Soc., 114, 383-385 (1992)"TotalSynthesisof (±)-Renieramycin A,"T.
An efficient totalsynthesis of spatol exploiting this remarkable reaction will soonbe completed.
Stereocontrolled total synthesis of (+)-vincristine
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)
What is most remarkable about these advances and althoughit couldnot have been imagined at the stage we initiated our efforts, theC20′ analogues of vinblastine are available in three stepsfrom commercially available materials (Scheme ). Although vinblastine is a true trace natural product, representing0.00025% of the dried leaf weight of the periwinkle, its biosyntheticprecursors catharanthine and vindoline are the major alkaloid componentsof the plant. They are readily available, relatively inexpensive startingmaterials. As a result, such C20′ analogues are not only readilyaccessible using the unique chemistry we introduced but also inexpensiveto prepare on scales needed for preclinical development. Thus, theinnovative chemistry developed in route to the total synthesis ofvinblastine–the Fe(III)-mediated single-step coupling of catharanthineand vindoline that proceeds with complete control of the pivotal C16′stereochemistry and the in situ Fe(III)-mediated hydrogen atom transferfree radical functionalization (Markovnikov hydroazidation) of the key C20′ center–permitsthe exploration of exciting analogues previously unimaginable.
Stereocontrolled Total Synthesis of (+)-UCS1025A - …
Lett., 10, 2259-2261 (2008) (doi: 10.1021/ol800677p [PDF] [Supporting Information]) "Total Synthesis of (－)-Kainic Acid via Intramolecular Michael Addition: A Second-Generation Route," Hiroshi Sakaguchi, Hidetoshi Tokuyama, and Tohru Fukuyama Org.
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 (−)-Stemaphylline
To the best of our knowledge, this is the first report of isolation of vinblastine and vincristine from an endophytic fungus Fusarium oxysporum isolated from Indian Catharanthus roseus plant. As earlier reported from other sources, the necessary precursors such as tryptophan and geraniol which are essential for the formation of vinblastine and vincristine were provided in the growth medium and 76 µg of vinblastine and 67 µg of vincristine is obtained per liter of culture filtrate. Thus, the total amount of vinca alkaloids (vinblastine and vincristine) using our fungal protocol is 0.0143% which is 2.86% more than the conventional plant-based method which yields 0.005% vinca alkaloids . In order to increase the concentration of these drug from micrograms to grams per liter, efforts should be made to optimize the culture conditions by figuring out the biosynthetic pathway of the fungus Fusarium oxysporum along with genetic engineering methods which can lead to abundant production of these life-saving drugs. This green synthesis method is eco-friendly, non-toxic and cheap; unlike the chemical synthesis routes which were being used earlier and provided insufficient quantities of drugs.
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.−
Stereocontrolled total synthesis of (+)-vincristine.
Stereocontrolled total synthesis of (+)-vincristine - CORE
Lett., 5, 1891-1893 (2003)"TotalSynthesis of Leustroducsin B,"Kousei Shimada, Yosuke Kaburagi, and Tohru FukuyamaJ.
Stereocontrolled total synthesis of (+)-vincristine
Kan,Tetrahedron Lett., 38, 5831-5834 (1997)"StereocontrolledTotal Synthesis of (±)-Gelsemine,"T.
Stereocontrolled total synthesis of (+) ..
Chem., 69, 501-505 (1997)"StereocontrolledTotal Synthesis of (±)-Gelsemine,"T.
Total Synthesis of vinblastine, 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 ).
"Stereocontrolled total synthesis of (+)-vincristine"
Lett., 9, 2055-2058 (2007) (doi: 10.1021/ol070376i [PDF] [Supporting Information]) "Stereocontrolled Total Synthesis of (-)-Kainic Acid," Hiroshi Sakaguchi, Hidetoshi Tokuyama, and Tohru Fukuyama Org.
Stereocontrolled total synthesis of (+)-vincristine…
Soc., 133, 418-419 (2011) (doi: 10.1021/ja109516f) [PDF] [Supporting Information] 1 (Experimental) 2 (Spectrum)) 2010 "Total Synthesis of Tryprostatins A and B," Takayuki Yamakawa, Eiji Ideue, Jun Shimokawa, Tohru Fukuyama Angew.
Total Synthesis of (+)-Spongistatin 1. An Effective …
Commun., 1757-1759 (2006) (doi: 10.1039/b601628f) "Total Synthesis of (±)-Morphine," Kenji Uchida, Satoshi Yokoshima, Toshiyuki Kan, and Tohru Fukuyama Org.
(2002) Stereocontrolled Total Synthesis of (+) ..
Lett., 13, 2068-2070 (2011) (doi: 10.1021/ol200434a) [PDF] [Supporting Information] "Concise Total Synthesis of (+)-Lyconadin A," Takuya Nishimura, Aditya K.
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