- Characterization of CYP154F1 from Thermobifida fusca YX and Extension of Its Substrate Spectrum by Site-Directed Mutagenesis
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Previous studies on cytochrome P450 monooxygenases (CYP) from family 154 reported their substrate promiscuity and high activity. Hence, herein, the uncharacterized family member CYP154F1 is described. Screening of more than 100 organic compounds revealed
- Rühlmann, Ansgar,Groth, Georg,Urlacher, Vlada B.
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- The crystal structure of the versatile cytochrome P450 enzyme CYP109B1 from Bacillus subtilis
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The crystal structure of the versatile CYP109B1 enzyme from Bacillus subtilis has been solved at 1.8 ? resolution. This is the first structure of an enzyme from this CYP family, whose members are prevalent across diverse species of bacteria. In the crysta
- Zhang, Aili,Zhang, Ting,Hall, Emma A.,Hutchinson, Sean,Cryle, Max J.,Wong, Luet-Lok,Zhou, Weihong,Bell, Stephen G.
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- DoE (Design of Experiments) assisted allylic hydroxylation of enones catalysed by a copper-aluminium mixed oxide
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The allylic hydroxylation of enones using dioxygen as the oxidant has been studied. The reaction was first examined in the absence of any catalyst, using β-ionone as a model substrate. Then a new copper-aluminium mixed oxide, Cu-Al Ox, was prepared and ch
- Garcia-Cabeza, Ana Leticia,Marin-Barrios, Ruben,Azarken, Redouan,Moreno-Dorado, F. Javier,Ortega, Maria J.,Vidal, Hilario,Gatica, Jose M.,Massanet, Guillermo M.,Guerra, Francisco M.
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- Studies on the enantioselective oxidation of β-ionone with a whole E. coli system expressing cytochrome P450 monooxygenase BM3
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Recombinant Escherichia coli cells, expressing an NADH-dependent cytochrome P450 monooxygenase BM-3 mutant, were used for the hydroxyalation of the sesquiterpenoid β-ionone to (R)-4-hydroxy-β-ionone. The decrease in enantioselectivity of cytochrome P450 monooxygenase BM-3 catalyzed hydroxylation of β-ionone can be ascribed to the overoxidation of the desired product. In this initial study we report, that by addressing reaction conditions the enantiomeric excess can be increased and the overoxidation can be reduced. Furthermore, we report herein the kinetic resolution of racemic 4-hydroxy-β-ionone using the same P450 monooxygenase for the production of (S)-4-hydroxy-β-ionone. Although the enantioselectivity of the enzyme is rather low for this reaction, this reaction could be of interest with improved P450 BM-3 variants. Both systems need further investigations and optimizations for preparative application.
- Zehentgruber, Daniela,Urlacher, Vlada B.,Luetz, Stephan
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- Practical synthesis of canthaxanthin
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In this study, a novel route for the total synthesis of canthaxanthin is described. The synthesis is firstly based on an epoxidation of α-ionone with metachloroperbenzoic acid to afford the epoxide, followed by conversion of the epoxide to 3-hydroxyl-β-ionone in the presence of sodium methoxide. Next, 3-hydroxyl-C14-aldehyde was obtained by a Darzens condensation with 4-hydroxyl-β-ionone and methyl chloroacetate, which can be converted to 3-hydroxyl-C15-phophonate via a Wittig–Horner condensation with tetraethyl methylenebisphosphonate. Then, a Wittig–Horner condensation with 3-hydroxyl-C15-phosphonate and C10-trienedial resulted in 4,4′-dihydroxyl-β-carotene, followed by an oxidation afforded the target product canthaxanthin. The overall yield of this route is 37% from α-ionone. The synthetic steps are easily operated and are practical for the large-scale production.
- Pi, Shiqing,Xi, Meiyang,Deng, Liping,Xu, Huiting,Feng, Chengjie,Shen, Runpu,Wu, Chunlei
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p. 493 - 497
(2019/11/03)
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- Selective oxygenation of ionones and damascones by fungal peroxygenases
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Apocarotenoids are among the most highly valued fragrance constituents, being also appreciated as synthetic building blocks. This work shows the ability of unspecific peroxygenases (UPOs, EC1.11.2.1) from several fungi, some of them being described recently, to catalyze the oxyfunctionalization of α- and β-ionones and α- and β-damascones. Enzymatic reactions yielded oxygenated products such as hydroxy, oxo, carboxy, and epoxy derivatives that are interesting compounds for the flavor and fragrance and pharmaceutical industries. Although variable regioselectivity was observed depending on the substrate and enzyme, oxygenation was preferentially produced at the allylic position in the ring, being especially evident in the reaction with α-ionone, forming 3-hydroxy-α-ionone and/or 3-oxo-α-ionone. Noteworthy were the reactions with damascones, in the course of which some UPOs oxygenated the terminal position of the side chain, forming oxygenated derivatives (i.e., the corresponding alcohol, aldehyde, and carboxylic acid) at C-10, which were predominant in the Agrocybe aegerita UPO reactions, and first reported here.
