoselective Synthesis of α-Amino Acids. Reductive Amination of α-Keto Acids with Ammonia Catalyzed by Acid-Stable Iridium Hydride Complexes in Water
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An acid-stable hydride complex [Cp*IrIII(bpy)H]+ {1, Cp* = η5-C5Me5, bpy = 2,2′-bipyridine} serves as the active catalyst for the highly chemoselective synthesis of α-amino acids by reductive aminatio
- Ogo, Seiji,Uehara, Keiji,Abura, Tsutomu,Fukuzumi, Shunichi
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p. 3020 - 3021
(2007/10/03)
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- Dynamic kinetic resolution via dual-function catalysis of modified cinchona alkaloids: Asymmetric synthesis of α-hydroxy carboxylic acids
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A highly enantioselective catalytic transformation of racemic α-hydroxy acids to optically active α-hydroxy acids is reported. A new procedure was developed for the condensation of racemic α-hydroxy acids with trichloromethyl chloroformate (diphosgene) at room temperature in the presence of activated charcoal to form 5-substituted-1,3-dioxolane-2,4-diones in 90-100% yield. An efficient dynamic kinetic resolution of 5-aryl dioxolanediones was realized via a modified cinchona alkaloid-catalyzed alcoholytic opening of the dioxolanedione ring, generating a variety of optically active α-hydroxy esters in 91-96% ee and 61-85% chemical yield. In this dynamic kinetic resolution, the modified cinchona alkaloid was found to serve dual catalytic roles, mediating both the rapid racemization of the 5-aryl dioxolanediones and the enantioselective alcoholytic ring opening of the 5-aryl dioxolanediones. Consequently, both enantiomers of the 5-aryl dioxolanediones were converted to highly enantiomerically enriched aromatic α-hydroxy esters in yields (61-85%), far exceeding the maximum of 50% for a normal kinetic resolution. This development not only represents an expansion of the scope of asymmetric acyl-transfer catalysis of synthetic catalysts but also provides a new approach for the development of efficient chemical dynamic kinetic resolutions promoted by a single catalyst. 5-Alkyl dioxolanediones were resolved by a conventional but highly enantioselective kinetic resolution to provide α-hydroxy acids and esters in high optical purity and good yields. Copyright
- Tang, Liang,Deng, Li
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p. 2870 - 2871
(2007/10/03)
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- New cyclic depsipeptide antibiotics, clavariopsins A and B, produced by an aquatic hyphomycetes, Clavariopsis aquatica: 2. Structure analysis
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The structures of new cyclic decadepsipeptides, clavariopsins A and B, were determined to be cyclo[-(R)-2-hydroxyisovaleryl-L-pipecolyl-L-MeVal- L-Val-L-MeAsp-L-Melle-L-Melle-Gly-L-MeVal-L-Tyr(OMe)-] and cyclo[-(R)-2- hydroxyisovaleryl-L-pipecoly-L-Val-L-Val-L-MeAsp-L-Melle-L-Melle-Gly-L- MeVal-L-Tyr(OMe)-], respectively, by spectroscopic analyses, especially using 2D NMR techniques. The absolute stereochemistry was elucidated by the advanced Marfey's method and chiral HPLC analysis.
- Suzuki,Ojika,Sakagai,Kaida,Fudou,Kameyama
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- An efficient α-hydroxylation of carbonyls using the HOF·CH3CN complex
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The complex HOF·CH3CN, made directly from fluorine and aqueous acetonitrile, was used for α-hydroxylation of various ketones, esters and acids via their trimethyl silyl enol ethers. The reaction is usually complete in a few minutes at room temperature or below and has high yields.
- Dayan, Sharon,Bareket, Yifat,Rozen, Shlomo
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p. 3657 - 3664
(2007/10/03)
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- Reaction of carboxylic acids with diethyl phosphorocyanidate; a novel synthesis of homologated α-hydroxycarboxylic acids from carboxylic acids
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Carboxylic acids react with 2 equivalents of diethyl phosphorocyanidate in the presence of triethylamine to give dicyanophosphates in good yields; these dicyanophosphates can be hydrolyzed easily to give homologated α- hydroxycarboxylic acids.
