- Hydroperoxide lyase cascade in pea seedlings: Non-volatile oxylipins and their age and stress dependent alterations
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The profiles of non-volatile oxylipins of pea (Pisum sativum) seedlings were examined by gas chromatography-mass spectrometry after in vitro incubation with α-linolenic acid. The 13-lipoxygenase/hydroperoxide lyase (HPL) products were predominant in the leaves, while the roots possess both 13- and 9-HPL products. Allene oxide synthase (AOS) and divinyl ether synthase (DES) products were not detected in the leaves or in the roots of any age. The HPL cascade produces a diversity of oxylipins, including the compounds (2E)-4-hydroxy-traumatic, (10E)-9,12-dihydroxy-10-dodecenoic and 9,12-dihydroxydodecanoic acids, as well as (2E)-4-hydroxy-2-nonenoic acid, which has not yet been detected in plants. Oxylipin patterns were altered by infection, water deficit, as well as by plant age. Infection caused the specific strong accumulation of azelaic (nonane-1,9-dioic) acid in the leaves. The azelaic acid content in the aged (14 and 18 day-old) leaves was significantly higher than in the younger leaves. Water deficit induced the accumulation of (2E)-4-hydroxy-2-nonenoic acid and (2E)-traumatic acid in the roots. Results demonstrate that: (1) the HPL cascade is the predominant branch of the lipoxygenase pathway in pea seedlings; (2) the HPL products may have the regulatory role both in growth control and adaptation.
- Mukhtarova, Lucia S.,Mukhitova, Fakhima K.,Gogolev, Yuri V.,Grechkin, Alexander N.
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Read Online
- Discovery and Engineering of a Novel Baeyer-Villiger Monooxygenase with High Normal Regioselectivity
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Baeyer-Villiger monooxygenases (BVMOs) are remarkable biocatalysts for the Baeyer-Villiger oxidation of ketones to generate esters or lactones. The regioselectivity of BVMOs is essential for determining the ratio of the two regioisomeric products (“normal” and “abnormal”) when catalyzing asymmetric ketone substrates. Starting from a known normal-preferring BVMO sequence from Pseudomonas putida KT2440 (PpBVMO), a novel BVMO from Gordonia sihwensis (GsBVMO) with higher normal regioselectivity (up to 97/3) was identified. Furthermore, protein engineering increased the specificity constant (kcat/KM) 8.9-fold to 484 s?1 mM?1 for 10-ketostearic acid derived from oleic acid. Consequently, by using the variant GsBVMOC308L as an efficient biocatalyst, 10-ketostearic acid was efficiently transformed into 9-(nonanoyloxy)nonanoic acid, with a space-time yield of 60.5 g L?1 d?1. This study showed that the mutant with higher regioselectivity and catalytic efficiency could be applied to prepare medium-chain ω-hydroxy fatty acids through biotransformation of long-chain aliphatic keto acids derived from renewable plant oils.
- Zhang, Guang-Xiang,You, Zhi-Neng,Yu, Jia-Mei,Liu, Yuan-Yang,Pan, Jiang,Xu, Jian-He,Li, Chun-Xiu
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Read Online
- PCSK9 ANTAGONIST COMPOUNDS
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Disclosed are compounds of Formula (A), or a pharmaceutically acceptable salt thereof: where A, X, R1, and R2 are as defined herein, which compounds have properties for antagonizing PCSK9. Also described are pharmaceutical formulations comprising the compounds of Formula (I) or their salts, and methods of treating cardiovascular disease and conditions related to PCSK9 activity, e.g. atherosclerosis, hypercholesterolemia, coronary heart disease, metabolic syndrome, acute coronary syndrome, or related cardiovascular disease and cardiometabolic conditions.