- Aranda, Carmen,Babot, Esteban D.,Del R?o, José C.,Gutiérrez, Ana,Hofrichter, Martin,Kiebist, Jan,Mart?nez, Angel T.,Scheibner, Katrin,Ullrich, René
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p. 5375 - 5383
(2020/06/08)
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- In Vitro Regio- and Stereoselective Oxidation of β-Ionone by Human Liver Microsomes
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The metabolism of the norisoprenoid β-ionone was investigated in vitro using human liver microsomes and 11 different recombinant cytochrome P450 enzymes expressed in Trichoplusia ni cells. β-Ionone was found to be oxidized via 4S-hydroxylation by CYP2B6 i
- Marumoto, Shinsuke,Shimizu, Ryoyu,Tanabe, Genzoh,Okuno, Yoshiharu,Miyazawa, Mitsuo
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p. 292 - 299
(2017/02/26)
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- Expansion of first-in-class drug candidates that sequester toxic all-trans-retinal and prevent light-induced retinal degeneration
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All-trans-retinal, a retinoid metabolite naturally produced upon photoreceptor light activation, is cytotoxic when present at elevated levels in the retina. To lower its toxicity, two experimentally validated methods have been developed involving inhibition of the retinoid cycle and sequestration of excess of all-trans-retinal by drugs containing a primary amine group. We identified the first-in-class drug candidates that transiently sequester this metabolite or slow down its production by inhibiting regeneration of the visual chromophore, 11-cis-retinal. Two enzymes are critical for retinoid recycling in the eye. Lecithin:retinol acyltransferase (LRAT) is the enzyme that traps vitamin A (all-trans-retinol) from the circulation and photoreceptor cells to produce the esterified substrate for retinoid isomerase (RPE65), which converts all-trans-retinyl ester into 11-cis-retinol. Here we investigated retinylamine and its derivatives to assess their inhibitor/substrate specificities for RPE65 and LRAT, mechanisms of action, potency, retention in the eye, and protection against acute light-induced retinal degeneration in mice. We correlated levels of visual cycle inhibition with retinal protective effects and outlined chemical boundaries for LRAT substrates and RPE65 inhibitors to obtain critical insights into therapeutic properties needed for retinal preservation.
- Zhang, Jianye,Dong, Zhiqian,Mundla, Sreenivasa Reddy,Hu, X. Eric,Seibel, William,Papoian, Ruben,Palczewski, Krzysztof,Golczak, Marcin
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supporting information
p. 477 - 491
(2015/01/30)
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- Synthesis and in vitro characterization of ionone-based compounds as dual inhibitors of the androgen receptor and NF-κB
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Current therapeutic strategy for advanced prostate cancer is to suppress the androgen receptor (AR) signaling. However, lethal castration-resistant prostate cancer (CRPC) arises due to AR reactivation via multiple mechanisms, including mutations in the AR and cross-talk with other pathways such as NF-κB. We have previously identified two ionone-based antiandrogens (SC97 and SC245), which are full antagonists of the wild type and the clinically-relevant T877A, W741C and H874Y mutated ARs. Here, we discovered SC97 and SC245 also inhibit NF-κB. By synthesizing a series of derivatives of these two compounds, we have discovered a novel compound 3b that potently inhibits both AR and NF-κB signalling, including the AR F876L mutant. Compound 3b showed low micromolar antiproliferative activites in C4-2B and 22Rv1 cells, which express mutated ARs and are androgen-independent, as well as DU-145 and PC-3 cells, which exhibit constitutively activated NF-κB signalling. Our studies indicate 3b is effective against the CRPC cells.