- Mizuno, Masanori,Shioiri, Takayuki
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p. 9209 - 9210
(2007/10/03)
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- Enantioselectivity of Pseudomonas cepacia lipase for the acetylation of 2-hydroxy carboxylic acid esters+
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Structurally different ethyl or methyl 2-hydroxy carboxylates were resolved by Pseudomonas cepacia lipase-catalysed acetylations with vinyl acetate in diethylether. One type of the alcoholic substrates (2-hydroxy-2-arylacetates and 2-hydroxy-3-arylpropinates) contained a HO-group at the stereocentre. These compounds were resolved with high enantioselectivity (ee 91 → 99) at ca. 50% conversion. The other alcoholic substrates ((threo-2-hydroxy-3-methylbutyrate and threo- or erythro-2-hydroxy-3-aryl-3-arylthio(or aryloxy)propionates) with two stereocentres generally resulted in enantiopure products and the reactions stopped at 50 % conversion.
- Sundholm, Oskari,Kanerva, Liisa T.
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p. 625 - 640
(2007/10/03)
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- Electrogenerated chiral cationic glycine equivalents - Part 2: Chiral 3-methoxy-2,5-morpholinediones from (S)-α-hydroxy acids and dimethyl aminomalonate
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Chiral 3-methoxy-2,5-morpholinediones which are cyclic N,O-acetals have proved to be excellent chiral cationic amino acid equivalents, especially if larger nucleophiles are employed. They are easily obtained from dipeptolides formed between chiral α-hydroxy acids and dimethyl amino malonate via regioselective electrochemical methoxylation followed by intramolecular lactonizatian after decarboxylation. The lactonization can be performed quantitatively from the open-chain peptolide by condenzation under reduced pressure at elevated temperature. The easy separation of the desired amino acid and the α-hydroxy acid being the chiral auxiliary by extraction is valuable.
- Kardassis, Georgios,Brungs, Peter,Nothhelfer, Christoph,Steckhan, Eberhard
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p. 3479 - 3488
(2007/10/03)
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- Enantioselective synthesis of α-hydroxy carboxylic acids: Direct conversion of α-oxocarboxylic acids to enantiomerically enriched α-hydroxy carboxylic acids via neighboring group control
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α-Oxocarboxylic acids can be reduced to the corresponding α-hydroxy carboxylic acids employing DIP-CI(TM) as a reducing agent. The α-carboxylic substituent exerts a remarkable neighboring group effect on the reduction. The reaction presumably proceeds in an intramolecular fashion through a 'rigid' bicyclic transition state assembly, which produces enantioselectivities approaching 99%.
- Wang, Zhe,La, Brittany,Fortunak, Joseph M.,Meng, Xian-Jun,Kabalka, George W.
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p. 5501 - 5504
(2007/10/03)
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- Derivatives of cyclodepsipeptide PF 1022
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Novel PF 1022 derivatives--cyclodepsipeptides represented by the below-described formula (I)--and acid addition salts thereof, which have been synthesized according to the present invention, have anthelmintic activities against various parasitic worms which are parasitic on human bodies, domestic animals and pet animals. They are therefore useful as anthelmintics for the prevention or treatment of parasitic infections. STR1 wherein R1, R2, R3, R4, Q, X, Y and Z have been defined herein.
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- Esters of L-carnitine and acyl L-carnitine with hydoxy acids for producing pharmcaeutical compositions for treating dermatoses
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Dermatosis is treated by a method comprising topically applying an effective amount of an ester of L-carnitine or an acyl L-carnitine with a hydroxy carboxylic acid selected from the group consisting of α-hydroxybutyric acid, α-hydroxyisocaproic acid, α-hydroxyisovaleric acid, malic acid and tartronic acid, to a patient in need thereof.
