- Design, synthesis, and anti-tobacco mosaic virus (TMV) activity of phenanthroindolizidines and their analogues
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On the basis of our previous structure-activity relationship (SAR) and antiviral mechanism studies, a series of phenanthroindolizidines and their analogues 3-20 were designed, targeting tobacco mosaic virus (TMV) RNA, synthesized, and systematically evaluated for their antiviral activity against TMV. The bioassay results showed that most of these compounds displayed good anti-TMV activity, and some of them exhibited higher antiviral activity than that of commercial Ningnanmycin (perhaps the most successful registered antiplant viral agent). Especially, (S)-deoxytylophorinine (5) with excellent anti-TMV activity (inactivation activity, 59.8%/500 μg mL-1 and 40.3%/100 μg mL-1; curative activity, 65.1%/500 μg mL -1 and 43.7%/100 μg mL-1; and protection activity, 70.2%/500 μg mL-1 and 51.3%/100 μg mL-1) emerged as a potential inhibitor of the plant virus. Compound 20 exhibited a strong in vivo protection effect against TMV at 100 μg mL-1, which indicated that phenanthroindolizidine analogues with a seven-membered D ring have a new and interesting structural scaffold and have great potential for further development as tobacco protection agents.
- Wang, Ziwen,Wei, Peng,Wang, Lizhong,Wang, Qingmin
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- Design, synthesis and in-vitro biological evaluation of antofine and tylophorine prodrugs as hypoxia-targeted anticancer agents
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Phenanthroindolizidines, such as antofine and tylophorine, are a family of natural alkaloids isolated from different species of Asclepiadaceas. They are characterized by interesting biological activities, such as pronounced cytotoxicity against different human cancerous cell lines, including multidrug-resistant examples. Nonetheless, these derivatives are associated with severe neurotoxicity and loss of in vivo activity due to the highly lipophilic nature of the alkaloids. Here, we describe the development of highly polar prodrugs of antofine and tylophorine as hypoxia-targeted prodrugs. The developed quaternary ammonium salts of phenanthroindolizidines showed high chemical and metabolic stability and are predicted to have no penetration through the blood–brain barrier. The designed prodrugs displayed decreased cytotoxicity when tested under normoxic conditions. However, their cytotoxic activity considerably increased when tested under hypoxic conditions.
- Abdalla, Ashraf N.,Abdullah, Omeima,Chen, Linwei,Fischer, Peter M.,Guise, Chris P.,Liu, Yuxiu,Omran, Ziad,Patterson, Adam V.,Rauch, Cyril,Sindi, Ikhlas A.,Smaill, Jeff B.,Wang, Qingmin
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- Total synthesis of (R)-tylophorine by using an asymmetric hydrogenation of the allyl alcohol
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An efficient synthesis of naturally occurring (R)-tylophorine is described. The alkaloid was prepared in seven steps from a known phenanthryl aldehyde with an overall yield of 14.2%. Asymmetric hydrogenation of an allyl alcohol was employed as a key step for installing a stereogenic center with good enantioselectivity (77% ee), and the ee value of the ω-chloro alcohol was improved to 95% by recrystallization. After azidation and oxidation of the enantio-enriched ω-chloro alcohol to the precursor of the Schmidt reaction, the chirality transfer in the stereospecific 1,2-migration furnished the chiral carbon in the alkaloid. Finally, a one-pot deformylation/Pictet-Spengler cyclization completed the total synthesis of (R)-tylophorine.
- Li, Rui,Liu, Chun-Fang,Yu, Chun-Jiao,Gu, Peiming
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supporting information
p. 2170 - 2172
(2018/05/04)
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- Two optically pure isomers of NK007 and bactericidal applications
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The invention relates to two optically pure isomers of NK007 for short and applications in a bactericidal aspect. Compounds NK007-3 and NK007-4 have good bactericidal activity, can be used for treating plant bacteria diseases selected from fusarium wilt of cucumber, cercospora brown spot of peanut, apple ring spot, alternaria solani, puccinia polysora, rice bakanae disease, sclerotinia rot of colza, phytophthora capsici disease, wheat sharp eyespot, bipolaris maydis, watermelon anthracnose, potato late blight, rice sheath blight disease and cucumber gray mold.
