- Enantioselective synthesis of 3-hydroxytetradecanoic acid and its methyl ester enantiomers as new antioxidants and enzyme inhibitors
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Optically pure R and S enantiomers of 3-hydroxytetradecanoic acid and its methyl esters were synthesised by porcine pancreas lipase catalysed hydrolysis of racemic methyl 3-hydroxytetradecanoate in aqueous medium, with the aim of determining their antioxidant, antielastase and antiurease activities. The effects of the weight ratio of substrate/lipase and the reaction time were investigated. Optimum reaction conditions were determined. The resolution reaction with porcine pancreas lipase afforded (R)-3-hydroxytetradecanoic acid, which is a component of bacterially important lipid A, with greater than 99 % ee in excellent enantiomeric ratio (>900) after 7 h incubation with a substrate/lipase weight ratio of 3:1 and 43 % conversion of the substrate. Methyl (S)-3-hydroxytetradecanoate, which is the unreacted enantiomer of the racemic substrate, could be recovered with 98 % ee after 7 h resolution with a substrate/lipase weight ratio of 1:1 and 60 % conversion. (R)-3- Hydroxytetradecanoic acid was converted to its ester and the S methyl ester to its acid. This biocatalytic enantioselective resolution in aqueous medium presents an environmentally friendly and green chemistry method for the synthesis of R and S enantiomers of 3-hydroxytetradecanoic acid and its methyl esters.
- Kuecuek, Hatice Baspinar,Yusufoglu, Ayse
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Read Online
- Enzymatic Regio- And Enantioselective C-H Oxyfunctionalization of Fatty Acids
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Directed evolution of a P450 hydroxylase (P450BSβ) achieves an engineered enzyme that is able to catalyze C-H oxyfunctionalization of fatty acids (FAs) in a highly regio- and enantioselective fashion (>20:1 Cβ/Cα and > 99% ee in all cases). The biocatalyst displays high reactivity (TON up to 1540), takes inexpensive H2O2 as oxidant, and converts C11-C18 saturated FAs as well as naturally derived unsaturated oleic and linoleic acids to optically pure β-hydroxy FAs. Merging biocatalysis with chemical transformation, we further offer a chemoenzymatic strategy to access valuable FA derivatives bearing 1,3-diol, β-amino, β-lactone, and β-lactam functionalities in either enantiomeric form. Molecular docking studies provide a rationale for the regio- and enantioselectivity of this reaction.
- Bai, Wen-Ju,Chen, Hao,Huang, Mengfei,Wang, Xiqing,Yan, Wenliang
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p. 10625 - 10630
(2021/09/02)
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- Synthesis of monophosphoryl lipid A using 2-naphtylmethyl ethers as permanent protecting groups
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Lipid A, which is a conserved component of lipopolysaccharides of gram-negative bacteria, has attracted considerable interest for the development of immuno-adjuvants. Most approaches for lipid A synthesis rely on the use of benzyl ethers as permanent protecting groups. Due to the amphiphilic character of lipid A, these compounds aggregate during the hydrogenation step to remove benzyl ethers, resulting in a sluggish reaction and by-product formation. To address this problem, we have developed a synthetic approach based on the use of 2-naphtylmethyl ether (Nap) ethers as permanent protecting group for hydroxyls. At the end of a synthetic sequence, multiple of these protecting groups can readily be removed by oxidation with 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ). Di-allyl N,N-diisopropylphosphoramidite was employed to install the phosphate ester and the resulting allyl esters were cleaved using palladium tetrakistriphenylphosphine. The synthetic strategy allows late stage introduction of different fatty acids at the amines of the target compound, which is facilitated by Troc and Fmoc as orthogonal amino-protecting groups.
- Verpalen, Enrico C.J.M.,Brouwer, Arwin J.,Boons, Geert-Jan
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supporting information
(2020/10/09)
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- Bacilotetrins A and B, Anti-Staphylococcal Cyclic-Lipotetrapeptides from a Marine-Derived Bacillus subtilis
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LC-MS and NMR spectroscopy guided metabolic profiling and dereplication of a crude extract obtained from the fermentation of a marine-derived bacterium, Bacillus subtilis, followed by chromatographic isolation yielded two new cyclic-lipotetrapeptides, bacilotetrins A (1) and B (2). Based on extensive 1D and 2D NMR and high-resolution ESIMS data analysis, the structures of 1 and 2 were elucidated, revealing the unique structures of these lipopeptides consisting of three leucines and a glutamic acid residue cyclized with a lipophilic 3-hydroxy fatty acid. The absolute stereochemistries at selected stereocenters in 1 and 2 were assigned by chemical derivatization and comparison to literature data. Compounds 1 and 2 exhibited anti-MRSA activity with MIC values of 8 to 32 μg/mL. However, these compounds showed no cytotoxicity when tested against prostate and liver cancer cell lines using the standard SRB assay.