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Page/Page column 72
(2021/03/05)
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- PCSK9 ANTAGONIST COMPOUNDS
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Disclosed are compounds of Formula (I), or a pharmaceutically acceptable salt thereof: (I) wherein A, A1, A2, R1, R2 and R3 are as defined herein, which compounds have properties for antagonizing PCSK9. Also described are pharmaceutical formulations comprising the compounds of Formula I or their salts, and methods of treating cardiovascular disease and conditions related to PCSK9 activity, e.g. atherosclerosis, hypercholesterolemia, coronary heart disease, metabolic syndrome, acute coronary syndrome, or related cardiovascular disease and cardiometabolic conditions.
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Page/Page column 80-81
(2021/06/26)
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- The CYP74B and CYP74D divinyl ether synthases possess a side hydroperoxide lyase and epoxyalcohol synthase activities that are enhanced by the site-directed mutagenesis
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The CYP74 family of cytochromes P450 includes four enzymes of fatty acid hydroperoxide metabolism: allene oxide synthase (AOS), hydroperoxide lyase (HPL), divinyl ether synthase (DES), and epoxyalcohol synthase (EAS). The present work is concerned with catalytic specificities of three recombinant DESs, namely, the 9-DES (LeDES, CYP74D1) of tomato (Solanum lycopersicum), 9-DES (NtDES, CYP74D3) of tobacco (Nicotiana tabacum), and 13-DES (LuDES, CYP74B16) of flax (Linum usitatissimum), as well as their alterations upon the site-directed mutagenesis. Both LeDES and NtDES converted 9-hydroperoxides of linoleic and α?linolenic acids to divinyl ethers colneleic and colnelenic acids (respectively) with only minorities of HPL and EAS products. In contrast, LeDES and NtDES showed low efficiency towards the linoleate 13-hydroperoxide, affording only the low yield of epoxyalcohols. LuDES exhibited mainly the DES activity towards α?linolenate 13-hydroperoxide (preferred substrate), and HPL activity towards linoleate 13-hydroperoxide, respectively. In contrast, LuDES converted 9-hydroperoxides primarily to the epoxyalcohols. The F291V and A287G mutations within the I-helix groove region (SRS-4) of LuDES resulted in the loss of DES activity and the acquirement of the epoxyalcohol synthase activity. Thus, the studied enzymes exhibited the versatility of catalysis and its qualitative alterations upon the site-directed mutagenesis.
- Gorina, Svetlana S.,Grechkin, Alexander N.,Iljina, Tatiana M.,Mukhtarova, Lucia S.,Smirnova, Elena O.,Toporkova, Yana Y.
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- Novel insights into oxidation of fatty acids and fatty alcohols by cytochrome P450 monooxygenase CYP4B1
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CYP4B1 is an enigmatic mammalian cytochrome P450 monooxygenase acting at the interface between xenobiotic and endobiotic metabolism. A prominent CYP4B1 substrate is the furan pro-toxin 4-ipomeanol (IPO). Our recent investigation on metabolism of IPO related compounds that maintain the furan functionality of IPO while replacing its alcohol group with alkyl chains of varying structure and length revealed that, in addition to cytotoxic reactive metabolite formation (resulting from furan activation) non-cytotoxic ω-hydroxylation at the alkyl chain can also occur. We hypothesized that substrate reorientations may happen in the active site of CYP4B1. These findings prompted us to re-investigate oxidation of unsaturated fatty acids and fatty alcohols with C9–C16 carbon chain length by CYP4B1. Strikingly, we found that besides the previously reported ω- and ω-1-hydroxylations, CYP4B1 is also capable of α-, β-, γ-, and δ-fatty acid hydroxylation. In contrast, fatty alcohols of the same chain length are exclusively hydroxylated at ω, ω-1, and ω-2 positions. Docking results for the corresponding CYP4B1-substrate complexes revealed that fatty acids can adopt U-shaped bonding conformations, such that carbon atoms in both arms may approach the heme-iron. Quantum chemical estimates of activation energies of the hydrogen radical abstraction by the reactive compound 1 as well as electron densities of the substrate orbitals led to the conclusion that fatty acid and fatty alcohol oxidations by CYP4B1 are kinetically controlled reactions.
