- Human and rodent aldo-keto reductases from the AKR1B subfamily and their specificity with retinaldehyde
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NADP(H)-dependent cytosolic aldo-keto reductases (AKR) are mostly monomeric enzymes which fold into a typical (α/β)8-barrel structure. Substrate specificity and inhibitor selectivity are determined by interaction with residues located in three highly variable loops (A, B, and C). Based on sequence identity, AKR have been grouped into families, namely AKR1-AKR15, containing multiple subfamilies. Two human enzymes from the AKR1B subfamily (AKR1B1 and AKR1B10) are of special interest. AKR1B1 (aldose reductase) is related to secondary diabetic complications, while AKR1B10 is induced in cancer cells and is highly active with all-trans-retinaldehyde. Residues interacting with all-trans-retinaldehyde and differing between AKR1B1 and AKR1B10 are Leu125Lys and Val131Ala (loop A), Leu301Val, Ser303Gln, and Cys304Ser (loop C). Recently, we demonstrated the importance of Lys125 as a determinant of AKR1B10 specificity for retinoids. Residues 301 and 304 are also involved in interactions with substrates or inhibitors, and thus we checked their contribution to retinoid specificity. We also extended our study with retinoids to rodent members of the AKR1B subfamily: AKR1B3 (aldose reductase), AKR1B7 (mouse vas deferens protein), AKR1B8 (fibroblast-growth factor 1-regulated protein), and AKR1B9 (Chinese hamster ovary reductase), which were tested against all-trans isomers of retinaldehyde and retinol. All enzymes were active with retinaldehyde, but with kcat values (0.02-0.52 min -1) much lower than that of AKR1B10 (27 min-1). None of the enzymes showed oxidizing activity with retinol. Since these enzymes (except AKR1B3) have Lys125, other residues should account for retinaldehyde specificity. Here, by using site-directed mutagenesis and molecular modeling, we further delineate the contribution of residues 301 and 304. We demonstrate that besides Lys125, Ser304 is a major structural determinant for all-trans-retinaldehyde specificity of AKR1B10.
- Ruiz, F. Xavier,Moro, Armando,Gallego, Oriol,Ardèvol, Albert,Rovira, Carme,Petrash, J. Mark,Parés, Xavier,Farrés, Jaume
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Read Online
- Iron-Catalyzed Vinylzincation of Terminal Alkynes
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Organozinc reagents are among the most commonly used organometallic reagents in modern synthetic chemistry, and multifunctionalized organozinc reagents can be synthesized from structurally simple, readily available ones by means of alkyne carbozincation. However, this method suffers from poor tolerance for terminal alkynes, and transformation of the newly introduced organic groups is difficult, which limits its applications. Herein, we report a method for vinylzincation of terminal alkynes catalyzed by newly developed iron catalysts bearing 1,10-phenanthroline-imine ligands. This method provides efficient access to novel organozinc reagents with a diverse array of structures and functional groups from readily available vinylzinc reagents and terminal alkynes. The method features excellent functional group tolerance (tolerated functional groups include amino, amide, cyano, ester, hydroxyl, sulfonyl, acetal, phosphono, pyridyl), a good substrate scope (suitable terminal alkynes include aryl, alkenyl, and alkyl acetylenes bearing various functional groups), and high chemoselectivity, regioselectivity, and stereoselectivity. The method could significantly improve the synthetic efficiency of various important bioactive molecules, including vitamin A. Mechanistic studies indicate that the new iron-1,10-phenanthroline-imine catalysts developed in this study have an extremely crowded reaction pocket, which promotes efficient transfer of the vinyl group to the alkynes, disfavors substitution reactions between the zinc reagent and the terminal C–H bond of the alkynes, and prevents the further reactions of the products. Our findings show that iron catalysts can be superior to other metal catalysts in terms of activity, chemoselectivity, regioselectivity, and stereoselectivity when suitable ligands are used.