- Tareq, Fakir Shahidullah,Shin, Hee Jae
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p. 2889 - 2892
(2017/12/01)
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- SYNTHETIC GLUCOPYRANOSYL LIPID ADJUVANTS
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PROBLEM TO BE SOLVED: To provide a novel glucopyranosyl lipid adjuvant (GLA) for inducing or enhancing immune responses, and a vaccine composition and a pharmaceutical composition comprising the GLA. SOLUTION: The present invention provides a GLA represented by a compound of the following formula, and a vaccine composition and a pharmaceutical composition comprising the GLA. SELECTED DRAWING: None COPYRIGHT: (C)2016,JPOandINPIT
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Paragraph 0182
(2016/11/24)
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- SYNTHETIC DERIVATIVES OF MPL AND USES THEREOF
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In one aspect, the present disclosure provides compounds of formulae (I) and (II). In another aspect, a compound of formula (I) or (II) is formulated into compositions with an antigen, optionally with a vesicle. In some embodiments, compositions are administered intramuscularly.
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Paragraph 0146
(2014/11/13)
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- Chemical synthesis of burkholderia lipid a modified with glycosyl phosphodiester-linked 4-amino-4-deoxy-β-L-arabinose and its immunomodulatory potential
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Modification of the Lipid A phosphates by positively charged appendages is a part of the survival strategy of numerous opportunistic Gram-negative bacteria. The phosphate groups of the cystic fibrosis adapted Burkholderia Lipid A are abundantly esterified by 4-amino-4-deoxy-b-larabinose (β-L-Ara4N), which imposes resistance to antibiotic treatment and contributes to bacterial virulence. To establish structural features accounting for the unique pro-inflammatory activity of Burkholderia LPS we have synthesised Lipid A substituted by β-L-Ara4N at the anomeric phosphate and its Ara4N-free counterpart. The double glycosyl phosphodiester was assembled by triazolyl-tris-(pyrrolidinyl)phosphonium-assisted coupling of the β-L-Ara4N H-phosphonate to α-lactol of β(1→6) diglucosamine, pentaacylated with (R)-(3)-acyloxyacyl-and Alloc-protected (R)-(3)-hydroxyacyl residues. The intermediate 1,1'-glycosyl-H-phosphonate diester was oxidised in anhydrous conditions to provide, after total deprotection, β-L-Ara4N-substituted Burkholderia Lipid A. The β-L-Ara4N modification significantly enhanced the pro-inflammatory innate immune signaling of otherwise non-endotoxic Burkholderia Lipid A.
- Hollaus, Ralph,Ittig, Simon,Hofinger, Andreas,Haegman, Mira,Beyaert, Rudi,Kosma, Paul,Zamyatina, Alla
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supporting information
p. 4102 - 4114
(2015/10/19)
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- TOLL-LIKE RECEPTOR 2-AGONISTIC LIPOPEPTIDES, AND METHOD OF MAKING THE SAME
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The present disclosure is directed to a novel class of toll-like receptor 2-agnonistic (TLR2) lipopeptide compounds having specific structures, and synthetic methods of making the compounds. These compounds provide high potency of agonistic activities with human, other than murine, TLR2, and are useful as vaccine adjuvants. Vaccines are perhaps one of the most successful medical interventions against infectious disease.
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Paragraph 0121-0122; 0308-0309
(2014/08/06)
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- Imaging mass spectrometry and genome mining reveal highly antifungal virulence factor of mushroom soft rot pathogen
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Soft rot diseases caused by a variety of bacteria account for severe losses in agriculture, devastating fruits, vegetables, and cultivated mushrooms. After bacterial infection, often owing to direct contact or transmission by insects, virulence factors and lytic enzymes cause degradation of plant and mushroom tissues, thereby turning crop into mush. In many cases, the chemical mediators of soft rot diseases have remained elusive, as in the long-known mushroom pathogen Janthinobacterium agaricidamnosum. This motile Gram-negative bacterium has been found to be the causative agent of soft rot disease of the cultured button mushroom, Agaricus bisporus. Typical symptoms of the infection are lesions turning into sticky blotches on the cap surface and a complete dissolution of the mushroom within only a few days (Figure 1A, B). We reasoned that knowledge on the causative agent of the soft rot would have a double benefit. Foremost, it could aid in understanding the pathobiology of the mushroom pathogen, which may be a starting point for protective measures. Second, there is an increasing need for novel antifungals, since the incidents of severe and even lethal fungal infections and resistance towards antifungals are on the rise. We hypothesized that mushroom soft rot bacteria could excrete antifungal agents as virulence factors, which might also be active against human pathogens. Herein we report the discovery and full characterization of a highly antifungal virulence factor from the soft rot pathogen Janthinobacterium agaricidamnosum guided by imaging mass spectrometry and genome mining.