- Thesseling, Florian A.,Hutter, Michael C.,Wiek, Constanze,Kowalski, John P.,Rettie, Allan E.,Girhard, Marco
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- Allene Oxide Synthase Pathway in Cereal Roots: Detection of Novel Oxylipin Graminoxins
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Young roots of wheat, barley, and sorghum, as well as methyl jasmonate pretreated rice seedlings, undergo an unprecedented allene oxide synthase pathway targeted to previously unknown oxylipins 1–3. These Favorskii-type products, (4Z)-2-pentyl-4-tridecene-1,13-dioic acid (1), (2′Z)-2-(2′-octenyl)-decane-1,10-dioic acid (2), and (2′Z,5′Z)-2-(2′,5′-octadienyl)-decane-1,10-dioic acid (3), have a carboxy function at the side chain, as revealed by their MS and NMR spectral data. Compounds 1–3 were the major oxylipins detected, along with the related α-ketols. Products 1–3 were biosynthesized from (9Z,11E,13S)-13-hydroperoxy-9,11-octadecadienoic acid, (9S,10E,12Z)-9-hydroperoxy-10,12-octadecadienoic acid (9-HPOD), and (9S,10E,12Z,15Z)-9-hydroperoxy-10,12,15-octadecatrienoic acid, respectively, via the corresponding allene oxides and cyclopropanones. The data indicate that conversion of the allene oxide into the cyclopropanone is controlled by soluble cyclase. The short-lived cyclopropanones are hydrolyzed to products 1–3. The collective name “graminoxins” has been ascribed to oxylipins 1–3.
- Grechkin, Alexander N.,Ogorodnikova, Anna V.,Egorova, Alevtina M.,Mukhitova, Fakhima K.,Ilyina, Tatiana M.,Khairutdinov, Bulat I.
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p. 336 - 343
(2018/06/04)
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- USES OF VANADIUM TO OXIDIZE ALDEHYDES AND OZONIDES
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The present invention relates to uses of vanadium to convert aldehydes and ozonides into their respective acids and/or ketones. More particularly, this invention relates to the oxidative work-ups following ozonolysis using vanadium, using vanadium during ozonolysis, and using vanadium to oxidize aldehydes in general. The invention also relates to methods comprising the ozonolysis of oleyl alcohol in the presence of either an acid or an alcohol.
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Paragraph 00055-00057
(2018/04/13)
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- Simultaneous Enzyme/Whole-Cell Biotransformation of C18 Ricinoleic Acid into (R)-3-Hydroxynonanoic Acid, 9-Hydroxynonanoic Acid, and 1,9-Nonanedioic Acid
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Regiospecific oxyfunctionalization of renewable long chain fatty acids into industrially relevant C9 carboxylic acids has been investigated. One example was biocatalytic transformation of 10,12-dihydroxyoctadecanoic acid, which was produced from ricinoleic acid ((9Z,12R)-12-hydroxyoctadec-9-enoic acid) by a fatty acid double bond hydratase, into (R)-3-hydroxynonanoic acid, 9-hydroxynonanoic acid, and 1,9-nonanedioic acid with a high conversion yield of ca. 70%. The biotransformation was driven by enzyme/whole-cell biocatalysts, consisting of the esterase of Pseudomonas fluorescens and the recombinant Escherichia coli expressing the secondary alcohol dehydrogenase of Micrococcus luteus, the Baeyer-Villiger monooxygenase of Pseudomonas putida KT2440 and the primary alcohol/aldehyde dehydrogenases of Acinetobacter sp. NCIMB9871. The high conversion yields and the high product formation rates over 20 U/g dry cells with insoluble reactants indicated that various (poly-hydroxy) fatty acids could be converted into multi-functional products via the simultaneous enzyme/whole-cell biotransformations. This study will contribute to the enzyme-based functionalization of hydrophobic substances. (Figure presented.).