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- Total Synthesis of Phenanthroindolizidine Alkaloids by Combining Iodoaminocyclization with Free Radical Cyclization
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A concise and modular synthesis of phenanthroindolizidine alkaloids was achieved by combining iodoaminocylization with a free radical cyclization approach. The route described allowed the preparation of (±)-tylophorine, (±)-antofine, and (±)-deoxypergularinine in six steps. When commercially available l-prolinol was used as a chiral building block, (S)-(+)-tylophorine was also synthesized in 49% yield and >99% ee over five linear steps.
- Liu, Gong-Qing,Reimann, Marcel,Opatz, Till
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p. 6142 - 6148
(2016/07/26)
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- Two NK007 optical pure isomers and synthesis and application thereof
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The invention relates to two optical pure isomers called NK007 for short, synthesis thereof and application thereof in the aspects of plant virus resistance and immunoregulatory activity. Compounds NK007-1 and NK007-2 have good anti-tobacco-mosaic-virus activity, and can be used for treating plant virus diseases. The compounds NK007-1 and NK007-2 have good immunoregulatory activity and can be used for preparing medicine treating rheumatic arthritis. The method for testing the immunoregulatory activity of the compounds can be used for screening novel arthritis medicine. Please see the chemical structural formulae of the compounds in the specifications.
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- Asymmetric Total Synthesis of Tylophorine through a Formal [2+2] Cycloaddition Followed by Migrative Ring Opening of a Cyclobutane
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The asymmetric total synthesis of phenanthroindolizidine alkaloid (-)-tylophorine was achieved by asymmetric transfer hydrogenation of a cyclic imine. The cyclic imine with a pendant phenanthrene core was synthesized by a TfOH-promoted domino ring-contraction/ring-opening sequence of a cyclobutanol bearing an azide group, which was constructed by a formal [2+2] cycloaddition of a 2′-vinyl-1,1′-biaryl-2-yl ketone enolate. Catalytic asymmetric hydrogenation of the cyclic imine intermediate allowed the late-stage construction of the asymmetric center.
- Yamaoka, Yousuke,Taniguchi, Marie,Yamada, Ken-Ichi,Takasu, Kiyosei
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p. 2819 - 2825
(2015/09/15)
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- An enantioselective strategy for the total synthesis of (S)-tylophorine via catalytic asymmetric allylation and a one-pot DMAP-promoted isocyanate formation/Lewis acid catalyzed cyclization sequence
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A new asymmetric total synthesis of a phenanthroindolizidine alkaloid (S)-tylophorine is reported, which features a catalytic asymmetric allylation of aldehydes and an unexpected one-pot DMAP promoted isocyanate formation and Lewis acid catalyzed intramolecular cyclization reaction. In addition, White's direct C-H oxidation catalyst system converting monosubstituted olefins to linear allylic acetates was also employed for late-stage transformation. This journal is the Partner Organisations 2014.
- Su, Bo,Zhang, Hui,Deng, Meng,Wang, Qingmin
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p. 3616 - 3621
(2014/06/09)
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- Collective asymmetric synthesis of (-)-Antofine, (-)-cryptopleurine, (-)-tylophorine, and (-)-tylocrebrine with tert- butanesulfinamide as a chiral auxiliary
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A collective asymmetric synthesis of phenanthroindolizidine and phenanthroquinolizidine alkaloids (-)-antofine, (-)-cryptopleurine, (-)-tylophorine, and (-)-tylocrebrine was achieved by means of a reaction sequence involving efficient generation of chiral homoallylic amine intermediates by asymmetric allylation of the corresponding tert-butanesulfinyl imine. From these intermediates, the pyrrolidine and piperidine rings were constructed by means of an intramolecular SN2 substitution reaction and a ring-closing metathesis reaction, respectively. The unusual C5-methoxy-substituted phenanthrene moiety of (-)-tylocrebrine was generated by means of an InCl3-catalyzed cycloisomerization reaction of an o-propargylbiaryl compound.
- Zheng, Yanlong,Liu, Yuxiu,Wang, Qingmin
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p. 3348 - 3357
(2014/05/06)
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- Short asymmetric synthesis of phenanthroindolizidines through chiral homoallylic sulfinamines
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An efficient stereocontrolled preparation of chiral phenanthroindolizidines is detailed. The synthesis relies on the stereoselective indium-mediated allylation of 2-(phenanthren-9-yl)acetaldehyde derivatives with chiral tert-butylsulfinamide. Chemoselecti
- Anton-Torrecillas, Cintia,Gonzalez-Gomez, Jose C.