- Graupner, Katharina,Scherlach, Kirstin,Bretschneider, Tom,Lackner, Gerald,Roth, Martin,Gross, Harald,Hertweck, Christian
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supporting information
p. 13173 - 13177
(2013/03/14)
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- Crystal structure of H2O2-dependent cytochrome P450SPαwith its bound fatty acid substrate: Insight into the regioselective hydroxylation of fatty acids at the α position
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Cytochrome P450SPα (CYP152B1) isolated from Sphingomonas paucimobilis is the first P450 to be classified as a 2O 2-dependent P450. P450SPα hydroxylates fatty acids with high α-regioselectivity. Herein we report the crystal structure of P450SPαwith palmitic acid as a substrate at a resolution of 1.65 A. The structure revealed that the Cα of the bound palmitic acid in one of the alternative conformations is 4.5 A from the heme iron. This conformation explains the highly selective α-hydroxylation of fatty acid observed in P450SPα. Mutations at the active site and the F-G loop of P450SPα did not impair its regioselectivity. The crystal structures of mutants (L78F and F288G) revealed that the location of the bound palmitic acid was essentially the same as that in the WT, although amino acids at the active site were replaced with the corresponding amino acids of cytochrome P450BSβ (CYP152A1), which shows β-regioselectivity. This implies that the high regioselectivity of P450SPα is caused by the orientation of the hydrophobic channel, which is more perpendicular to the heme plane than that of P450 BSβ.
- Fujishiro, Takashi,Shoji, Osami,Nagano, Shingo,Sugimoto, Hiroshi,Shiro, Yoshitsugu,Watanabe, Yoshihito
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experimental part
p. 29941 - 29950
(2012/04/10)
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- Chemical synthesis of a glycolipid library by a solid-phase strategy allows elucidation of the structural specificity of immunostimulation by rhamnolipids
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The first synthesis of a glycolipid library by hydrophobically assisted switching phase (HASP) synthesis is described. HASP synthesis enables flexible switching between solution-phase steps and solid-supported reactions conducted with molecules attached to a hydrophobic silica support. A library of glycolipids derived from the lead compound 1 - a strongly immunostimulatory rhamnolipid - with variations in the carbohydrate part, the lipid components, and the stereochemistry of the 3-hydroxy fatty acids was designed and synthesized. The enantiose lective synthesis of the 3-hydroxy fatty acid building blocks was achieved by employing asymmetric hydrogenation of 3-oxo fatty acids. Glycolipids were prepared by this approach without any intermediary isolation steps, mostly in excellent yields. Final deprotection to the carboxylic acids was accomplished by enzymatic ester cleavage. All prepared rhamnolipids were tested for their immunostimulatory properties against human monocyte cells by assaying the secretion of the cytokine tumor necrosis factor α (TNFα) into the medium. The observed structure-activity relationships of rhamnolipids indicate a specific, recognition-based mode of action, with small structural variations in the rhamnolipids resulting in strong effects on the immunostimulatory activities of the rhamnolipids at low micromolar concentrations.
- Bauer, Joerg,Brandenburg, Klaus,Zaehringer, Ulrich,Rademann, Joerg
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p. 7116 - 7124
(2007/10/03)
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- Synthesis and immunobiological activity of an original series of acyclic lipid A mimics based on a pseudodipeptide backbone
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Nδ-L-Homoserinyl-D-ornithinol pseudodipeptides N-acylated with typical Escherichia coli lipid A fatty acid residues and mono-O- or bis-O-phosphorylated have been prepared and their properties investigated. The derivatives carrying two phosphate groups were found to be inducers of NO production. In addition, while they were unable to induce significantly the production of interleukin-6 (IL-6) by human PBMC cells, these compounds behaved also as potent antagonists of LPS-induced IL-6 production in the same human cells system. In conclusion, the molecules described here are the first members of an original class of immunobiologically active lipid A mimics based on an acyclic pseudodipeptide backbone carrying only the essential functionalities of the parent lipid A structure (OM-174). As the products exhibit very low endotoxicity and pyrogenicity, this class of lipid A mimics therefore opens a new generation of immunoadjuvants that possibly could reach clinical applications.