- Hu, Meng-Yang,Huang, Qiang,Su, Yu-Xuan,Sun, Wei,Wang, Wei-Na,Zhu, Shou-Fei
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- Synthesis of C11-to-C14 methyl-shifted all-: Trans -retinal analogues and their activities on human aldo-keto reductases
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Human aldo-keto reductases (AKRs) are enzymes involved in the reduction, among other substrates, of all-trans-retinal to all-trans-retinol (vitamin A), thus contributing to the control of the levels of retinoids in organisms. Structure-activity relationship studies of a series of C11-to-C14 methyl-shifted (relative to natural C13-methyl) all-trans-retinal analogues as putative substrates of AKRs have been reported. The synthesis of these retinoids was based on the formation of a C10-C11 single bond of the pentaene skeleton starting from a trienyl iodide and the corresponding dienylstannanes and dienylsilanes, using the Stille-Kosugi-Migita and Hiyama-Denmark cross-coupling reactions, respectively. Since these reagents differ by the location and presence of methyl groups at the dienylorganometallic fragment, the study also provided insights into the ability of the different positional isomers to undergo cross-coupling and the sensitivity of these processes to steric hindrance. The resulting C11-to-C14 methyl-shifted all-trans-retinal analogues were found to be active substrates when tested with AKR1B1 and AKR1B10 enzymes, although relevant differences in substrate specificities were noted. For AKR1B1, all analogues exhibited higher catalytic efficiency (kcat/Km) than parent all-trans-retinal. In addition, only all-trans-11-methylretinal, the most hydrophobic derivative, showed a higher value of kcat/Km = 106 000 ± 23 200 mM-1 min-1 for AKR1B10, which is in fact the highest value from all known retinoid substrates of this enzyme. The novel structures, identified as efficient AKR substrates, may serve in the design of selective inhibitors with potential pharmacological interest. This journal is
- Alvarez, Rosana,Barracco, Vito,De Lera, Angel R.,Domínguez, Marta,Farrés, Jaume,Jiménez, Rafael,López, Susana,Parés, Xavier,Pequerul, Raquel,Rivas, Aurea
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p. 4788 - 4801
(2020/07/13)
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- Method for preparing vitamin A and vitamin A ester
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The invention provides a novel method for preparing vitamin A and vitamin A ester by taking farnesol as a raw material. The method comprises the following steps: carrying out oxidation reaction on farnesol and oxygen under the action of a catalyst and a cocatalyst to generate farnesal; carrying out dehydrogenation reaction on farnesal to generate dehydrofarnesal; carrying out cyclization reactionon the dehydrofarnesal under the catalysis of acid to generate a cyclized intermediate; carrying out a reaction on the cyclized intermediate with chloroisopentenol to generate vitamin A; carrying outan esterification reaction on vitamin A to generate vitamin A ester. The method avoids the defects of an existing process, and the process line is economical and effective.
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- Preparation method of vitamin A and vitamin A ester
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The invention provides a novel method for preparing vitamin A and vitamin A ester with farnesene as a raw material. The method comprises the following steps: reacting farnesene with acetoacetate underthe action of a catalyst to obtain farnesyl keto ester; carrying out a cyclization reaction and a dehydrogenation reaction on farnesene acetone, and then reacting a reaction product with vinyl magnesium halide to generate vinyl alcohol; carrying out a rearrangement reaction on vinyl alcohol to obtain vitamin A; and subjecting the vitamin A to an esterification reaction to obtain the vitamin A ester. The method avoids the defects of the existing processes, and the process line of the method is economical and effective.
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- Retinal-based polyene fluorescent probe for selectively detection of Cu2+ in physiological saline and serum
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Retinal is a flexible natural chromophore and widely present in organisms. The slender conjugated polyene structure retinal is conducive to entering protein structure. In this work, a novel turn-on fluorescent probe for Cu2+ based on retinal and phenylenediamine was designed and synthesized. The probe achieved recognition of copper ions in human serum complex protein environment. Furthermore, the high sensitivity, selectivity for Cu2+ and the sensing mechanism was also investigated.
- Li, Yang,Lan, Haichuang,Yan, Xia,Shi, Xiaotao,Liu, Xiao,Xiao, Shuzhang
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- Mimicking light-sensing chromophore in visual pigments and determination isomerization site
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Three retinal derivatives are designed and synthesized under the inspiration of natural visual pigments. The retinal derivative V3 (retinal-phenylenediamine) is able to respond sensitively to visual light in the absence of a protein environment through isomerization and deprotonation. The response process is applied to verification of information security.
- Li, Yang,Lan, Haichuang,Yan, Xia,Shi, Xiaotao,Liu, Xiao,Xiao, Shuzhang
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- Preparation method of tretinoin
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The invention discloses a preparation method of tretinoin. The method comprises the following steps: 1) hydrolyzing vitamin A acetate under an alkaline condition to obtain vitamin A; and 2) in an oxygen atmosphere, carrying out an oxidation reaction on the vitamin A in an ionic liquid bis-(3-methyl-1-imidazole)ethylene tetrafluoroborate under the catalytic action of RuCl2(PPh3)3 to obtain tretinoin. The method has the advantages of mild reaction conditions, easily available reaction raw materials, no need of purification of intermediates, reaction yield of up to 90%, purity of 99%, and good industrial application prospect.
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Paragraph 0020; 0029-0030
(2020/05/11)
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- Z -isomerization of retinoids through combination of monochromatic photoisomerization and metal catalysis
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Catalytic Z-isomerization of retinoids to their thermodynamically less stable Z-isomer remains a challenge. In this report, we present a photochemical approach for the catalytic Z-isomerization of retinoids using monochromatic wavelength UV irradiation treatment. We have developed a straightforward approach for the synthesis of Z-retinoids in high yield, overcoming common obstacles normally associated with their synthesis. Calculations based on density functional theory (DFT) have allowed us to correlate the experimentally observed Z-isomer distribution of retinoids with the energies of chemically important intermediates, which include ground- and excited-state potential energy surfaces. We also demonstrate the application of the current method by synthesizing gram-scale quantities of 9-cis-retinyl acetate 9Z-a. Operational simplicity and gram-scale ability make this chemistry a very practical solution to the problem of Z-isomer retinoid synthesis.
