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Soc., 116, 3125-3126 (1994)"TotalSynthesis of (+)-Leinamycin,"Y.
Concise Total Synthesis of (+)-Lyconadin A , Nishimura Takuya, Unni Aditya K., Yokoshima Satoshi, Fukuyama Tohru , JOURNAL OF THE AMERICAN CHEMICAL SOCIETY , Vol.133 , No.3R , 418-419 , (2011)
After formation of the piperidine ring by sequential removalof the protective groups and intramolecular nucleophilic cyclization,the total synthesis of vincristine was completed by formylation of N1.
Soc., 114, 383-385 (1992)"TotalSynthesisof (±)-Renieramycin A,"T.
A subsequent asymmetric variantof this approach was developedin which the tether linking the initiating dienophile and 1,3,4-oxadiazolebears a chiral substituent that sets the absolute stereochemistryof the remaining six stereocenters in the cascade cycloadducts, providingtwo distinct and concise asymmetric total syntheses of vindoline (Figure )., Since the approach enlisted ashortened dienophile tether that resulted in both good facial controland milder reaction conditions for the cascade cycloaddition, itsimplementation for the synthesis of vindoline required the developmentof a ring expansion reaction to provide a six-membered ring suitablyfunctionalized for introduction of the Δ6,7-doublebond found in the core structure of the natural product. Two uniqueapproaches were developed that defined our use of a protected hydroxymethylgroup as the substituent that controls the stereochemical course ofthe cycloaddition cascade. The first entailed a facile tautomerizationof a reactive α-amino aldehyde generated from the primary alcohol,which is trapped as a remarkable N,O-ketal that undergoes a subsequent hydrolytic ring expansion uponfurther activation of the primary alcohol., The second approach relied upon a thermodynamically controlled reversiblering opening reaction of an intermediate aziridinium ion for whichthe stereochemical features of the reactions are under stereoelectroniccontrol. In the course of these studies,several analogues of vindoline were prepared containing deep-seatedstructural changes presently accessible only by total synthesis.−
Ashighlighted earlier, a powerful Fe(III)-promoted coupling ofcatharanthine with vindoline generating anhydrovinblastine was enlisted and combined with a newly developedin situ Fe(III)/NaBH4-promoted oxidation to provide vinblastinein a single operation (Figure ). This development not only converted the syntheticefforts into one capable of use for the systematic exploration ofthe vinblastine structure but also assured that supplies of any analogueneeded for preclinical studies or clinical introduction could be accessedby total synthesis. Consequently, in addition to its use in the completionof the total syntheses of vinblastine (12 steps), vincristine, anda series of additional naturally occurring Vinca alkaloids, the approach also permits the incorporationof vindoline analogues containing single site peripheral changes tothe structure as well as more deep-seated changes to the vindolinecore accessible only by total synthesis.
Stereocontrolled total synthesis of (+)-vincristine
Central to the further advancementof this work was the use ofa biomimetic Fe(III)-promoted couplingof vindoline with catharanthine, and the additionaldevelopment of a subsequent in situ Fe(III)-mediated hydrogen-atominitiated free radical alkene oxidation for C20′-alcohol introduction that allows for their single-step incorporationinto total syntheses of vinblastine, related natural products includingvincristine, and key analogues (Figure ).
With use of the newly developed methodology and in addition toongoing efforts to systematically define the importance of each embeddedstructural feature of vinblastine, two classes of analogues alreadyhave been discovered that enhance the potency of the natural products>10-fold. In one instance, remarkable progress has also been madeon the refractory problem of reducing Pgp transport responsible forclinical resistance with a series of derivatives made accessible onlyusing the newly developed synthetic methodology. Unlike the removalof vinblastine structural features or substituents, which typicallyhas a detrimental impact, the additions of new structural featureshave been found that can enhance target tubulin binding affinity andfunctional activity while simultaneously disrupting Pgp binding, transport,and functional resistance. Already analogues are in hand that aredeserving of full preclinical development, and it is a tribute tothe advances in organic synthesis that they are readily accessibleeven on a natural product of a complexity once thought refractoryto such an approach.
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Stereocontrolled Total Synthesis of (+)-UCS1025A - …
Soc., 121, 3791-3792 (1999)"EfficientTotalSyntheses of (±)-Vincadifformine and (–)-Tabersonine,"Satoshi Kobayashi, Ge Peng, and Tohru Fukuyama,Tetrahedron Lett., 40, 1519-1522 (1999)-1998"SyntheticStudies on CP-225,917 and CP-263,114,"Nobuaki Waizumi, Tetsuji Itoh, and Tohru Fukuyama,Tetrahedron Lett., 39, 6015-6018 (1998)"A Novel KetoneSynthesis by a Palladium-Catalyzed Reaction of Thiol Esters andOrganozinc Reagents,"Hidetoshi Tokuyama, Satoshi Yokoshima, Tohru Yamashita, and TohruFukuyama,Tetrahedron Lett., 39, 3189-3192 (1998)"2-(2-Aminophenyl)-acetaldehydeDimethyl Acetal: A Novel Reagent for the Protection of Carboxylic Acids,"Eri Arai, Hidetoshi Tokuyama, M.
Stereocontrolled Total Synthesis of (−)-Stemaphylline
Soc., 121, 6501-6502 (1999)"SyntheticStudy on Ecteinascidin 743 Starting from D-Glucose,"Atsushi Endo, Toshiyuki Kan, and Tohru Fukuyama,Synlett, 1103-1105 (1999)"TotalSynthesis of Polyamine Toxin HO-416b Utilizing the2-Nitrobenzenesulfonamide Protecting Group,"Yuko Hidai, Toshiyuki Kan, and Tohru Fukuyama,Tetrahedron Lett., 40, 4711-4714 (1999)"RadicalCyclization of 2-Alkenylthioanilides: A Novel Synthesis of2,3-Disubstituted Indoles,"Hidetoshi Tokuyama, Tohru Yamashita, Matthew T.
Stereocontrolled total synthesis of (+)-vincristine.
Lett., 1, 973-976 (1999)"N-Carboalkoxy-2-Nirobenzenesulfonamides:A Practical Preparation of N-Boc-, N-Alloc-, and N-Cbz-ProtectedPrimary Amines,"Tohru Fukuyama, Mui Cheung, Toshiyuki Kan,Synlett, 1301-1303 (1999)"StereocontrolledTotal Synthesis of (+)-K252a,"Yoshihisa Kobayashi, Teppei Fujimoto, and Tohru Fukuyama,J.
Stereocontrolled total synthesis of (+)-vincristine - CORE
Soc., 122, 7825-7826 (2000)"A NovelTransformation of Primary Amines to N-Monoalkylhydroxylamines,"Hidetoshi Tokuyama, Takeshi Kuboyama, Akiko Amano, Tohru Yamashita,andTohru FukuyamaSynthesis, 1299-1304 (2000)"An EfficientTotal Synthesis of (-)-Vindoline,"Satoshi Kobayashi, Toshihiro Ueda, Tohru FukuyamaSynlett, 883-886 (2000)"Synthesis of2,3-Disubstituted Indoles by Palladium-Mediated Coupling of2-Iodoindoles,"Hidetoshi Tokuyama, Yosuke Kaburagi, Xiaoqi Chen, and Tohru Fukuyama,Synthesis, 429-434 (2000)1999"StereocontrolledTotal Synthesis of (±)-Catharanthine via Radical-Mediated IndoleFormation,"Matthew T.
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