- Cha, Hee-Jeong,Seo, Eun-Ji,Song, Ji-Won,Jo, Hye-Jin,Kumar, Akula Ravi,Park, Jin-Byung
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p. 696 - 703
(2017/12/26)
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- FLOUROALKYL, FLOUROALKOXY, PHENOXY, HETEROARYLOXY, ALKOXY, AND AMINE 1,4-BENZOQUINONE DERIVATIVES FOR TREATMENT OF OXIDATIVE STRESS DISORDERS
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Disclosed herein are compounds and methods of using such compounds for treating or suppressing oxidative stress disorders, including mitochondrial disorders, impaired energy processing disorders, neurodegenerative diseases and diseases of aging, or for modulating one or more energy biomarkers, normalizing one or more energy biomarkers, or enhancing one or more energy biomarkers, wherein the compounds are tocopherol quinone derivatives. Further disclosed are compounds, compositions, and methods for treatment of, or prophylaxis against, radiation exposure.
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Paragraph 0131; 0312
(2017/07/14)
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- Combined Biocatalytic and Chemical Transformations of Oleic Acid to ω-Hydroxynonanoic Acid and α,ω-Nonanedioic Acid
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A practical chemoenzymatic method for the synthesis of 9-hydroxynonanoic acid and 1,9-nonanedioic acid (i.e., azelaic acid) from oleic acid [(9Z)-octadec-9-enoic acid] was investigated. Biotransformation of oleic acid into 9-(nonanoyloxy)nonanoic acid via 10-hydroxyoctadecanoic acid and 10-keto-octadecanoic acid was driven by a C-9 double bond hydratase from Stenotrophomonas maltophilia, an alcohol dehydrogenase from Micrococcus luteus, and a Baeyer–Villiger monooxygenase (BVMO) from Pseudomonas putida KT2440, which was expressed in recombinant Escherichia coli. After production of the ester (i.e., the BVMO reaction product), the compound was chemically hydrolyzed to n-nonanoic acid and 9-hydroxynonanoic acid because n-nonanoic acid is toxic to E. coli. The ester was also converted into 9-hydroxynonanoic acid and the n-nonanoic acid methyl ester, which can be oxygenated into the 9-hydroxynonanoic acid methyl ester by the AlkBGT from P. putida GPo1. Finally, 9-hydroxynonanoic acid was chemically oxidized to azelaic acid with a high yield under fairly mild reaction conditions. For example, whole-cell biotransformation at a high cell density (i.e., 10 g dry cells/L) allowed the final ester product concentration and volumetric productivity to reach 25 mM and 2.8 mM h?1, respectively. The overall molar yield of azelaic acid from oleic acid was 58%, based on the biotransformation and chemical transformation conversion yields of 84% and 68%, respectively. (Figure presented.).
- Koppireddi, Satish,Seo, Joo-Hyun,Jeon, Eun-Yeong,Chowdhury, Partha Sarathi,Jang, Hyun-Young,Park, Jin-Byung,Kwon, Yong-Uk
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p. 3084 - 3092
(2016/10/09)
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- Ni-Catalyzed Carboxylation of Unactivated Alkyl Chlorides with CO2
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A catalytic carboxylation of unactivated primary, secondary, and tertiary alkyl chlorides with CO2 at atmospheric pressure is described. This protocol represents the first intermolecular cross-electrophile coupling of unactivated alkyl chlorides, thus leading to new knowledge in the cross-coupling arena.
- B?rjesson, Marino,Moragas, Toni,Martin, Ruben
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supporting information
p. 7504 - 7507
(2016/07/06)
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- Synthesis of a series of hydroxycarboxylic acids as standards for oxidation of nonanoic acid
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The synthesis of a series of nonanoic acids hydroxylated in terminal,ω-1,ω-2,ω-3 positions is described. These compounds will be employed as useful standards for the study of enzymatic and microbiological oxidation of nonanoic acid.