- Kahremany, Shirin,Sander, Christopher Lane,Tochtrop, Gregory P.,Kubas, Adam,Palczewski, Krzysztof
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supporting information
p. 8125 - 8139
(2019/09/19)
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- Catalytic synthesis of 9-cis-retinoids: Mechanistic insights
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The regioselective Z-isomerization of thermodynamically stable all-trans retinoids remains challenging, and ultimately limits the availability of much needed therapeutics for the treatment of human diseases. We present here a novel, straightforward approach for the catalytic Z-isomerization of retinoids using conventional heat treatment or microwave irradiation. A screen of 20 transition metal-based catalysts identified an optimal approach for the regioselective production of Z-retinoids. The most effective catalytic system was comprised of a palladium complex with labile ligands. Several mechanistic studies, including isotopic H/D exchange and state-of-the-art quantum chemical calculations using coupled cluster methods indicate that the isomerization is initiated by catalyst dimerization followed by the formation of a cyclic, six-membered chloropalladate catalyst-substrate adduct, which eventually opens to produce the desired Z-isomer. The synthetic development described here, combined with thorough mechanistic analysis of the underlying chemistry, highlights the use of readily available transition metal-based catalysts in straightforward formats for gram-scale drug synthesis.
- Kahremany, Shirin,Kubas, Adam,Tochtrop, Gregory P.,Palczewski, Krzysztof
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supporting information
p. 10581 - 10595
(2019/07/22)
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- Preparation process of vitamin A intermediate and vitamin A acetate
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The invention discloses a preparation process of a vitamin A intermediate. Compared with a traditional Kuraray synthesis route, the preparation process directly carries out halogenation reaction on analcohol metal intermediate without hydrolysis in an anhydrous and oxygen-free environment, not only reduces one-step chemical reaction and shortens working procedures, but also reduces the use of reagents and solvents, at the same time also improves the utilization rate of metallization reagents, greatly reduces pollution, and improves safety and economic benefits. The invention also provides a preparation method of vitamin A acetate based on the vitamin A intermediate, and the obtained vitamin A acetate has higher purity and is easy to store.
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- MULTILAYERED EMULSION FILM AND METHOD FOR PREPARING THE SAME
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Multilayer thin emulsion films are disclosed. Also disclosed are methods for preparing the multilayer thin emulsion films. According to the methods, an amphiphilic block polymer is used as a surfactant to form a polymer thin film at the oil/water interface, ionic lecithin is used as an auxiliary surfactant to prepare physically stable ionic oil-in-water nanoemulsions, and a layer-by-layer assembly technique is used to alternately laminate polymer thin films and nanoemulsion layers. The multilayer thin emulsion films enable slow release of active substances in specific temperature ranges and are structurally biocompatible while possessing improved capture efficiency and physically stable membrane structures. Spinodal decomposition of the multilayer thin emulsion films is induced by heating, allowing release of oils and active substances loaded into the nanoemulsions. Therefore, the multilayer thin emulsion films are expected to be useful as smart drug release materials in a variety of applications, including cosmetics, pharmaceuticals, and biotherapy.
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- COSMETIC COMPOSTION COMRPISING ACTIVE INGREDIENT PRECURSOR AND ENZYME FOR MAINTAIN CONSTANTLY CONCENTRATION OF SKIN ACTIVE SUBSTANCE
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PURPOSE: A cosmetic composition containing enzyme and precursor with an activity at low temperature is provided to promoter skin cell activation and to improve anti-wrinkling and elasticity. CONSTITUTION: A cosmetic composition contains an enzyme with an activity at 0°C-15°C and at least one precursor which produces an active ingredient by reaction with the enzyme. The enzyme is hydrolase such as lipase, choline esterase, phosphatase, dioxyribonuclease, carboxypeptidase, pepsin, trypsin, or chemotrypsin. The precursor is retinyl palmitate, tocopheryl acetate, or piceid. The cosmetic composition is used for anti-aging, skin moisturizing, or skin whitening. The active ingredient is retinol, tocopherol, or resveratrol.
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Paragraph 0039-0041
(2018/05/24)
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- Preparation method of vitamin A palmitate
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The invention belongs to the technical field of medicines, in particular to preparation of vitamin A palmitate and a composition thereof. Aiming at solving the technical problem, the invention provides a preparation method of vitamin A palmitate. The preparation method comprises the steps of carrying out alcoholysis on vitamin A acetate with an alcohol solvent to obtain retinol, and then adding methyl palmitate for alcoholysis again to obtain vitamin A palmitate. The preparation method is simple in process, is environmentally friendly, and has high purity and high yield.
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Paragraph 0017-0028
(2018/10/27)
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- METHOD FOR SYNTHESIS OF 9-CIS-BETA-CAROTENE AND FORMULATIONS THEREOF
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The present invention relates to a method for total chemical synthesis of 9-cis-β-carotene (9CBC), and further provides stable formulations thereof.
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- Dietary Supplement Containing Vitamin A, D3 and Vitamin K2 and Uses Thereof
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A composition comprising vitamin A, vitamin D and vitamin K2 (K2-MK-7) is provided. Advantageously, vitamin A is present in an amount of 1,000 IU to 10,000 IU, vitamin D is present in an amount of 400 IU to 10,000 IU and vitamin K2 is present in an amount of 45 μg to 1,000 μg. In one advantageous form, vitamin A is retinol or an ester form thereof a method for limiting the accumulation of calcium and a method for limiting the occurrence of cardiovascular disease or events is provided by administering an effective amount of the present composition.