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p. 7018 - 7025
(2014/10/15)
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- Concise synthesis of tylophorine
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The phenanthroindolizidine alkaloid tylophorine has been synthesized in the (R)- and racemic forms. One of the routes involves three steps from a known compound employing a Stevens rearrangement as the pivotal reaction. The phenanthrene moiety was constructed by either a base-catalyzed cyclization of 2-alkynylbiphenyls or a double Suzuki coupling of a 2,2′-dibromobiphenyl with vic-bis(pinacolatoboryl)alkene in other routes.
- Lin, Qi-Xian,Ho, Tse-Lok
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p. 2996 - 3001
(2013/03/29)
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- An enantioselective strategy for the synthesis of (S)-tylophorine via one-pot intramolecular schmidt/bischler-napieralski/imine-reduction cascade sequence
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A novel enantioselective strategy for the total synthesis of (S)-tylophorine was developed in an overall yield of 48% with more than 99% ee from readily avaliable azido acid and phenanthryl alcohol. This route features an Evans stereoselective alkylation and an unprecedented one-pot intramolecular Schmidt/Bischler-Napieralski/imine-reduction cascade sequence, in which three new bonds and two rings formed in 84% yield. The intramolecular Schmidt rearrangement of the azido aldehyde was proved to be racemization-free.
- Su, Bo,Chen, Fazhong,Wang, Qingmin
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p. 2775 - 2779
(2013/04/24)
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- Palladium-catalyzed annulation of 2,2′-diiodobiphenyls with alkynes: Synthesis and applications of phenanthrenes
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A range of phenanthrene derivatives were efficiently synthesized by the palladium-catalyzed annulation of 2,2′-diiodobiphenyls with alkynes. The scope, limitations and regioselectivity of the reaction were investigated. The described method was adopted to synthesize 9,10-dialkylphenanthrenes, sterically overcrowded 4,5-disubstituted phenanthrenes and phenanthrene-based alkaloids. Reactions of highly methoxy-substituted biphenyls with 2-(2-propynyl)pyrrolidine and 2-(2-propynyl)piperidine gave 2-(9-phenanthylmethyl)pyrrolidines and 2-(9-phenanthylmethyl)piperidines, respectively. The products were transformed to phenanthroindolizidine and phenanthroquinolizidine alkaloids by the Pictet-Spengler reaction.
- Lin, Yu-De,Cho, Chun-Lung,Ko, Chih-Wei,Pulte, Anna,Wu, Yao-Ting
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p. 9979 - 9988
(2013/01/15)
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- Cobalt-catalyzed carbon-carbon bond formation: Synthesis and applications of enantiopure pyrrolidine derivatives[1]
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In the presence of cobalt catalysts and tetramethylethylenediamine (TMEDA), the iodine atom in (S)-2-(iodomethyl)pyrrolidines was replaced by an aryl or an alkynyl group from the corresponding Grignard reagent, and the coupling products were obtained in good to excellent yields (16 examples; 75-94% yields). The scope and limitations of this protocol were examined. The stereochemistry of the pyrrolidines was unaffected by the reaction conditions. The coupling products are important building blocks of phenanthroindolizidine alkaloids. Palladium-catalyzed formal [4+2] cycloaddition of 2,2′-diiodobiphenyl with the thus-generated (S)-2-(3-trimethylsilyl-2-propynyl)pyrrolidine gave a good yield of the desilylated phenanthrene, which was then converted into unnatural (+)-(S)-tylophorine by the Pictet-Spengler cyclization. Copyright
- Hsu, Shih-Fan,Ko, Chih-Wei,Wu, Yao-Ting
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p. 1756 - 1762
(2011/09/20)
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- Synthesis of tylocrebrine and related phenanthroindolizidines by VOF 3-mediated oxidative aryl-alkene coupling
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A highly convergent strategy to prepare phenanthroindolizidines is reported involving three consecutive C-C coupling reactions. This sequence features a novel VOF3-mediated aryl-alkene coupling in the final step, which enables regioselective preparation of C5-substituted phenanthroindolizidines for the first time. This strategy has been applied to the synthesis of eight natural and unnatural members in this class to investigate the scope of this chemistry and to explore structure-activity relationships.
- Niphakis, Micah J.,Georg, Gunda I.