- Liu, Weiguo,Zhou, Jinming,Geng, Guoyan,Lin, Rongtuan,Wu, Jian Hui
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p. 227 - 234
(2014/04/03)
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- β-Carotene autoxidation: Oxygen copolymerization, non-vitamin A products, and immunological activity
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Carotenoids are reported to have immunological effects independent of vitamin A activity. Although antioxidant activity has been suggested as a basis of action, the ability of carotenoids to autoxidize to numerous non-vitamin A products with immunological activity is an alternative yet to be fully explored. We have undertaken a systematic study of β-carotene autoxidation and tested the product mixture for immunological activity. Autoxidation proceeds predominantly by oxygen copolymerization, leading to a defined, reproducible product corresponding to net uptake of almost 8 molar equivalents of oxygen. The product, termed OxC-beta, empirical formula C40H60O 15 versus C40H56 for β-carotene, contains more than 30% oxygen (w/w) and 85% β-carotene oxygen copolymers (w/w) as well as minor amounts of many C8-C18 norisoprenoid compounds. No vitamin A or higher molecular weight norisoprenoids are present. The predominance of polymeric products has not been reported previously. The polymer appears to be a less polymerized form of sporopollenin, a biopolymer found in exines of spores and pollen. Autoxidations of lycopene and canthaxanthin show a similar predominance of polymeric products. OxC-beta exhibits immunological activity in a PCR gene expression array, indicating that carotenoid oxidation produces non-vitamin A products with immunomodulatory potential.
- Burton, Graham W.,Daroszewski, Janusz,Nickerson, James G.,Johnston, James B.,Mogg, Trevor J.,Nikiforov, Grigory B.
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supporting information
p. 305 - 316
(2014/05/06)
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- Unusually Broad Substrate Profile of Self-Sufficient Cytochrome P450 Monooxygenase CYP116B4 from Labrenzia aggregata
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A new member of the CYP116B subfamily - P450LaMO - was discovered in Labrenzia aggregata by genomic data mining. It was successfully overexpressed in Escherichia coli, purified, and subsequently characterized spectroscopically, and its catalytic properties were assessed. Substrate profiling of the P450LaMO revealed that it was a versatile catalyst, exhibiting hydroxylation and epoxidation activities as well as O-dealkylation and asymmetric sulfoxidation activities. Diverse compounds, including alkylbenzenes, aromatic bicyclic molecules, and terpenoids, were shown to be hydroxylated by P450LaMO. Such diverse catalytic activities are uncommon for the bacterial P450s, and the P450LaMO -mediated stereoselective hydroxylation of inactivated C-H bonds - ubiquitous and relatively unreactive in organic molecules - is particularly unusual. The self-sufficient nature of P450LaMO, coupled with its broad substrate range, highlights it as an ideal template for directed evolution towards various applications.
- Yin, Yue-Cai,Yu, Hui-Lei,Luan, Zheng-Jiao,Li, Ren-Jie,Ouyang, Peng-Fei,Liu, Jing,Xu, Jian-He
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p. 2443 - 2449
(2015/08/24)
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- Facile lipase catalysed syntheses of (S)-(+)-4-hydroxy-β-ionone and (S)-(+)-4-hydroxy-β-damascone: Chiral flavorants and synthons
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Enantioselective syntheses of (S)-(+)-4-hydroxy-β-ionone and (S)-(+)-4-hydroxy-β-damascone have been achieved through pig pancreatic lipase catalysed trans-esterification. These molecules find utility as constituent in fruit-type fragrance and flavor form
- More, Gauri P.,Bhat, Sujata V.
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p. 4148 - 4149
(2013/07/26)
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- Chimeric self-sufficient P450cam-RhFRed biocatalysts with broad substrate scope
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A high-throughput screening protocol for evaluating chimeric, self-sufficient P450 biocatalysts and their mutants against a panel of substrates was developed, leading to the identification of a number of novel biooxidation activities.
- Robin, Aelig,Koehler, Valentin,Jones, Alison,Ali, Afruja,Kelly, Paul P.,O'Reilly, Elaine,Turner, Nicholas J.,Flitsch, Sabine L.
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supporting information; experimental part
p. 1494 - 1498
(2012/01/13)
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- Structural analysis of CYP101C1 from Novosphingobium aromaticivorans DSM12444
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CYP101C1 from Novosphingobium aromaticivorans DSM12444 is a homologue of CYP101D1 and CYP101D2 enzymes from the same bacterium and CYP101A1 from Pseudomonas putida. CYP101C1 does not bind camphor but is capable of binding and hydroxylating ionone derivatives including α- and β-ionone and β-damascone. The activity of CYP101C1 was highest with β-damascone (kcat=86 s-1) but α-ionone oxidation was the most regioselective (98% at C3). The crystal structures of hexane-2,5-diol- and β-ionone-bound CYP101C1 have been solved; both have open conformations and the hexanediol-bound form has a clear access channel from the heme to the bulk solvent. The entrance of this channel is blocked when β-ionone binds to the enzyme. The heme moiety of CYP101C1 is in a significantly different environment compared to the other structurally characterised CYP101 enzymes. The likely ferredoxin binding site on the proximal face of CYP101C1 has a different topology but a similar overall positive charge compared to CYP101D1 and CYP101D2, all of which accept electrons from the ArR/Arx class I electron transfer system.Crystal clear: CYP101C1 oxidises ionone derivatives fast (kcat≤86 s-1) and with high regioselectivity (≤98%). Its crystal structure (shown) provides structural insights into how this enzyme differs from those that bind camphor from the same CYP family, and further information on how open conformations of CYP enzymes are involved in substrate entry and binding.