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- Rabbit 3-hydroxyhexobarbital dehydrogenase is a NADPH-preferring reductase with broad substrate specificity for ketosteroids, prostaglandin D2, and other endogenous and xenobiotic carbonyl compounds
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3-Hydroxyhexobarbital dehydrogenase (3HBD) catalyzes NAD(P) +-linked oxidation of 3-hydroxyhexobarbital into 3-oxohexobarbital. The enzyme has been thought to act as a dehydrogenase for xenobiotic alcohols and some hydroxysteroids, but its physiological function remains unknown. We have purified rabbit 3HBD, isolated its cDNA, and examined its specificity for coenzymes and substrates, reaction directionality and tissue distribution. 3HBD is a member (AKR1C29) of the aldo-keto reductase (AKR) superfamily, and exhibited high preference for NADP(H) over NAD(H) at a physiological pH of 7.4. In the NADPH-linked reduction, 3HBD showed broad substrate specificity for a variety of quinones, ketones and aldehydes, including 3-, 17- and 20-ketosteroids and prostaglandin D2, which were converted to 3α-, 17β- and 20α-hydroxysteroids and 9α,11β- prostaglandin F2, respectively. Especially, α-diketones (such as isatin and diacetyl) and lipid peroxidation-derived aldehydes (such as 4-oxo- and 4-hydroxy-2-nonenals) were excellent substrates showing low Km values (0.1-5.9 μM). In 3HBD-overexpressed cells, 3-oxohexobarbital and 5β-androstan-3α-ol-17-one were metabolized into 3-hydroxyhexobarbital and 5β-androstane-3α,17β-diol, respectively, but the reverse reactions did not proceed. The overexpression of the enzyme in the cells decreased the cytotoxicity of 4-oxo-2-nonenal. The mRNA for 3HBD was ubiquitously expressed in rabbit tissues. The results suggest that 3HBD is an NADPH-preferring reductase, and plays roles in the metabolisms of steroids, prostaglandin D2, carbohydrates and xenobiotics, as well as a defense system, protecting against reactive carbonyl compounds.
- Endo, Satoshi,Matsunaga, Toshiyuki,Matsumoto, Atsuko,Arai, Yuki,Ohno, Satoshi,El-Kabbani, Ossama,Tajima, Kazuo,Bunai, Yasuo,Yamano, Shigeru,Hara, Akira,Kitade, Yukio
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p. 1366 - 1375
(2013/11/19)
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- Substrate specificity and subcellular localization of the aldehyde-Alcohol redox-Coupling reaction in carp cones
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Our previous study suggested the presence of a novel conespecific redox reaction that generates 11-cis-retinal from 11-cisretinol in the carp retina. This reaction is unique in that 1) both 11-cis-retinol and all-trans-retinal were required to produce 11-cis-retinal; 2) together with 11-cis-retinal, all-trans-retinol was produced at a 1:1 ratio; and 3) the addition of enzyme cofactors such as NADP(H) was not necessary. This reaction is probably part of the reactions in a cone-specific retinoid cycle required for cone visual pigment regeneration with the use of 11-cis-retinol supplied from Mueller cells. In this study, using purified carp cone membrane preparations, we first confirmed that the reaction is a redox-coupling reaction between retinals and retinols. We further examined the substrate specificity, reaction mechanism, and subcellular localization of this reaction. Oxidation was specific for 11-cis-retinol and 9-cis-retinol. In contrast, reduction showed low specificity: many aldehydes, including all-trans-, 9-cis-, 11-cis-, and 13-cis-retinals and even benzaldehyde, supported the reaction. On the basis of kinetic studies of this reaction (aldehyde-alcohol redox-coupling reaction), we found that formation of a ternary complex of a retinol, an aldehyde, and a postulated enzyme seemed to be necessary, which suggested the presence of both the retinol- and aldehydebinding sites in this enzyme. A subcellular fractionation study showed that the activity is present almost exclusively in the cone inner segment. These results suggest the presence of an effective production mechanism of 11-cis-retinal in the cone inner segment to regenerate visual pigment.
- Sato, Shinya,Fukagawa, Takashi,Tachibanaki, Shuji,Yamano, Yumiko,Wada, Akimori,Kawamura, Satoru
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p. 36589 - 36597
(2014/01/17)
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- Synthesis of dienyl ketones via palladium(II)-catalyzed direct cross-coupling reactions between simple alkenes and vinyl ketones: Application to the synthesis of vitamin a1 and bornelone
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An efficient and general method for the synthesis of conjugated dienyl ketones via palladium(II) acetate catalyzed direct cross-coupling between simple alkenes and vinyl ketones is reported. This method has been successfully applied for the synthesis of V
- Zhang, Xiang,Wang, Min,Zhang, Ming-Xin,Xu, Yun-He,Loh, Teck-Peng
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p. 5531 - 5533
(2013/11/19)
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- Cross-coupling reactions of organosilicon compounds in the stereocontrolled synthesis of retinoids
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This paper presents a full account of the use of Hiyama cross-coupling reactions in a highly convergent approach to retinoids in which the key step is construction of the central C10-C11 bond. Representatives of two families of oxygen-activated dienyl silanes (ethoxysilanes and silanols) and of all reported families of "safety-catch" silanols (siletanes, silyl hydrides, allyl-, benzyl-, aryl-, 2-pyridyl- and 2-thienylsilanes) were regio- and stereoselectively prepared and stereospecifically coupled to an appropriate electrophile by treatment with a palladium catalyst and a nucleophilic activator. Both all-trans and 11-cis-retinoids, and their chain-demethylated analogues, were obtained in good yields regardless of the geometry (E/Z) and of the steric congestion in each fragment. This comprehensive study conclusively establishes the Hiyama cross-coupling reaction, with its mild reaction conditions and stable, easily prepared, ecologically advantageous silicon-based coupling partners, as the most effective route to retinoids reported to date.