- Rajabi, Mehdi,Lanfranchi, Moreno,Campo, Federica,Panza, Luigi
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supporting information
p. 1149 - 1154
(2014/04/03)
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- Multistep enzymatic synthesis of long-chain α,ω-Dicarboxylic and ω-hydroxycarboxylic acids from renewable fatty acids and plant oils
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A multistep enzyme catalysis was successfully implemented to produce long-chain α,ω-dicarboxylic and ω-hydroxycarboxylic acids from renewable fatty acids and plant oils. Sebacic acid as well as ω-hydroxynonanoic acid and ω-hydroxytridec-11-enoic acid were produced from oleic and ricinoleic acid. Copyright
- Song, Ji-Won,Jeon, Eun-Yeong,Song, Da-Hyun,Jang, Hyun-Young,Bornscheuer, Uwe T.,Oh, Deok-Kun,Park, Jin-Byung
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supporting information
p. 2534 - 2537
(2013/04/23)
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- Exaltone (=Cyclopentadecanone) from Isomuscone (=Cyclohexadecanone), a one-C-atom ring-contraction methodology via a stereospecific favorskii rearrangement: Regioselective application to (-)-(R)-muscone
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Treatment of cyclohexadecanone (1g; with I2 (2.2 mol-euqiv.) and KOH in MeOH) furnished the unsaturated (Z)-ester 2g in 83% yield, via a stereospecific Favorskii rearrangement (Scheme 1). Further treatment with 3-chloroperbenzoic acid (m-CPBA) afforded the unreported epoxy ester 3g (88% yield), which was cleaved in 33% yield to Exaltone (=cyclopentadecanone; 1f) with NaOH in MeOH/H2O and then HCl at 65°. This methodology was similarly extended to higher (C17) and lower (C15 to C11) cyclic ketone analogues, as well as regioselectively to (-)-(R)-muscone (5c) and homomuscone (5f) (Scheme 2). Olfactive properties of the corresponding macrocyclic 1-oxaspiro[2,n]alkanes and -alkenes 4 and 8, resulting from a Coreyi-Chaykovsky oxiranylation, are also presented. Copyright
- Chapuis, Christian,Robvieux, Fabrice,Cantatore, Carole,Saint-Leger, Christine,Maggi, Laurent
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experimental part
p. 428 - 447
(2012/05/07)
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- Stereocontrolled synthesis of the PPAR-γ agonist 10-nitrolinoleic acid
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(Figure presented) The naturally occurring PPAR-γ ligand 10-nitrooctadeca-9(E),12(Z)-dienoic acid (10-nitrolinoleic acid) (2a) was prepared as a single regio- and geometrical isomer in a practical eight-step, convergent sequence. The synthetic route featured a nitro aldol reaction between 9-oxononanoic acid methyl ester (3) and 1-nitronon-3(Z)-ene (4) in the key carbon-carbon bond forming step. The ability of 2a (and its methyl ester 9) to bind to PPAR-γ in a ligand-binding assay is reported.
- Dunny, Elizabeth,Evans, Paul
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supporting information; experimental part
p. 5334 - 5336
(2010/10/19)
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- Osmium tetroxide-promoted catalytic oxidative cleavage of olefins: An organometallic ozonolysis
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A mild, organometallic alternative to ozonolysis utilizing oxone and OsO4 is presented. This is a direct oxidation of olefins via the carbon-carbon cleavage of an osmate ester by the action of oxone. Twenty-four different olefins were converted to their corresponding ketones or carboxylic acids in high yields (> 80%). Free alcohols, acetate- and benzyl-protected alcohols, and 1,2-diols were stable under these conditions. This method should be applicable for traditional organic synthesis. Copyright
- Travis, Benjamin R.,Narayan, Radha S.,Borhan, Babak
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p. 3824 - 3825
(2007/10/03)
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- Preparation of ω-hydroxynonanoic acid and its ester derivatives
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Methyl ricinoleate was ozonized in methanol or in acetic acid and the intermediate hydroperoxides were reduced electrochemically on Pb-cathode to give 9-hydroxynonanoic acid 1 in high yields. The acid 1 was also prepared by direct castor oil ozonolysis in methanol followed by sodium borohydride reduction of the intermediate hydroperoxides. The cost of the electricity for the electroreduction was at least 30 times lower as compared with sodium borohydride consumption. 9-Hydroxynonanoic acid was then transformed to alkyl 9-acetoxynonanoates 3a-3d, for which 1H nuclear magnetic reasonance, mass, and infrared spectra are given. Esterification of the hydroxy acid 1 with boric acid and pyrolysis of the resultant orthoborates produced 8-nonenoic acid 4 in a 45% yield. Reaction of 4 with lower aliphatic alcohols in presence of Amberlyst 15 produced alkyl 8-noneates 5a-5d along with some amounts of a cis/trans mixture of alkyl 7-noneates.
