- Two-Phase Synthesis of Taxol
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Taxol (a brand name for paclitaxel) is widely regarded as among the most famed natural isolates ever discovered, and has been the subject of innumerable studies in both basic and applied science. Its documented success as an anticancer agent, coupled with early concerns over supply, stimulated a furious worldwide effort from chemists to provide a solution for its preparation through total synthesis. Those pioneering studies proved the feasibility of retrosynthetically guided access to synthetic Taxol, albeit in minute quantities and with enormous effort. In practice, all medicinal chemistry efforts and eventual commercialization have relied upon natural (plant material) or biosynthetically derived (synthetic biology) supplies. Here we show how a complementary divergent synthetic approach that is holistically patterned off of biosynthetic machinery for terpene synthesis can be used to arrive at Taxol.
- Kanda, Yuzuru,Nakamura, Hugh,Umemiya, Shigenobu,Puthukanoori, Ravi Kumar,Murthy Appala, Venkata Ramana,Gaddamanugu, Gopi Krishna,Paraselli, Bheema Rao,Baran, Phil S.
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supporting information
p. 10526 - 10533
(2020/07/27)
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- Route optimization and synthesis of taxadienone
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Early process development toward the scalable production of taxadienone on a decagram scale is described. A continuous flow reactor was employed to safely run a potentially hazardous cyclopropane ring opening. The route featured two copper-mediated additions, a Diels-Alder reaction and a palladium-catalyzed Negishi coupling, to construct the final structure.
- Krasutsky, Sergiy G.,Jacobo, Sheila H.,Tweedie, Scott R.,Krishnamoorthy, Ravi,Filatov, Alexander S.
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p. 284 - 289
(2015/01/30)
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- Total synthesis of taxane terpenes: Cyclase phase Dedicated to Professor Melanie S. Sanford on the occasion of her receipt of the Tetrahedron Young Investigator Award
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A full account of synthetic efforts toward a lowly oxidized taxane framework is presented. A non-natural taxane, dubbed 'taxadienone', was synthesized as our first entry into the taxane family of diterpenes. The final synthetic sequence illustrates a seven-step, gram-scale, and enantioselective route to this tricyclic compound in 18% overall yield. This product was then modified further to give (+)-taxadiene, the lowest oxidized member of the taxane family of natural products.
- Ishihara, Yoshihiro,Mendoza, Abraham,Baran, Phil S.
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p. 5685 - 5701
(2013/07/19)
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- Zinc/iron-mediated ring opening of dibromocyclopropanes for in situ Diels-Alder reactions with electron-deficient aldehydes and imines
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Dibromocyclopropanes can be ring-opened by utilizing zinc dibromide in catalytic amounts and iron powder in substoichiometric amounts. The presence of the carbonyl group of aldehydes, ketones, glyoxylic esters, or imines is necessary for the ring-opening
- Puenner, Florian,Hilt, Gerhard
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p. 5580 - 5584
(2013/09/12)
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- Scalable enantioselective total synthesis of taxanes
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Taxanes form a large family of terpenes comprising over 350 members, the most famous of which is Taxol (paclitaxel), a billion-dollar anticancer drug. Here, we describe the first practical and scalable synthetic entry to these natural products via a concise preparation of (+)-taxa-4(5),11(12)-dien-2-one, which has a suitable functional handle with which to access more oxidized members of its family. This route enables a gram-scale preparation of the 'parent' taxane-taxadiene-which is the largest quantity of this naturally occurring terpene ever isolated or prepared in pure form. The characteristic 6-8-6 tricyclic system of the taxane family, containing a bridgehead alkene, is forged via a vicinal difunctionalization/Diels-Alder strategy. Asymmetry is introduced by means of an enantioselective conjugate addition that forms an all-carbon quaternary centre, from which all other stereocentres are fixed through substrate control. This study lays a critical foundation for a planned access to minimally oxidized taxane analogues and a scalable laboratory preparation of Taxol itself.
- Mendoza, Abraham,Ishihara, Yoshihiro,Baran, Phil S.
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scheme or table
p. 21 - 25
(2012/03/26)
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- Dibromocarbene and bromofluorocarbene addition to substituted allylsilanes
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The dibromocarbene or bromofluorocarbene addition to substituted allyldisilanes afforded instable gem-dibromocyclopropanes or a gem-bromofluorocyclopropane, respectively. These gem-bromohalogenocyclopropanes undergo a spontaneous ring opening at room temp
- Aouf, Chahinez,Santelli, Maurice
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experimental part
p. 688 - 691
(2011/03/21)
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- Preparation of multisubstituted allenes from allylsilanes
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A three-step route of converting allylsilanes to functionalized allenes was developed. Thermal decomposition of 1,1-dibromo-2-(silylmethyl)cyclopropanes, which were quantitatively prepared by treatment of allylsilane derivatives with CHBr3/KOs
- Ogasawara, Masamichi,Ge, Yonghui,Uetake, Koichi,Fan, Liyan,Takahashi, Tamotsu
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p. 3871 - 3876
(2007/10/03)
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- Part 1: Efficient strategies for the construction of variably substituted bicyclo[5.3.1]undecenones (AB taxane ring systems)
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Strategies for the construction of cyclic molecules containing variably substituted bicyclo[5.3.1]undecenones (AB taxane ring systems) are described. These routes employ a multi-component coupling protocol that utilizes sequential magnesium-mediated carbometallation of propargyl alcohols and intramolecular Diels-Alder reactions (IMDA). The cycloaddition generates the key eight-membered taxane ring as a single diastereomer, induced by preferential Lewis acid (diethylaluminum chloride or boron trifluoride etherate) complexation with the cross-ring oxygens, Both the electronic nature of the dienophile and the neighbouring group non-bonded interactions contribute to the success of these cycloadditions.