- Bergueiro, Julian,Montenegro, Javier,Cambeiro, Fermin,Saa, Carlos,Lopez, Susana
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supporting information; experimental part
p. 4401 - 4410
(2012/06/01)
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- Synthesis of 11-cis-retinoids by hydrosilylation-protodesilylation of an 11,12-didehydro precursor: Easy access to 11- and 12-mono- and 11,12-dideuteroretinoids
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An expeditious, highly efficient approach to 11-cis-retinoids was achieved by semihydrogenation of a readily available 11-yne precursor through a hydrosilylation-protodesilylation protocol. The complete chemo-, regio-, and syn-stereoselectivity of the method also allowed direct access to 11- and 12-monodeutero-, and 11,12-dideutero-11-cis-retinoids. The analogous trans series was not accessible by this route, and was synthesized by means of Hiyama coupling. Copyright
- Bergueiro, Julián,Montenegro, Javier,Saá, Carlos,López, Susana
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supporting information
p. 14100 - 14107
(2013/01/15)
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- Laser flash photolysis study on the retinol radical cation in polar solvents
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Laser flash photolysis (LFP) of retinol in argon-saturated methanol gives rise to a transient at 580 nm (transient A). Formation of transient A is accompanied by a transient growth at 370 nm. The rate of this growth is retinol concentration-dependent. The transient growth at 370 nm was removed in the presence of N2O, which is known to scavenge solvated electrons. These results can be interpreted by formation of retinol+ (λmax = 580 nm) and solvated electrons following LFP of retinol. Subsequently, the solvated electrons are rapidly scavenged by retinol to form retinol- (λmax = 370 nm in methanol). On the other hand, transient A is not ascribed to the retinyl cation, as was previously proposed, because the retinyl cation, generated from LFP of retinyl acetate, and transient A show different reactivities towards halide ions (e.g. kBr = 1.7 × 109 and 1.51 × 1010 M-1 s-1 respectively, in acetonitrile). After demonstrating the identity of transient A as retinol+, its reactions with carotenoids were examined in air-saturated polar solvents. In the presence of carotenoids, an enhancement in the decay of retinol+ was observed and was accompanied by formation of the corresponding carotenoid radical cations via electron transfer from carotenoids to retinol+. Furthermore, the reactivity of retinol+ towards pyridine derivatives was investigated in air-saturated polar solvents. It was found that the decay of retinol + was accelerated with concomitant formation, with the same rate, of a transient at 370 nm. Similar observations were obtained with increasing pH of air-saturated aqueous 2% Triton X-100 of retinol+. The 370 nm (or 380 nm in the case of Triton X-100) transient is attributed to the base adducts or deprotonated neutral radicals. On the basis of these results, the reactivities of the retinyl cation and retinol+ are compared and the consequences of retinol+ formation within biological environments are discussed.
- El-Agamey, Ali,Fukuzumi, Shunichi
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scheme or table
p. 6437 - 6446
(2011/10/10)
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- Syntheses of 13C2-labelled 11Z-retinals
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To enable solid-state NMR investigations of the rhodopsin chromophore and its photointermediates, a series of 11Z-retinal isotopomers have been synthesised containing pairs of adjacent 13C labels at C9/C10, C10/C11 or C11/C12, respectively. The C9 labelled carbon atom was introduced through the Heck reaction of a 13C-labelled Weinreb acrylamide derivative, and the label at the C12 position derived from a 13C-containing ethoxy Bestmann-Ohira reagent. The 13C labels at C10 and C11 were introduced through the reaction of β-ionone with labelled triethyl phosphonoacetate.
- McLean, Neville J.,Gansmuller, Axel,Concistre, Maria,Brown, Lynda J.,Levitt, Malcom H.,Brown, Richard C.D.
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p. 8404 - 8410
(2011/11/12)
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- RETINITIS PIGMENTOSA TREATMENT AND PROPHALAXIS
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The invention relates to a method of instilling insulin ophthalmic drops in the conjunctival sac for treating retinitis pigmentosa due to any etiological factors both genetic and non genetic. The retinitis pigmentosa is treated with Insulin and/or IGF-I with or without known anti-retinitis pigmentosa therapeutic, pharmaceutical, biochemical, and biological agents or compounds. The invention furthermore uses this method as prophylactic on patients where the patients are predisposed to develop retinitis pigmentosa. The invention additionally treats other oculopathies associated with and/or contributing to retinitis pigmentosa.
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- Synthesis of C40-symmetrical fully conjugated carotenoids by olefin metathesis
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In an effort to push olefin metathesis to the limits of conjugation in reactants and products, the C40-symmetrical carotenoids β,β-carotene (1), lycopene (2), (3R,3′R)-zeaxanthin (3), and rac-isozeaxanthin (4), which are conjugated undecaenes, have been synthesized from C21-terminal hexaenes by treatment with Grubbs' second-generation Ru catalyst in dichloromethane at 50 °C.
