- 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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- 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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- 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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- 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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- 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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- 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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- 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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- Stereocontrolled synthesis of acyclic terpenoids via N-ylide [2,3]rearrangement of ammonium salts with the stereodefined isoprene unit
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Stereocontrolled elongation of a functionalized isoprene unit on the E or Z terminal methyl of terpenoids was achieved by N-ylide rearrangement of the common ammonium salts under selected reaction conditions. A 1,5-diene or conjugated triene skeleton can be furnished by reductive or oxidative removal of the amino group of the rearrangement product, respectively. As an application to natural-product synthesis, all-(E)-terpenoid (E)-11d and (E,Z)-terpenoid (Z)-11c were converted into β-sinensal and (13Z)-retinol, respectively. General aspects of these transformations and a plausible transition state for the N-ylide rearrangement are discussed.
- Honda, Kiyoshi,Tabuchi, Masayuki,Kurokawa, Hiroki,Asami, Masatoshi,Inoue, Seiichi
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p. 1387 - 1396
(2007/10/03)
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- A pericyclic cascade to the stereocontrolled synthesis of 9-cis- retinoids
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A domino reaction that is pericyclic in nature is thought to be triggered upon treatment of alkenynol 10 with arylsulfenyl chlorides. The process comprises an ordered sequence of sigmatropic rearrangements: a reversible [2,3]-allyl sulfenate to allyl sulfoxide shift, followed by a [2,3]-propargyl sulfenate to allenyl sulfoxide rearrangement, and last a stereodifferentiating [1,5]-sigmatropic hydrogen migration leading to polyene 13. The occurrence of the C7 to C11 hydrogen migration has been demonstrated by labeling experiments. The double diastereoselection of the [1,5]- sigmatropic hydrogen shift to afford a single isomer of the final polyene 13 is thought to arise from a combination of the electronic effect of the sulfoxide at one terminus, and the steric effect imparted by the bulky trimethylcyclohexenyl substituent at the other terminus. The overall process thus constitutes a stereoselective synthesis of an E,Z,Z-triene fragment from an alkenynol and, in particular, a retinoid with the 7E,9Z,11Z,13E configuration on the conjugated polyenic side chain. Application of this method to the synthesis of retinoids, including labeled analogues, is straightforward.
- Iglesias, Beatriz,Torrado, Alicia,De Lera, Angel R.,Lopez, Susana
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p. 2696 - 2705
(2007/10/03)
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- Highly Z selective synthesis of functionalized monoterpenoids via N-ylide [2,3]sigmatropic rearrangement and its application to 13-cis-retinol
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Highly stereoselective elongation of a functionalized E isoprene unit on the Z terminal methyl of prenol was achieved by the N-ylide rearrangement of N-tiglyl-β-methallyldimethyl-ammonium salt. (E,Z)-Rearrangement product was converted into 13-cis-retinol via useful conjugated triene isoprenoid synthon.
- Honda, Kiyoshi,Yoshii, Ichiro,Inoue, Seiichi
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p. 671 - 672
(2007/10/03)
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- Process for the synthesis of vitamin A and certain ones of derivatives
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According to this process, one effects a stereospecific reduction of the two hydroxyl groups of an ether-diol by a mixture (titanium trichloride, lithium aluminum hydride) at a temperature between 5° C. and about 40° C. and that optionally, one converts the resulting ether into vitamin A, retinol or retinoic acid.Application to the synthesis of all-trans compounds selected from the group consisting of vitamin A and its ethers, retinol and retinoic acid, and their 13-cis isomers.
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- Base-catalyzed isomerization of retinoic acid. Synthesis and differentiation-inducing activities of 14-alkylated all-trans-, 13-cis-, and 20,14-retro-retinoic acids
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Retinoic acid (1) is isomerized regioselectively by excess amounts of lithium diisopropylamide (LDA) to give 20,14-retro-retinoic acid (3). Alkylation of the intermediate dianion of retinoic acid gave 14-alkylated derivatives of 3. By isomerization of the alkylated retro isomers under basic conditions, several 14-alkyl-all-trans- and -13-cis-retinoic acids were synthesized. The retinoidal activities of these derivatives were examined, based on the ability to induce differentiation of human promyelocytic leukemia cell line HL-60. 20,14-retro-Retinoic acid (3) is 1/50 as active as retinoic acid (1). Although 14-methyl-20,14-retro-retinoic acid (4) is as active as 3, the introduction of a 14-methyl group into all-trans- and 13- cis-retinoic acid resulted in decreased activity. Introduction of bulkier alkyl groups at the C-14 position caused the disappearance of the activity.
- Tanaka,Kagechika,Kawachi,Fukasawa,Hashimoto,Shudo
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p. 567 - 572
(2007/10/02)
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- Process for the preparation of vitamin A
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Vitamin A containing practically no 2-cis or 6-cis isomer is prepared by hydrogenation of the aldehyde of vitamin A, optionally in the form of a complex with hydroquinone, in the presence of a ruthenium hydride catalyst.
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- Synthesis of New Aromatic Retinoid Analogues by Low-Valent Titanium Induced Reductive Elimination
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The low-valent titanium reductive elimination reaction, already applied to the stereospecific synthesis of vitamin A and 13-cis-retinol, was used to prepare several retinoic acid analogues in the all-trans configuration or in the 13-cis configuration.This highly stereospecific trans-diene formation allowed an improved synthesis of the title compounds without any purification of the intermediates before the final stage.
- Solladie, Guy,Girardin, Andre,Lang, Gerard
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p. 2620 - 2628
(2007/10/02)
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- THE HIGHLY STEREOSELECTIVE SYNTHESIS OF ALL-TRANS AND 13-CIS VITAMIN A VIA DOUBLE ELIMINATION REACTION
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Stereocontrolled convergent synthesis of vitamin A was achieved by the double elimination method employing the C10 sulfone and the C10 aldehydes as starting materials.Thus the all-trans and 13-cis isomers were obtained with the stereochemical purity of 95percent and 90percent, respectively.
- Otera, Junzo,Misawa, Hiromitsu,Mandai, Tadakatsu,Onishi, Takashi,Suzuki, Shigeaki,Fujita, Yoshiji
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p. 1883 - 1886
(2007/10/02)
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- Transient Phenomena in the Pulse Radiolysis of Retinyl Polyenes. 1. Radical Anions
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The spectra and kinetics of formation and decay of radical anions of a number of retinyl polyenes have been studied in methanol and 2-propanol at room temperature, using pulse radiolysis and kinetic spectrophotometry.The bimolecular rate constants for the attachment of solvated electrons, e-MeOH, to the retinyl polyenes are in the diffusion-controlled limit (8.6 x 109-1.6 x 1010 M-1 s-1).The radical anions of retinol and retinol acetate have their spectral maxima at 370-390 nm, and undergo decay very slowly with second-order kinetics.On the other hand, the radical anions of retinal, retinal n-butylamine Schiff base, and retinoic acid/ester have spectral maxima at 430-510 nm, and decay by first-order kinetics in methanol with rate constants in the range 1 x 104-1 x 106 s-1.The decay rates of radical anions of retinal and retinoic acid/ester become considerably longer on going from methanol to less acidic alcohol, 2-propanol, suggesting that protonation by solvent is the major mode of their decay in protic media.In the case of retinal Schiff base, an additional slow process with bimolecular rate constant 9.0 x 107 M-1 s-1 im methanol is observed for the formation of radical anion and is ascribed to the electron-transfer reaction from the methanol radical, .CH2OH.
- Raghavan, N.V.,Das, P.K.,Bobrowski, K.
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p. 4569 - 4573
(2007/10/02)
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