- Ma, Ming,Bell, Stephen G.,Yang, Wen,Hao, Yiming,Rees, Nicholas H.,Bartlam, Mark,Zhou, Weihong,Wong, Luet-Lok,Rao, Zihe
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experimental part
p. 88 - 99
(2011/12/15)
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- A convenient cross-metathesis approach to trisporins
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Three series of trisporins have been prepared using a strategy in which a cross-metathesis is the key step. This reaction has proved to be highly regioselective, allowing the combination of α- or β-ionone derivatives having a 1,1-disustituted olefin with
- López-Sánchez, Cristóbal,Hernández-Cervantes, Carmen,Rosales, Antonio,álvarez-Corral, Míriam,Mu?oz-Dorado, Manuel,Rodríguez-García, Ignacio
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scheme or table
p. 9542 - 9549
(2010/02/27)
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- Expedient construction of the ziegler intermediate useful for the synthesis of forskolin via consecutive rearrangements
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"Chemical Equation Presented" The Ziegler Intermediate, useful for the total synthesis of forskolin, was synthesized in 10 reaction steps starting from commercially available a-lonone. This highly efficient synthesis relies on the success of two consecuti
- Ye, Heping,Deng, Gang,Liu, Jun,Qiu, Fayang G.
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supporting information; experimental part
p. 5442 - 5444
(2010/02/28)
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- All-Trans-Retinol: All-Trans-13,14-Dihydroretinol Saturase and Methods of Its Use
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Compositions of all-trans-retinol: all-trans-13,14-dihydroretinal saturase and methods of use thereof are provided.
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- Development of aqua-soluble compounds based on vitamin A series molecules: Synthetic transformations of β-ionone
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Several β-ionyl compounds bearing hydrophilic moieties like a carbohydrate, amine, phosphate and amino acid have been prepared and characterized. The solubilisation behaviour of these compounds has been examined by studying their UV-Vis absorption behavio
- Libsu, Solomon,Singh, Anil K
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p. 1297 - 1302
(2008/09/18)
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- Synthesis, olfactory evaluation, and determination of the absolute configuration of the 3,4-didehydroionone stereoisomers
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The synthesis of 3,4-didehydroionone isomers 4, (+)-6, and (-)-6 and of 3,4-didehydro-7,8-dihydroionone isomers 5, (+)-7, and (-)-7 was accomplished starting from commercially available racemic α-ionone (1). Their preparation of the racemic forms 4-7 was first achieved by mean of a number of chemo- and regioselective reactions (Schemes 1 and 2). The enantio- and diastereoselective lipase-mediated kinetic acetylation of 4-hydroxy-γ- ionone (10a/10b) provided 4-hydroxy-γ-ionone (+)-10a/(±)-10b and (+)-4-(acetyloxy)-γ-ionone ((+)12b) (Scheme 3). The latter compounds were used as starting materials to prepare the 3,4-didehydro-γ-ionones (+)- and (-)-6 and the 3,4-didehydro-7,8-dihydro-γ-ionones (+)- and (-)-7 in enantiomer-enriched form. The absolute configuration of (+)-12b was determine by chemical correlation with (+)-(6S)-γ-ionone ((+)-3) and with (-)-(6S)-α-ionone ((-)-1) therefore allowing to assign the (S)-configuration to (+)-6 and (+)-7. Olfactory evaluation of the above described 3,4-didehydroionone isomers shows a significant difference between the enantiomers and regioisomers both in fragrance feature and in detection threshold (Table).