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- Making optically active alpha-hydroxy acids or precursors
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Disclosed is a process for making an α-hydroxy acid which is essentially all L or all D with respect to the chiral C atom bonded to the carboxy group of said acid which comprises (1) hydrocarboxylating an enol acylate, which has a chiral C atom that is essentially all L or all D, with CO and water or an organic hydroxyl compound, thereby producing a reaction mixture containing diastereomeric α-acyloxy acids or esters having two chiral centers and having essentially no enantiomeric pairs, (2) separating the diastereomers by conventional physical means and (3) hydrolyzing at least one of said separated diastereomers to make at least the α-hydroxy acid which is essentially all L or all D with respect to the chiral C atom bonded to the carboxy group of said acid. Also disclosed is a process for making an α-hydroxy acid which is essentially all L or all D with respect to the chiral C atom bonded to the carboxy group of said acid which comprises (1) hydrocarboxylating an enol acylate, the enol portion of which has a chiral C atom that is essentially all L or all D, with CO and water or an organic hydroxyl compound, thereby producing a reaction mixture containing diastereomeric α-acyloxy acids or esters having two chiral centers and having essentially no enantiomeric pairs, (2) hydrolyzing the product of (1) to make a diastereomeric mixture containing α-hydroxy acids, and (3) separating by conventional physical means from the product of (2) at least one α-hydroxy acid which is essentially all L or all D with respect to the chiral C atom bonded to the carboxy group of said acid.
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- Effects of Gln102Arg and Cys97Gly mutations on the structural specificity and stereospecificity of the L-lactate dehydrogenase from Bacillus stearothermophilus
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The L-lactate dehydrogenase of Bacillus stearothermophilus (BSLDH) is a thermostable enzyme with considerable potential for applications in asymmetric synthesis. An understanding of the factors controlling its structural specificity and stereospecificity is therefore of interest. In this paper the effects of Gln102 → Arg and Cys97 → Gly mutations have been evaluated. In a survey of thirteen 2-keto acids, the Q102R mutation was found to reduce the activity of BSLDH toward the reduction of RCOCOOH substrates with small or hydrophilic R groups without affecting its activity toward those with larger, hydrophobic R substituents. In addition, the mutants have a high affinity for C3- and C4-2-keto dicarboxylates. The extent of fructose 1,6-diphosphate activation of the mutant enzymes was similar to its effect on wild-type BSLDH. The mutants also retained the synthetically desirable thermostability. As a probe of the commitment of BSLDH to L stereospecificity, the Q102R mutation was introduced to allow the new 102R site to compete with Arg171 for binding of the COO- groups of the RCOCOOH substrates, which would reverse the normal RCOCOOH orientation at the active site and thereby open up the possibility of the formation of a D-2-hydroxy acid in place of the natural L product. However, L stereospecificity in 2-keto acid reduction was strictly retained by the Q102R mutants. This was confirmed by preparative-scale reductions of pyruvate and phenylpyruvate to give the corresponding L-hydroxy acids in enantiomerically pure form and by comparison of the kinetics of oxidation of L- and D-lactate and L- and D-phenyl lactate. No evidence for substrate activity for the D enantiomers of either of these was seen with WT or mutant enzymes. Some catalysis of D-malate oxidation by both WT and mutant BSLDH was observed, but the L enantiomer was still preferred to approximately the same degree in both cases. That the inability of BSLDH and its 102R mutants to catalyze D-2-hydroxy acid oxidations was not simply due to the failure of the D enantiomers to bind at the active site was established by a comparison of competitive inhibition constants for the above L- and D-hydroxy acids. CD spectroscopy showed that the Gln102 → Arg mutations were not benign but induced significant structural perturbations. Electrostatic potential contours suggest that the structural changes are partly due to long-range interactions of the positive charge of the guanidinium group of Arg102 with several other residues that form an area of negative potential adjacent to the active site. The Cys97 → Gly mutation, while inadvertent, was of interest because of the potential specificity effects arising from its location adjacent to the hinge of the flexible 98-110 loop. However, its effects on BSLDH specificity were minor.