- Laurent, Alain,Villalva-Servin, Nidia P.,Forgione, Pat,Wilson, Peter D.,Smil, David V.,Fallis, Alex G.
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p. 215 - 226
(2007/10/03)
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- Simple and efficient synthesis of bromine-substituted 1,3-dienes and 1,3,5-cycloheptatriene by vacuum pyrolysis of gem-dibromocyclopropanes
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To establish whether the results obtained by the gas phase pyrolysis of 6,6-dihalobicyclo[3.1.0]hexanes by HeI photoelectron spectroscopy using a high power CW CO2 laser as a directed heat source can be achieved on a preparatory scale using a modified apparatus, we carried out the gas phase pyrolysis of a few representative gem-dibromocyclopropanes such as 1,1-dibromo-2,2,3,3-tetramethylcyclopropane (1), 1,1-dibromo-2,2-dimethyl-cyclopropane (2), 1,1-dibromo-cis-2,3-dimethylcyclopropane (3), 1,1-dibromo-trans-2,3-dimethylcyclopropane (4), 6,6-dibromobicyclo[3.1.0]hexane (5) and 7,7-dibromobicyclo[4.1.0]heptane (6). Except 7,7-dibromobicyclo[4.1.0]heptane, that gave 1,3,5-cycloheptatriene in 72% yield at 525°C, 1, 2, 3, 4 and 5 readily lose HBr at 400-560°C in the gas phase to produce β-bromo-1,3-dienes in high chemical yields and purity. The dienes are potentially useful starting substrates for the Diels-Alder reactions.
- Werstiuk, Nick H.,Roy, Chandra D.
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p. 3255 - 3258
(2007/10/03)
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- Taxane diterpenes 5: Synthesis of the A- and C-rings: An unusual rearrangement of an N-hydroxyimino lactone
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Ring A of taxol was synthesized from the bromodiene 5 and acryloyl chloride to give 6, which was resolved by separation of diastereomers 7. Allylic oxidation of 7 gave 8, which on deprotection, esterification and reduction gave 11. Heating 11 followed by reduction and protection gave 13. The C-ring component was made using asymmetric Birch reduction methodology combined with standard functional group manipulations to give 28. Combining 13 and 28 gave 29, which was converted into 33. Thermolysis of 33 did not generate a nitrile oxide but rather ionized to an oxydienyl cation, eventually leading to 34.
- Magnus, Philip,Westwood, Nicholas,Spyvee, Mark,Frost, Christopher,Linnane, Patrick,Tavares, Francis,Lynch, Vince
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p. 6435 - 6452
(2007/10/03)
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- Concise synthesis of taxol A-ring components: Remote diastereoselective additions of alkenyl lithiums to aldehydes
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The acid chloride 6 provides access to 7 (R,S and S,S) which upon bromine-lithium exchange undergoes remarkably highly diastereoselective additions to aldehydes; 7 is also readily elaborated into the acetal 10.
- Frost, Christopher,Linnane, Patrick,Magnus, Philip,Spyvee, Mark
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p. 9139 - 9142
(2007/10/03)
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- SYNTHETIC EFFORTS DIRECTED TOWARDS THE TAXOL SKELETON. THE SATURATED C-RING APPROACH
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The type 2 intramolecular Diels-Alder reaction is utilized to assemble a taxol precursor.
- Shea, K. J.,Haffner, C. D.
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p. 1367 - 1370
(2007/10/02)
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- SYNTHESIS OF SOME 3-SUBSTITUTED-2,4-DIMETHYL-1,3-PENTADIENES
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Pyrolysis of various 1-bromo-2,2,3,3-tetramethylcyclopropanes leads to the corresponding 3-substituted-2,4-dimethylpenta-1,3-dienes in good yield.
- Warner, Philip M.,Le, Diem
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p. 1341 - 1348
(2007/10/02)
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- Siver Ion-induced Allylation of Furan with Cyclopropyl Halides
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Allyl species generated from 1-bromo-2-phenylcyclopropane and seven different 1,1-dihalocyclopropanes with the aid of silver perchlorate reacted with furan in a regio- and stereoselective manner to give a series of 2-allylfuran derivatives in fair to good yields.
- Shimizu, Nobujiro,Watanabe, Kenji,Tsuno, Yuho
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p. 1165 - 1166
(2007/10/02)
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