- Fontan, Noelia,Dominguez, Marta,Ulvarez, Rosana,De Lera, Ungel R.
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scheme or table
p. 6704 - 6712
(2012/01/03)
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- Broad-spectrum antiviral activity including human immunodeficiency and hepatitis C viruses mediated by a novel retinoid thiosemicarbazone derivative
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Aromatic aldehyde-derived thiosemicarbazones 4-6, the S-substituted modified thiosemicarbazones 7/8, and a vitamin A-derived (retinoid) thiosemicarbazone derivative 12 were investigated as inhibitors of human hepatitis C virus (HCV) subgenomic RNA replicon Huh7 ET (luc-ubi-neo/ET) replication. Compounds 4-6 and 12 were found to be potent suppressors of HCV RNA replicon replication. The trifluoromethoxy-substituted thiosemicarbazone 6 and the retinoid thiosemicarbazone derivative 12 were even superior in selectivity to the included reference agent recombinant human alpha-interferon-2b, showing potencies in the nanomolar range of concentration. In addition, compounds 5, 6, 8 and 12 were tested as inhibitors of cytopathic effect (CPE) induced by human varicella-zoster virus (VZV) and/or human cytomegalovirus (HCMV). Compounds 4-6, 8 and 12 were additionally examined as inhibitors of CPE induced by cowpox virus and vaccinia virus. Thiosemicarbazone 4 was inhibitory on cowpox and vaccinia virus replication comparable in potency and selectivity to the reference agent cidofovir. Retinoid thiosemicarbazone derivative 12 was active as micromolar inhibitor of VZV, HCMV, and, in addition, human immunodeficiency virus type 1 (HIV-1) replication. These results indicate that thiosemicarbazone derivatives are appropriate lead structures to be evaluated in targeted antiviral therapies for hepatitis C (STAT-C), and that the vitamin A-related thiosemicarbazone derivative 12 emerges as a broad-spectrum antiviral agent, co-suppressing the multiplication of important RNA and DNA viruses.
- Kesel, Andreas J.
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experimental part
p. 1656 - 1664
(2011/05/06)
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- Efficient, low-cost synthesis of retinal (Vitamin A aldehyde)
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Inexpensive retinyl acetate has been subjected to transesterification followed by allylic oxidation to give retinal in 98% yield as a 92:8 mixture of all-trans/13-cis isomers after chromatographic separation. More convenient methods of isolating the all-trans isomer have also been employed. Georg Thieme Verlag Stuttgart ? New York.
- Hruszkewycz, Damian P.,Cavanaugh, Kathryn R.,Takamura, Kathryn T.,Wayman, Lora M.,Curley Jr., Robert W.
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experimental part
p. 2205 - 2207
(2011/09/14)
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- Properties and tissue distribution of a novel aldo-keto reductase encoding in a rat gene (Akr1b10)
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A recent rat genomic sequencing predicts a gene Akr1b10 that encodes a protein with 83% sequence similarity to human aldo-keto reductase (AKR) 1B10. In this study, we isolated the cDNA for the rat AKR1B10 (R1B10) from rat brain, and examined the enzymatic properties of the recombinant protein. R1B10 utilized NADPH as the preferable coenzyme, and reduced various aldehydes (including cytotoxic 4-hydroxy-2-hexenal and 4-hydroxy- and 4-oxo-2-nonenals) and α-dicarbonyl compounds (such as methylglyoxal and 3-deoxyglucosone), showing low Km values of 0.8-6.1μM and 3.7-67μM, respectively. The enzyme also reduced glyceraldehyde and tetroses (Km=96-390μM), although hexoses and pentoses were inactive and poor substrates, respectively. Among the substrates, 4-oxo-2-nonenal was most efficiently reduced into 4-oxo-2-nonenol, and its cytotoxicity against bovine endothelial cells was decreased by the overexpression of R1B10. R1B10 showed low sensitivity to aldose reductase inhibitors, and was activated to approximately two folds by valproic acid, and alicyclic and aromatic carboxylic acids. The mRNA for R1B10 was expressed highly in rat brain and heart, and at low levels in other rat tissues and skin fibroblasts. The results suggest that R1B10 functions as a defense system against oxidative stress and glycation in rat tissues.
- Endo, Satoshi,Matsunaga, Toshiyuki,Kuragano, Tsukasa,Ohno, Satoshi,Kitade, Yukio,Tajima, Kazuo,El-Kabbani, Ossama,Hara, Akira
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experimental part
p. 230 - 237
(2011/10/30)
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- Retinylisoflavonoid as a novel membrane antioxidant
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We report a novel molecular dyad as an antioxidant, retinylisoflavonoid, with a retinal analogue C22-aldehyde and the isoflavonoid daidzein covalently linked. Its physicochemical properties, pKa (pK a1 = 8.45, pKa2 = 11.42), oxidation potential (1.03 V vs NHE), and Log10 partition (Log P = 1.96), as well as the Trolox equivalent antioxidant capacity (TEAC = 0.4), have been characterized. Spectroscopic and quantum chemical investigations have revealed the following unique structural characters: (i) Either free in solution or included in liposomal membranes, the C22-aldehyde moiety of retinylisoflavonoid is coplanar with the B-ring of daidzein owing to the strong intramolecular hydrogen bonding C 14-=O···HO-B4′. Accordingly, the C 22-aldehyde moiety extends its π-conjugation significantly to the B-ring. (ii) The inherent amphiphilicity of retinylisoflavonoid allows the C22-aldehyde moiety embedded in the lipid phase of the liposomes, whereas the daidzein counterpart stays at the membrane surface, in effect facilitating interior-to-surface radical communication. As the result, the antilipooxidation activity of retinylisoflavonoid is improved significantly in protecting membrane lipids compared to the parent compounds alone or in combination, and importantly, the performance is more prominent under higher-level oxidative stress. This work provides an advanced case study of new antioxidant development based on optimized electronic and molecular structures.
