- 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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Paragraph 0056-0057
(2017/12/29)
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- A cross-metathesis approach to the synthesis of new etretinate type retinoids, ethyl retinoate and its 9Z-isomer
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Two aromatic retinoids were synthesized from styrene derivatives using a novel strategy with a cross-metathesis reaction as a key step. The biological activity of the new etretinate analogues was tested. Cross-metathesis reactions were also employed for the preparation of ethyl retinoate and its 9Z-isomer via the C15 + C5 route.
- Maj, Jadwiga,Morzycki, Jacek W.,Rárová, Lucie,Wasilewski, Grzegorz,Wojtkielewicz, Agnieszka
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p. 5430 - 5433
(2012/11/07)
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- Caesium fluoride-promoted Stille coupling reaction: An efficient synthesis of 9Z-retinoic acid and its analogues using a practical building block
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A highly efficient and rapid total synthesis of 9Z-retinoic acid was accomplished by caesium fluoride-promoted Stille coupling reaction; using a common building block, 9Z-retinoic acid analogues were also prepared by the same method without isomerisation of the Z-double bond. The Royal Society of Chemistry 2008.
- Okitsu, Takashi,Iwatsuka, Kinya,Wada, Akimori
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supporting information; experimental part
p. 6330 - 6332
(2009/04/13)
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- Preparation and biological activity of 13-substituted retinoic acids
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13-Demethyl or 13-substituted all-E- and 9Z-retinoic acids were synthesized using a palladium-catalyzed coupling reaction of enol triflates and tributylstannylolefins. Their biological activities were then measured. The 13-ethyl analogs exhibited approximately one-half of the antiproliferative and differentiation-inducing activity of ATRA in HL-60 cells. In contrast, in the 9Z-derivatives, all analogs, except for the 13-butyl derivatives, showed apoptosis-inducing activity.
- Wada, Akimori,Fukunaga, Kouki,Ito, Masayoshi,Mizuguchi, Yukari,Nakagawa, Kimie,Okano, Toshio
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p. 3931 - 3942
(2007/10/03)
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- Stereocontrolled synthesis of 13-substituted retinoic acids by palladium-catalyzed coupling reaction of alkenyl stannane with vinyl triflate
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A novel method for the stereoselective synthesis of all-E-, 13Z- and 9Z- retionic acid esters was developed by palladium-catalyzed cross coupling reactions of tetraenyl stannanes with E- or Z-vinyl triflates in good yields. Applying this methodology, 13-substituted all-E- and 9Z- retinoic acids were prepared in satisfactory yields.
- Wada,Fukunaga,Ito
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p. 800 - 802
(2007/10/03)
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- The suzuki coupling reaction in the stereocontrolled synthesis of 9-cis-retinoic acid and its ring-demethylated analogues
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The thallium-accelerated Suzuki coupling reaction of tetraenyl iodide 19 and cyclohexenyl boronate 18 afforded ethyl 9-cis-retinoate (12) in high yield. Both coupling partners of the Suzuki reaction are better reacted immediately after generation from their precursors, tetraenylstannane 10 and cyclohexenyl iodide 13. The geometrically homogeneous tetraenylstannane 10, comprising the polyenic side chain of ethyl 9-cis-retinoate and its ring-demethylated analogues, was synthesized by a stereoselective Horner - Wadsworth - Emmons reaction. On the other hand, easily available cyclohexanones are ideal starting materials for preparation of the cyclohexenyl boronates required for the synthesis of the ring-modified 9-cis-retinoic acid analogues. For hindered cyclohexanones, hydrazones were converted to cyclohexenyl iodides. Iodine - lithium exchange and trapping with B(OMe)3 then afforded the cyclohexenyl boronates. If the precursor cyclohexanone has secondary carbons, the alkenyllithium species was conveniently formed by elimination of the C,N-dilithiated intermediate obtained upon treating the trisylhydrazone with n-BuLi (Shapiro reaction). None of the above procedures allowed the generation of the more substituted organolithium from 2-methylcyclohexanone. However, the alternative Stille cross-coupling of 34 and 10 afforded 9-cis-1,1-bisdemethylretinoic acid 7. Both Suzuki and Stille coupling reactions took place under mild conditions, and the preservation of the retinoid side-chain geometry was therefore secured.