- Martin, Olivier R.,Zhou, Wei,Wu, Xinfu,Front-Deschamps, Sophie,Moutel, Stéphane,Schindl, Katharina,Jeandet, Patricia,Zbaeren, Claude,Bauer, Jacques A.
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p. 6000 - 6014
(2007/10/03)
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- New synthesis of glycolipid immunostimulants RC-529 and CRX-524
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An efficient and scalable synthesis of the potent vaccine adjuvant RC-529 (3) and TLR4 agonist CRX-524 (4) is described in eight steps from 1,3,4,6-tetra-O-acetyl-2-amino-2-benzyloxycarbonyl-2-deoxy-β-d- glucopyranose (10c) in ca. 25% overall yield. The synthesis features the strategic use of the N-Cbz group for β-glycosylation and the selective N,N,O-triacylation of common advanced intermediate 15 with (R)-3- tetradecanoyloxy or decanoyloxytetradecanoic acid (8, 9) late in the synthesis. A new method for preparing and enhancing the enantiopurity of (R)-3-hydroxytetradecanoic acid (6), a key component of 3 and 4 as well as bacterial lipid A, is also described.
- Bazin, Hélène G.,Bess, Laura S.,Livesay, Mark T.,Ryter, Kendal T.,Johnson, Craig L.,Arnold, Jeffrey S.,Johnson, David A.
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p. 2087 - 2092
(2007/10/03)
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- PROCESS FOR MAKING (2S, 3S, 5S) OXETANONE DERIVATIVES
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This invention relates to novel processes for making (2S, 3S, 5S) oxetanone derivative lipase inhibitor compounds and intermediates therefor, which processes for producing such derivatives that are useful as lipase inhibitors are capable of being scaled to commercial quantities. Further the invention relates to processes for producing salts and for producing pharmaceutical compositions compounds comprising at least one such oxetanone derivative or salt, as well as methods for using such compounds and compositions for inhibiting lipases.
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- An efficient method to chiral β-hydroxy acids: Synthesis of lipid-A side chain
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The synthesis of optically active β-hydroxy acids 5a-c is achieved in four steps from their corresponding terminal olefins 1a-c by employing Sharpless asymmetric dihydroxylation. The regioselective ring opening of chiral cyclic sulfites 3a-c with cyanide ion, constitutes the key reaction, thus producing the hydroxy nitriles 4a-c.
- Nandanan,Phukan, Prodeep,Sudalai
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p. 893 - 896
(2007/10/03)
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- An efficient synthesis of (R)-3-hydroxytetradecanoic acid
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A short, efficient synthesis of (R)-3-hydroxytetradecanoic acid, a key component of bacterial endotoxins, using (R)-oxirane acetic acid ethyl ester as the source of chirality is described. The method is general and can be used in the preparation of other chiral 3-hydroxy acids.
- Huang, Guangfei,Hollingsworth, Rawle I.
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p. 4113 - 4115
(2007/10/03)
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- Enzymatic preparation of (S)-3-hydroxytetradecanoic acid and synthesis of unnatural analogues of lipid A containing the (S)-acid
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Synthesis of unnatural analogues, that contain (S)-3-hydroxytetradecanoyl moieties in place of the corresponding natural (R)-isomers, of both lipid A and its biosynthetic precursor, designated precursor Ia or lipid IV(A), has been achieved through our recently developed procedure. (S)-3-Hydroxytetradecanoic acid was prepared from its racemate through the optical resolution by the use of a lipase and subsequent fractional recrystallization. The (S)-acyl analogue of lipid A exhibited slightly stronger interleukin-6 inducing activity than the corresponding natural lipid A, and the (S)-acyl analogue of the biosynthetic precursor was far more active than the natural precursor in inhibiting the induction of interleukin-6 by lipopolysaccharide.