- An, Cun-Bin,Liang, Ran,Ma, Xiao-Hua,Fu, Li-Min,Zhang, Jian-Ping,Wang, Peng,Han, Rui-Min,Ai, Xi-Cheng,Skibsted, Leif H.
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experimental part
p. 13904 - 13910
(2011/03/16)
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- Hiyama cross-coupling reaction in the stereospecific synthesis of retinoids
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The first application of the Hiyama reaction to the synthesis of retinoids is reported. A range of organosilicon moieties (siloxanes, silanols and three kinds of "safety-catch" silanols) were successfully coupled, under activation, to obtain trans-retinol or 11-cis-retinol with high yield and stereoselectivity. The advantageous properties of the silicon-based coupling partners and the mild reaction conditions firmly establish the Hiyama reaction as a viable (even superior) alternative to the traditional Suzuki and Stille couplings in the retinoid field.
- Montenegro, Javier,Bergueiro, Julian,Saa, Carlos,Lopez, Susana
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body text
p. 141 - 144
(2009/07/04)
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- Preparation of retinyl esters
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Long-chain esters of retinol are prepared via a chemoenzymatic process from short-chain retinyl esters and an appropriate long-chain acid or ester in the presence of an enzyme. Use of various additives enhance the yield of the desired ester and facilitated its purification.
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Page/Page column 13
(2009/08/14)
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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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Page/Page column 2; 23; Sheet 6/24
(2008/12/08)
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- COMPOSITIONS AND METHODS FOR TREATMENT OF OPHTHALMIC DISEASES AND DISORDERS
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Provided herein are compositions and methods for treating ophthalmic diseases and disorders. Compositions comprising retinylamine derivative compounds provided herein are useful for treating and preventing ophthalmic diseases and disorders, including diabetic retinopathy diabetic maculopathy, diabetic macular edema, retinal ischemia, ischemia-reperfusion related retinal injury, and metabolic optic neuropathy.
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Page/Page column 62
(2008/06/13)
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- METHODS FOR TREATMENT OF RETINAL DEGENERATIVE DISEASE
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A method is provided for treating a degenerative disease in a vertebrate eye. A method is further provided for preventing photoreceptor degeneration in a vertebrate eye.
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Page/Page column 34-35
(2008/06/13)
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- Accurate measurements of 13C-13C J-couplings in the rhodopsin chromophore by double-quantum solid-state NMR spectroscopy
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A new double-quantum solid-state NMR pulse sequence is presented and used to measure one-bond 13C-13C J-couplings in a set of 13C2-labeled rhodopsin isotopomers. The measured J-couplings reveal a perturbation of the electronic structure at the terminus of the conjugated chain but show no evidence for protein-induced electronic perturbation near the C11-C12 isomerization site. This work establishes NMR methodology for measuring accurate 1JCC values in noncrystalline macromolecules and shows that the measured J-couplings may reveal local electronic perturbations of mechanistic significance. Copyright
- Lai, Wai Cheu,McLean, Neville,Gansmueller, Axel,Verhoeven, Michiel A.,Antonioli, Gian Carlo,Carravetta, Marina,Duma, Luminita,Bovee-Geurts, Petra H. M.,Johannessen, Ole G.,De Groot, Huub J. M.,Lugtenburg, Johan,Emsley, Lyndon,Brown, Steven P.,Brown, Richard C. D.,DeGrip, Willem J.,Levitt, Malcolm H.
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p. 3878 - 3879
(2007/10/03)
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- Amphiphile cyclodextrins, preparation and use thereof for solubilizing organized systems and incorporating hydrophobic molecules
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The invention provides cyclodextrin derivatives that may be used to transport hydrophobic molecules for pharmaceutical or cosmetic applications, by forming organised systems in an aqueous medium, alone or with phospholipids. The cyclodextrin derivatives of the present invention have the formula: in which, R1 represents a steroid, R2 represents an alkyl or aryl group, substituted if applicable, R3 represents H or R2, all the R4 represent OR2, or one of the R4 represents —NHCO(CH2)mCONHR1, m is an integer ranging from 1 to 8, and n is equal to 5, 6 or 7.
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- Bioprecursors for percutaneous application
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The invention concerns a bioprecursor of formula (I), wherein A1 and A2 represent independently of each other a radical derived from a molecule capable of being used in dermatology or in cosmetology; X and Y represent independently of each other a hydrogen atom, a hydroxy group or a C1-C20 alkyl group; and n represents an integer between 0 and 10.