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p. 196 - 199
(2011/03/19)
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- Synthesis and antiviral activities of phenanthroindolizidine alkaloids and their derivatives
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Racemic phenanthroindolizidine alkaloids tylophorine, antofine, and deoxytylophorinine, and optically pure alkaloids S-(-)-tylophorine and R-(-)-tylophorine were synthesized and evaluated for their antiviral activities against tobacco mosaic virus (TMV). Further salinization modifications based on tylophorine increased stability and water solubility and improved the antiviral activity in application. The bioassay results showed that most of these synthesized compounds showed higher antiviral activity against TMV in vitro and in vivo than commercial Ningnanmycin. Especially, tylophorine salt derivatives 10, 11, 13, 17, and 22 emerged as potential inhibitors of plant virus. These findings demonstrate that these phenanthroindolizidine alkaloids and their salt derivatives represent a new template for antiviral studies and could be considered for novel therapy against plant virus infection.
- Wang, Kailiang,Su,Wang, Ziwen,Meng,Zheng,Yanna,Zhijin,Mi,Wang, Qingmin
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p. 2703 - 2709
(2011/07/31)
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- Asymmetric palladium-catalyzed carboamination reactions for the synthesis of enantiomerically enriched 2-(Arylmethyl)- and 2-(Alkenylmethyl)pyrrolidines
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The enantioselective synthesis of 2-(arylmethyl)- and 2-(alkenylmethyl) pyrrolidine derivatives via Pd-catalyzed alkene carboamination reactions is described. These transformations generate enantiomerically enriched products with up to 94% ee from readily
- Mai, Duy N.,Wolfe, John P.
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supporting information; experimental part
p. 12157 - 12159
(2010/11/03)
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- Efficient and chirally specific synthesis of phenanthro-indolizidine alkaloids by parham-type cycloacylation
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A concise, efficient and modular route involving Parhamtype cycloacylation as the key step has been used to synthesize six enantiopure phenanthro- indolizidine alkaloids 1a-c. The preparation of enantiomerically pure tylophora alkaloids and their seco analogues on a large-scale is now feasible. The alcohol intermediates 8a-c, which are difficult to prepare by other synthetic methodologies, have been synthesized by a metallation-cyclization-reduction sequence in excellent yields.
- Wang, Ziwen,Li, Zheng,Wang, Kailiang,Wang, Qingmin
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experimental part
p. 292 - 299
(2010/03/30)
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- Racemization-free synthesis of (S)-(+)-tylophorine from l -proline by radical cyclization
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Figure presented The phenanthroindolizidine alkaloid (S)-(+)-tylophorine was synthesized from l-proline in nine linear steps including a double bromination and a free-radical cyclization of an N-aziridinylimine as the key steps. The phenanthrene moiety was prepared from homoveratric acid and veratraldehyde and permits the variation of each oxygen-substituted ring.
- Stoye, Alexander,Opatz, Till
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supporting information; experimental part
p. 2140 - 2141
(2010/07/10)
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- Total syntheses of the tylophora alkaloids cryptopleurine, (-)-antofine, (-)-tylophorine, and (-)-ficuseptine C
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A concise, efficient and modular approach to the tylophora alkaloids is described, a family of potent cytotoxic agents that are equally effective against drug sensitive and multidrug resistant cancer cell lines. The advantages of the chosen route are illustrated by the total syntheses of the phenanthroquinolizidine cryptopleurine (1) and the phenanthroindolizidines (-)-antofine (2), (-)-tylophorine (3), and their only recently isolated congener (-)-ficuseptine C (4). The key steps consist in a Suzuki cross-coupling between a (commercial) boronic acid and a simple aryl-l,2-dihalide followed by elaboration of the resulting products into the corresponding 2-alkynyl-biphenyl derivatives 27, 33, 41 and 46. The latter undergo PtCl2-catalyzed cycloisomerizations with formation of the functionalized phenanthrenes 28, 34, 42 and 47, which were transformed into the targeted alkaloids by a deprotection/Pictet-Spengler annulation tandem. Due to the flexibility and robust character of this approach, it might enable a systematic exploration of the pharmacological profile of this promising class of bioactive natural products.
- Fuerstner, Alois,Kennedy, Jason W.J.