- Kallwass, Helmut K. W.,Luyten, Marcel A.,Parris, Wendy,Gold, Marvin,Kay, Cyril M.,Bryan Jones
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p. 4551 - 4557
(2007/10/02)
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- An Evaluation of the Substrate Specificity, and of Its Modification by Site-Directed Mutagenesis, of the Cloned L-Lactate Dehydrogenase from Bacillus stearothermophilus
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The L-lactate dehydrogenase of Bacillus stearothermophilus (BSLDH) is a stable, thermophilic oxidoreductase.It has been selected as a model of enzymes with considerable future promise in assymetric synthesis in that it has been cloned to ensure a plentiful and inexpensive supply and because of the potential for tailoring its specificity to accept unnatural substrate structures via the site-directed mutagenesis techniques of moleculer biology.In this study, the specificity of BSLDH toward representative α-keto acids possessing straight- and branched-chain alkyl,cycloalkyl, or aromatic side chains has been evaluated.The results show that substrates that are sterically bulky in the region of the α-keto group to be reduced are poorly accepted by the enzyme.Graphics analyses indicated that the low activities of these hindered substrates might be partly due to a bad interaction of the active site residue Gln102 with large or branched substituents adjacent to the α-keto group.Accordingly, Gln102 has been replaced by the smaller Asn residue by site-directed mutagenesis in an attempt to expand the active site volume available to receive substrates larger than the natural pyruvate.However, the kinetic data show that bulky α-keto acids are only marginally better accommodated by the Gln102 -> Asn mutant than by the wild-type enzyme.
- Luyten, Marcel A.,Bur, Daniel,Wynn, Hla,Parris, Wendy,Glod, Marvin,et al.
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p. 6800 - 6804
(2007/10/02)
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- Method of making a diastereomeric mixture containing two diastereomeric α-acyloxy acid esters
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In the process of hydrocarboxylating an enol acylate with CO and an organic hydroxyl compound to produce an α-acyloxy acid ester, the improvement comprising using as the organic hydroxyl compound reactant, an organic hydroxyl compound which has a chiral center that is essentially all L or D, thereby producing a reaction mixture having essentially no enantiomeric pairs and containing diastereomeric α-acyloxy acid esters having two chiral centers.
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- The Reaction of Copper Sulfate with Carboxylic Acids and their Derivatives in Aqueous Solutions under Hydrothermal Conditions
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Under hydrothermal conditions aqueous solutions of copper(II) sulfate (1) are reduced by means of saturated fatty acids with hydrogen at the α-atom to yield crystalline copper.In all cases carbon dioxide is liberated and lower fatty acids and ketones can be identified as reaction products. α-Hydroxy and α-aminocarboxylic acids proved to be very effective reducing agents towards 1.The yield of copper varied from 2 to 2.5 mol Cu per 1 mol of amino acid.The reaction of 1 is suppressed by sulfuric acid.The presence of hydrochloric acid or chlorides leads to the precipitation of copper(I) chloride.The mechanisms of the decomposition of the various types of carboxylic acids is discussed.It was also possible to precipitate metallic copper by means of various proteins. - Key words: Copper, Copper(II) Sulfate, Carboxylic Acids, Hydrothermal Reactions
- Seel, F.,Schuh, J.
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p. 157 - 162
(2007/10/02)
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- A HIGHLY EFFECTIVE ASYMMETRIC SYNTHESIS OF α-HYDROXY ACIDS BY ALKYLATION OF CHIRAL N-(BENZYLOXYACETYL)-TRANS-2,5-BIS(METHOXYMETHOXYMETHYL)PYRROLIDINE
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Alkylation of lithiated N-(benzyloxyacetyl)-trans-2,5-bis(methoxymethoxymethyl)-pyrrolidine proceeded with high stereoselectivity (>96percent de) and subsequent transformations of the alkylated products gave synthetically useful α-benzyloxy acids or α-hydroxy acids of high enantiomeric purity.
- Enomoto, Masayuki,Ito, Yoshio,Katsuki, Tsutomu,Yamaguchi, Masaru
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p. 1343 - 1344
(2007/10/02)
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- A SYNTHON FOR CHIRAL GLYCOLATE ENOLATE (ROC-HCOOR'): A CAMPHOR-BASED OXAZOLINE
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Alkylations of the anion (7a) derived from a camphor-based oxazoline proceed in good yield.Hydrolysis affords the corresponding α-hydroxy acids in high ee.
- Kelly, T. Ross,Arvanitis, Argyrios
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