- Liu, Wen-Chi,Oikawa, Masato,Fukase, Koichi,Suda, Yasuo,Winarno, Hendig,Mori, Saeko,Hashimoto, Masahito,Kusumoto, Shoichi
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p. 1441 - 1450
(2007/10/03)
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- Efficient asymmetric synthesis of (R)-3-hydroxy- and alkanoyloxytetradecanoic acids and method for the determination of enantiomeric purity
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An efficient synthesis of the (R)-3-hydroxy- and alkanoyloxytetradecanoic acid components of bacterial lipid A has been achieved using a Ru(II)-Binap-catalyzed low-pressure hydrogenation in the key step. The enantiomeric purity of p-bromophenacyl ester intermediate 4 could be assessed directly by chiral HPLC - obviating separate derivatization steps and/or chiral NMR shift studies.
- Keegan, David S.,Hagen, Steven R.,Johnson, David A.
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p. 3559 - 3564
(2007/10/03)
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- A new route to β-keto-δ-lactones: Practical preparation of (R)-3-hexyl-5,6-dihydro-4-hydroxy-6-undecyl-2H-pyran-2-one, a key intermediate in the asymmetric synthesis of tetrahydrolipstatin
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A formal asymmetric synthesis of the anti-obesity drug tetrahydrolipstatin is reported. The advanced intermediate (R)-3-hexyl-5,6-dihydro-4-hydroxy-6-undecyl-2H-pyran-2-one is prepared in a brief sequence using a novel cyclization reaction. The sequence is also used to prepare other β-ketolactones.
- Landi Jr.,Garofalo,Ramig
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p. 277 - 280
(2007/10/02)
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- Towards the Chemoenzymatic Synthesis of Lipid A
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New procedures have been developed for the synthesis of the two important components of lipid A; one is the lipase-catalyzed resolution of 3-hydroxytetradecanoic acid in tetrahydrofuran using vinyl acetate and the other is the synthesis of the disaccharide moiety using glycosylphosphite as the glycosylating reagent.
- Sugai, Takeshi,Ritzen, Helena,Wong, Chi-Huey
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p. 1051 - 1058
(2007/10/02)
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- Production of oxetanones
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The invention relates to a novel process for producing a compound having the formula STR1 wherein R1, R2 and X are described herein, via wherein R corresponding β-keto- and β-hydroxy-δ-lactones, as well as novel intermediates which occur in the process.
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- Asymmetric Reduction of Aliphatic Short- to Long-Chain β-Keto Acids by Use of Fermenting Bakers' Yeast
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Eleven β-keto acids, ranging from 3-oxobutanoic to 3-oxooctanoic acids, were reduced with fermenting bakers' yeast to the corresponding optically active β-hydroxy acids, which were isolated as the methyl esters.In all cases, the (R)-hydroxy acids were obtained in >/=98percent ee, except for 3-oxobutanoic acid, which afforded the (S)-hydroxy acid in 86percent ee.Inhibition of fermentation was observed for 3-oxoundecanoic to 3-oxotetradecanoic acids, leading to no reduction.Lowering of the substrate concentration was found to be appreciably effective in avoiding inhibition.
- Utaka, Masanori,Watabu, Hisashi,Higashi, Hiroshi,Sakai, Takashi,Tsuboi, Sadao,Torii, Sigeru
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p. 3917 - 3921
(2007/10/02)
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- The Preparation of Optically Pure 3-Hydroxyalkanoic Acid. The Enantioface-differentiating Hydrogenation of the C=O Double Bond with Modified Raney Nickel. XXXVII
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The enantioface-differentiating hydrogenation of methyl 3-oxoalkanoate (CH3(CH2)nCOCH2COOCH3, n=0, 6, 8, 10, 12) over the (R,R)-tartaric acid-NaBr-modified Raney nickel catalyst ((R,R)-TA-NaBr-MRNi) gave methyl (R)-3-hydroxyalkanoate (CH3(CH2)nCH(OH)CH2COOCH3, n=0, 6, 8, 10, 12) in an average optical yield of 85percent.After the methyl ester had been converted to dicyclohexylammonium salt of 3-hydroxyalkanoic acid, the salt was recrystallized three times from acetonitrile and then treated with acid to give optically pure (R)-3-hydroxyalkanoic acid (CH3(CH2)nCH(OH)CH2COOH, n=0, 6, 8, 10, 12) in a reasonable yield.From the hydrogenation product with (S,S)-TA-NaBr-MRNi, optically pure (S)-3-hydroxyalkanoic acid was obtained by the same process as above.
- Nakahata, Masaaki,Imaida, Motomasa,Ozaki, Hiroshi,Harada, Tadao,Tai, Akira
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p. 2186 - 2189
(2007/10/02)
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