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- Highly Efficient and General Synthetic Method of Various Retinyl Ethers
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Bromination of 4 by PBr3 under Cu(I) catalyst produces the ambidextrous allylic halide 5 regioselectively and stereoselectively. Hetero nucleophiles distinguish the allylic carbon containing Br from the one containing Cl in 5 to give the heteroatom-substituted C5 allylic chloride 3. The Julia olefination reaction with the C15 sulfone 2 provides diverse retinyl ethers 1.
- Lee, Jun Sup,Jeong, Young Cheol,Ji, Minkoo,Baik, Woonphil,Lee, Sijoon,Koo, Sangho
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p. 1937 - 1940
(2007/10/03)
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- Anti-aging nutritional supplement
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An anti-aging nutritional supplement composition includes vitamins, minerals, an inflammatory process support, a blood sugar/insulin support, a botanical antioxidants, a methylating factor, a DNA repair agent, a fat metabolizer, an absorption enhancer, a brain function support, whole foods, a cellular energizer, a nucleotide precursor, amino acids, a fatty acid complex, and digestive enzymes. The composition supplies nutritional supplements necessary for proper glycation, DNA methylation, anti-oxidation, and control of inflammatory processes. The composition and the method of use provide an effective anti-aging treatment by decreasing DNA damage, increasing DNA repair, and improving immune function of human body.
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- Nutritional supplement
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A nutritional supplement is provided that is designed to provide nutritional benefits as well as to assist the body with detoxification. By providing a supplement that serves both of these functions, the present invention may enable persons to improve their overall wellness.
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- Vitamin and zinc monomethionine compositions
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A dietary supplement composition that contains zinc monomethionine in combination with vitamin A, vitamin C, vitamin D, and a bioflavonoid that is formulated to be optimally absorbed and to help maintain normal human system functions.
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- Process for the preparation of vitamin a, intermediates, and process for the preparation of the intermediates
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There are provided a dihalogen derivative represented by formula (2): wherein X represents a halogen atom and R2represents a protective group for a hydroxyl group; a process for producing the same; and a process for producing vitamin A by use of said dihalogen derivative.
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- Selective isomerization of retinal upon two-photon excitation
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The products of photo-isomerization when excited directly up to the two-photon-allowed 1Ag- excited state of alltrans and five cis isomers of retinal were determined. The composition of the isomers at the photo-stationary state was drastically changed as compared to one-photon excitation. The production of the 13-cis isomer was selectively increased, and the production of the dicis isomers was observed in the case of a direct excitation upon the 31Ag- state, although they were hard to be produced by one-photon excitation in n-hexane solution. These results clearly evidenced that there exist isomerization pathways via two-photon-allowed excited states.
- Sashima, Tokutake,Hashimoto, Hideki,Koshihara, Shin-ya
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p. 380 - 385
(2007/10/03)
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- Process for producing vitamin a ester
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The invention relates to a process for producing all trans-vitamin A ester (I). According to the present invention, vitamin A ester (I) can simply be synthesized in good yields and high purity by the reaction of phosphonate compound (IV) with aldehyde (II) in an organic solvent in the presence of a base.
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- Process for producing retinol and intermediate compounds for producing the same
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There are disclosed a disulfone compound of formula (1): wherein Ar denotes an aryl group that may have a substituent, R1 denotes a hydrogen atom or a protective group of a hydroxyl group and the wavy line means that the disulfone compound is an E or Z geometrical isomer or a mixture thereof, a method for producing the same, intermediate compounds therefore and a process for producing retinol through the disulfone compound.
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- Vitamin a related compounds and process for producing the same
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There is provided a compound of the formula[I]: wherein R represents a hydrogen atom or a protective group for a hydroxyl group; andA represents a hydrogen atom, a halogen atom or a group of the formula A1: Q represents Q3: when A represents a halogen atom or a protective group for a hydroyl group, A represents Q4: ?wherein R1 and R2 represent a hydrogen atom or a protective group for a hydroxyl group; and when A represents a hydrogen atom, Q is Q2:
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Page column 12-13
(2010/01/30)
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- A novel, selective, and efficient route to carotenoids and related natural products via Zr-catalyzed carboalumination and Pd- and Zn-catalyzed cross coupling.
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[structure: see text]. A highly efficient and stereoselective protocol for the syntheses of symmetrical and unsymmetrical carotenoids involving Zr-catalyzed carboalumination of conjugated oligoenynes and Pd- and Zn-catalyzed alkenyl-alkenyl coupling has been developed and applied to the syntheses of beta- and gamma-carotene and vitamin A. gamma-Carotene of > or =99% isomeric purity was prepared in three linear steps (five steps overall) from beta-ionone, enyne 8, (E)-ICH=CHBr, and (E)-Me3SiC triple bond CCH=CHBr in 32% overall yield.
- Zeng,Negishi
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p. 719 - 722
(2007/10/03)
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- Dihalo-compound and process for producing vitamin A derivative
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There is disclosed a dihalo-compound of formula (1): wherein X1 and X2 represent different halogen atoms, R represents a hydrogen atom or a protective group for a hydroxyl group, and a process for producing vitamin A derivative via a sulfone derivative of formula (5): wherein Ar represents an optionally substituted aryl group, and R represents the same as defined above.
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