- Pazos,Iglesias,De Lera
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p. 8483 - 8489
(2007/10/03)
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- Stereoselective synthesis of 9-cis-retinoic acid by Suzuki reaction
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The entire polyenic side chain of ethyl 9-cis-retinoate (7) has been stereoselectively synthesized and attached to the hydrophobic ring by a high-yielding thallium-accelerated Suzuki cross-coupling reaction. The Suzuki reaction partners, tetraenyl iodide 18 and alkenyl organoborane 19, are more conveniently used immediately after generation from their precursors. Alternative approaches using either the Stille reaction or a Suzuki reaction with a shorter polyenic component proved less efficient. The highly convergent sequence can be adapted to the preparation of analogs of 9-cis-retinoic acid (2), the natural ligand for the retinoid X (RXR) subfamily of nuclear receptors.
- Pazos, Yolanda,De Lera, Angel R.
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p. 8287 - 8290
(2007/10/03)
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- A Novel Method for a Stereoselective Synthesis of Trisubstituted Olefin Using Tricarbonyliron Complex: A Highly Stereoselective Synthesis of (all-E)- and (9Z)-Retinoic Acids
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In order to establish the stereoselective synthesis of retinoic acids, which are ligand molecules of the retinoic acid receptors (RARs, all-E-isomer) and the retinoid X receptors (RXRs, 9Z-isomer), the reaction of β-ionone-tricarbonyliron complex 7 with carbanions was investigated. Treatment of 7 with the lithium salt of acetonitrile afforded (7E,9E)-β-ionylideneacetonitrile-tricarbonyliron complex 8 exclusively, via addition, dehydration, and migration of tricarbonyliron complex. On the contrary, the reaction of 7 with the lithium enolate of ethyl acetate and subsequent dehydration by thionyl chloride afforded the ethyl (7E,9Z)-β-ionylideneacetate-tricarbonyliron complex 16b predominantly. These compounds (8 and 16b) were converted to the corresponding β-ionylidene-acetaldehyde-tricarbonyliron complexes (10 and 22) in excellent yields, respectively. The Emmons-Horner reaction of these compounds with C5-phosphonate followed by the sequence of decomplexation and alkaline hydrolysis gave the corresponding retinoic acids (26 and 29).
- Wada, Akimori,Hiraishi, Saeko,Takamura, Norio,Date, Tadamasa,Aoe, Keiichi,Ito, Masayoshi
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p. 4343 - 4348
(2007/10/03)
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- Syntheses of high specific activity 2,3- and 3,4-[3H]2-9-cis-retinoic acid
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9-cis-Retinoic acid (9-cis-RA) is an endogenous hormone which binds and activates the retinoic acid receptors (RARs) and the retinoic X receptors (RXRs). In order to investigate the function of 9-cis-RA in vitro and in vivo high specific activity labeled 9-cis-RA was prepared. Two tritium labels were efficiently introduced at the 2,3- or 3,4-positions, respectively, in the cyclohexene ring moiety resulting in labeled 9-cis-RA with specific activity of 58-60 Ci/mmol. The critical ring-labeling step relies on a highly regioselective tritiation of either a terminal or an isolated double bond in the presence of the conjugated retinoate side chain. Moreover, the labeling is performed at the penultimate synthetic step resulting in optimization of radiochemical yields and ease of synthesis. This is the first reported synthesis of ring-labeled [3H]2-9-cis-Ra, and the methodology described herein is applicable to the synthesis of other retinoic acid isomers.
- Bennani,Boehm
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p. 1195 - 1200
(2007/10/02)
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- Stereoselective synthesis of 7E,9E- and 7E,9Z-β-ionylidene-acetaldehydes by use of tricarbonyl iron complex
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Stereoselective synthesis of 7E,9E- and 7E,9Z-β-ionylideneacetaldehydes was accomplished from the β-ionone tricarbonyl iron complex, and the latter was converted to 9Z-retinoic acid.
- Wada,Hiraishi,Ito
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p. 757 - 759
(2007/10/02)
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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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