- Serra, Stefano,Fuganti, Claudio,Brenna, Elisabetta
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p. 1110 - 1122
(2007/10/03)
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- Immobilisation of P450 BM-3 and an NADP+ Cofactor Recycling System: Towards a Technical Application of Heme-Containing Monooxygenases in Fine Chemical Synthesis
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Cytochrome P450 monooxygenases are potentially a very useful class of hydroxylation catalysts; they are able to introduce oxygen at activated and non-activated carbon-hydrogen bonds and thus lead to regio- and/or stereochemically pure compounds. However, this potential is lowered by their intrinsic low activity and inherent instability. P450-catalysed biotransformations require a constant supply of NAD(P)H, making the process an expensive one. To render these catalysts more suitable for industrial biocatalysis, the immobilisation of P450 BM-3 (CYP 102A1) from Bacillus megaterium in a sol-gel matrix was combined with a cofactor recycling system based on NADP+-dependent formate dehydrogenase (EC 1.2.1.2) from Pseudomonas sp. 101 and tested for practical applicability. This approach was used for the conversion of β-ionone, octane and naphthalene to the respective hydroxy compounds with DMSO as cosolvent using sol-gel immobilised P450 BM-3 mutants.
- Maurer, Steffen C.,Schulze, Holger,Schmid, Rolf D.,Urlacher, Vlada
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p. 802 - 810
(2007/10/03)
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The electrocyclisation of allenyldiene easily obtained from hydroxy-β-ionone has been studied with the aim to set up an efficient access to polyhydroxylated decalinic systems. Some aspects of the stereoselectivity of this reaction are discussed and the tr
- Leclaire,Jean,Lopez,Ricard,Plessix,Lallemand
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p. 6983 - 6998
(2007/10/02)
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- A simple access to a forskolin precursor
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Cyclization of acetoacetate of hydroxy-ionone 1 into lactone 2, a precursor of forskolin, is shown to occur in excellent yield using Cs2CO3 or Cs2CO3/K2CO3 mixture.
- Leclaire,Levet,Lallemand
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p. 1923 - 1927
(2007/10/02)
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- Selective Allylic Electron-transfer Oxidation of β-Ionone
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The reactions of β-ionone with one-electron oxidizing agents, in methylene chloride/alcohol, afford allylic oxygenated derivatives; the reactions are likely to proceed via a one-electron transfer mechanism.
- Calo, Vincenzo,Lopez, Luigi,Troisi, Luigino
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- Selective Allylic Electro-oxidation of α- and β-Ionones
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Allylic ring substitution of α- and β-ionones by, respectively, anodically generated cobalt(III)acetate and bromine, is selective and efficient; in contrast direct anodic oxidation is unselective but provides a route to the novel, rearranged, carotenoid end group (7).
- Guirado, Antonio,Moss, Gerard P.,Utley, James H. P.
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- A SYNTHETIC APPROACH TO TAXANE DITERPENES. A SYNTHESIS OF THE BICYCLOUNDECENONE RING SYSTEM
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Bicycloundecenone 2 corresponding to A and B rings in taxane diterpenes was synthesized.The eight-membered ring was constructed by a base-induced intramolecular cyclization of twelwe-membered lactam sulfoxides 15.
- Ohtsuka, Yasuo,Oishi, Takeshi
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p. 203 - 206
(2007/10/02)
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- Photochemical Reactions. Photochemistry of α,β-Unsaturated δ,ε-Epoxyketones of the Ionone Series
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On n,?*- as well as on ?,?*-excitation, the 4,5-epoxy-α-ionones (E)-1, (E)-2, and (E)-3 undergo (E)/(Z)-isomerization and subsequent γ-H-abstraction leading to the corresponding 4-hydroxy-β-ionones (E/Z)-9, E/Z)-13, and (E/Z)-17 as primary photoproducts.On photolysis of (E)-3, as an additional primary photoproduct, the β,γ-unsaturated δ,ε-epoxy ketone 18 was obtained.The other isolated compounds, namely the 2H-pyrans 10A+B and 14A+B as well as the retro-γ-ionones 11 and 15A+B, represent known types of products which are derived from the 4-hydroxy-β-ionones (E/Z)-9 and (E/Z)-13, respectively.
- Mathies, Peter,Frei, Bruno,Jeger, Oskar
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p. 192 - 206
(2007/10/02)
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- Fermentation of Fragrances: Biotransformation of β-Ionone by Lasiodiplodia theobromae
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Pre-grown mycelia of Lasiodiplodia theobromae ATCC 28570 transform β-ionone (1) into a large variety of metabolites, by mainly degrading the side-chain of the β-ionone molecule by a C2-unity.The enzyme system responsible for this degradation is proposed to be an oxygenase, which gives rise to the formation of the main product β-cyclo-homogeraniol (8) in analogy to a Baeyer-Villiger oxidation.Further enzymic actions of Lasiodiplodia such as hydrogenations and hydroxylations lead to an accumulation of several not yet described β-ionone metabolites.
- Krasnobajew, Victor,Helmlinger, Daniel
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p. 1590 - 1601
(2007/10/02)
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