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p. 7398 - 7410
(2007/10/03)
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- Enantiopure N-Acyldihydropyridones as Synthetic Intermediates: Asymmetric Synthesis of (-)-Septicine and (-)-Tylophorine
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A concise asymmetric synthesis of (-)-septicine (1) and (-)-tylophorine (2) was accomplished with a high degree of stereocontrol in eight and nine steps, respectively. Addition of 4-(1-butenyl)magnesium bromide to 1-acylpyridinium salt 3, prepared in situ from 4-methoxy-3-(triisopropylsilyl)pyridine and the chloroformate of (-)-trans-2-(α-cumyl)cyclohexanol, gave a 91% yield of diastereomerically pure dihydropyridone 7. Oxidative cleavage of 7 and subsequent reduction provided alcohol 6 in 81% yield. Conversion of 6 to the chloride followed by treatment with sodium methoxide gave indolizidinone 9 in high yield. Bromination and conjugate reduction of 9 with L-Selectride, and trapping the intermediate enolate with N-(5-chloro-2-pyridyl)triflimide, provided bromovinyl triflate 11. Palladium-catalyzed cross-coupling of excess (3,4-dimethoxyphenyl)zinc bromide and 11 gave (-)-septicine (1). On the basis of this synthesis, (-)-1 was assigned the R configuration. Reaction of 1 with vanadium(V) trifluoride oxide in TFA/CH2Cl2 effected oxidative coupling to give a 68% yield of (-)-tylophorine (2).
- Comins, Daniel L.,Chen, Xinghai,Morgan, Lawrence A.
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p. 7435 - 7438
(2007/10/03)
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- PHENANTHROINDOLIZIDINE ALKALOIDS FROM TYLOPHORA TANAKAE
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From the fresh leaves of Tylophora tanakae, ten phenanthroindolozine alkaloids were isolated.Among them, eight were new alkaloids and their structures were determined.Two known alkaloids were identified as isotylocrebrine and tylophorine. - Key words: Tylophora tanakae; Asclepiadaceae; phenanthroindolizidine alkaloids; 7-demethyltylophorine.
- Abe, Fumiko,Iwase, Yukiko,Yamauchi, Tatsuo,Honda, Keiichi,Hayashi, Nanao
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p. 695 - 700
(2007/10/02)
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- Asymmetric Total Synthesis of Naturally Occurring (R)-(-)-Enantiomer of Tylophorine via Intramolecular Double Michael Reaction
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The first asymmetric total synthesis of the naturally occurring (R)-(-)-enantiomer (1) of tylophorine was achieved with high enantioselectivity via the intramolecular double Michael reaction of α,β-unsaturated esters (10) and (20), having two different chiral auxiliaries, with t-butyldimethylsilyl trifluoromethanesulphonate in the presence of triethylamine. (-)-Phenylmenthol and (2R,4S,5R)-(-)-4-(t-butyldimethylsiloxymethyl)-5-hydroxy-2-phenyl-1,3-dioxane, readily available from D-glucose, were used as chiral auxiliaries.
- Ihara, Masataka,Takino, Yoshinobu,Tomotake, Mayumi,Fukumoto, Keiichiro
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p. 2287 - 2292
(2007/10/02)
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- Enantioselective synthesis of naturally occurring (-)-tylophorine by way of an asymmetric intramolecular double Michael reaction
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Treatment of the 8-phenylmenthyl α, β -unsaturated amide ester (3) with tert.-butyldimethylsilyl trifluoromethanesulfonate and triethylamine produced, with a complete diastereofacial selection, the indolizidines (4), which were converted into (-)-(R)-tylophorine (1).
- Ihara, Masataka,Takino, Yoshinobu,Fukumoto, Keiichiro,Kametani, Tetsuji
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- ASYMMETRIC TOTAL SYNTHESES OF (-)-TYLOPHORINE VIA THE HIGHLY ENANTIOSELECTIVE INTRAMOLECULAR DOUBLE MICHAEL REACTION
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Asymmetric total synthesis of (-)-tylophorine (2) was achieved with a high enantioselectivity through the intramolecular double Michael reaction of the α , β -unsaturated ester (8) having a novel chiral auxiliary with tert.-butyldimethylsilyl trifluoromethanesulfonate and Et3N.
- Ihara, Masataka,Takino, Yoshinobu,Fukumoto, Keiichiro,Kametani, Tetsuji
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p. 4135 - 4138
(2007/10/02)
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