- Kula, Jozef,Smigielski, Krzysztof,Quang, Thuat B.,Grzelak, Iwona,Sikora, Magdalena
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p. 811 - 817
(2007/10/03)
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- Preparation of ω-hydroxy acids by reduction of α,ω-methylene diesters with NaBH4
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By reaction of the dicesium salts of long chain dicarboxylic acids (C atoms > 9) with methylene iodide the corresponding methylene diesters were prepared. These acylals, by reduction with NaBH4 in THF, give the corresponding ω-hydroxy acids.
- Benitez, Pilar,Delgado, Ana,Farrera, Joan-Anton,Ribo, Josep M.
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p. 1697 - 1702
(2007/10/03)
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- Scandium trifluoromethanesulfonate as an extremely active Lewis acid catalyst in acylation of alcohols with acid anhydrides and mixed anhydrides
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Scandium trifluoromethanesulfonate (triflate), which is commercially available, is a practical and useful Lewis acid catalyst for acylation of alcohols with acid anhydrides or the esterification of alcohols by carboxylic acids in the presence of p-nitrobenzoic anhydrides. The remarkably high catalytic activity of scandium triflate can be used for assisting the acylation by acid anhydrides of not only primary alcohols but also sterically-hindered secondary or tertiary alcohols. The method presented is especially effective for selective macrolactonization of ω-hydroxy carboxylic acids.
- Ishihara, Kazuaki,Kubota, Manabu,Kurihara, Hideki,Yamamoto, Hisashi
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p. 4560 - 4567
(2007/10/03)
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- Process of preparing ω-hydroxy acids
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A new synthesis of ω-hydroxy acids, which employs commercially available starting materials and lowers the cost of production. The process involves coupling a fatty acyl group by enamine chemistry, followed by a ring expansion and selective reduction of ketoacid.
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- Lactones. 2. Enthalpies of hydrolysis, reduction, and formation of the C4-C13 monocyclic lactones. Strain energies and conformations
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The enthalpies of hydrolysis of the monocyclic lactones from γ-butyrolactone to tridecanolactone were determined calorimetrically, and the acyclic ethyl having the number of atoms were studied in the fashion. The enthalpies of reduction of the lactones to the corresponding α,ω-alkanediols with lithium triethylborohydride also were determined. The enthalpies of formation of the lactones and the ethyl esters were derived from these data. They were converted to values for the gas phase by measuring the enthalpies of vaporization of ethyl esters and of lactones. In the of γ-butyrolactone and δ-valerolactone, the enthalpies of formation were in good accord with the previously reported values determined via combustion calorimetry. The strain energies of the lactones were obtained via isodesmic reactions. Valerolactone had a strain energy of 11 kcal/mol, and the largest strain energy was found with octanolactone (13 kcal/mol). The conformations of γ-butyrolactone and δ-valerolactone were studied via MP2/6-31G* geometry optimizations, and the conformations of the other lactones were studied with use of the molecular mechanics program MM3. The energies of the lactones estimated via molecular mechanics were compared with the experimental results.
- Wiberg, Kenneth B.,Waldron, Roy F.
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p. 7697 - 7705
(2007/10/02)
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