- PROCESS FOR PREPARING TAXOL SIDE CHAIN USING HETEROGENEOUS TRIFUNCTIONAL CATALYST
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The present invention relates to an improved process for the preparation of taxol side chain by synthesizing (2R,3S)-2,3-dihydroxy-3-phenylpropionate with greater than 99% enantioselectivity and devoid of osmium even in crude form in a single pot using a recyclable multifunctional catalysts, conversion of diol obtained without further crystallization into bromoacetate, reaction of bromoacetate with NaN3 in organic solvent followed by deacetylation with to obtain azido alcohol, benzoylation followed by hydrogenation of azido alcohol to obtain the (2R,3S)-(N-)-benzoyl-3-phenylisoserine methyl ester in 67% yield.
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- Process for preparing taxol side chain using heterogeneous trifunctional catalyst
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The present invention relates to an improved process for the preparation of taxol side chain by synthesizing (2R,3S)-2,3-dihydroxy-3-phenylpropionate with greater than 99% enantioselectivity and devoid of osmium even in crude form in a single pot using a recyclable multifunctional catalysts, conversion of diol obtained without further crystallization into bromoacetate, reaction of bromoacetate with NaN3in organic solvent followed by deacetylation with to obtain azido alcohol, benzoylation followed by hydrogenation of azido alcohol to obtain the (2R,3S)-(N-)-benzoyl-3-phenylisoserine methyl ester in 67% yield.
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Page column 5
(2008/06/13)
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- A trifunctional catalyst for one-pot synthesis of chiral diols via heck coupling-N-oxidation-asymmetric dihydroxylation: Application for the synthesis of diltiazem and taxol side chain
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A heterogeneous bifunctional catalyst composed of OsO42--WO42- and a trifunctional catalyst comprising PdCl42--OsO42-- WO42-, designed and prepared by an ion-exchange technique using layered double hydroxides (LDH) as an ion-exchanger and their homogeneous bifunctional analogue, K2OsO4-Na2WO4 and trifunctional analogue, Na2PdCl4-K2OsO4-K2 OSO4-NNa2WO4, devised for the first time are evaluated for the synthesis of chiral vicinal diols. These bifunctional and trifunctional catalysts perform asymmetric dihydroxylation-N-oxidation and Heck-asymmetric dihydroxylation-N-oxidation, respectively, in the presence of Sharpless chiral ligand, (DHQD)2PHAL in a single pot using H2O2 as a terminal oxidant to provide N-methylmorpholine oxide (NMO) in situ by the oxidation of N-methylmorpholine (NMM). The heterogeneous bifunctional catalyst supported on LDH (LDH-OsW) displays superior activity to afford diols with higher yields over the other heterogeneous catalysts developed by the ion exchange on quaternary ammonium salts covalently bound to resin (resin-OsW) and silica (silica-OsW) or homogeneous catalysts in the achiral dihydroxylation reactions. The LDH-OsW and its homogeneous analogue are found to be very efficient in performing a simultaneous asymmetric dihydroxylation (AD)-N-oxidation of a wide and varied range of aromatic, cyclic, and mono, di-, and trisubstituted olefins to obtain chiral vicinal diols with higher yields and ee's using H2O2. Further, the use of OsO42--WO42-- WO42- catalysts as such or in the supported form offers a simplified procedure for catalyst recycling, which shows consistent activity for a number of cycles. In this process, OsVI is recycled to OsVIII by a coupled electron transfer-mediator (ETM) system based on NMO-WO42- using H2O2, leading to a mild and selective electron transfer. The one-pot biomimic synthesis of chiral diols is mediated by a recyclable trifunctional heterogeneous catalyst (LDH-PdOsW) consisting of active palladium, tungsten, and osmium species embedded in a single matrix. This protocol, which provides prochiral olefins and NMO in situ by Heck coupling and N-oxidation of NMM, respectively, required for the AD, unfolds a low cost process. We extended the present method to the one-pot synthesis of trisubstituted chiral vicinal diols with moderate to excellent ee's by AD of trisubstituted olefins that are obtained by in situ Heck arylation of disubstituted olefins. The heterogeneous trifunctional catalysts offers chiral diols with unprecedented ee's and excellent yields in the AD of prochiral cinnamates, which are obtained in situ from acrylates and halobenzenes for the first time. The new variants such as LDH support and Et3N·HX inherently composed in the heterogeneous multicomponent system and slow addition of H202 facilitates the hydrolysis of osmium monogylcolate ester to subdue the formation of bisglycolate ester to achieve higher ee's. Without resorting to recrystallization, the chiral diols of cinnamates thus synthesized with 99% ee's and devoid of osmium contamination are directly put to use in the synthesis of diltiazem and Taxol side chain with an overall improved yield to demonstrate the synthetic utility of the trifunctional heterogeneous catalyst. The high binding ability of the heterogeneous osmium catalyst enables the use of equimolar ratio of ligand to osmium to give excellent ee's in AD in contrast to the homogeneous osmium system in which the excess molar quantities of the expensive chiral ligand to osmium are invariably used. Further, the XRD, FT-IR, UV-vis DRS, and XPS studies indicate the retention of the coordination geometries of the specific divalent anions anchored to LDH matrix in their monomeric form during the ion exchange and after the reaction.
- Choudary, Boyapati M.,Chowdari, Naidu S.,Madhi, Sateesh,Kantam, Mannepalli L.
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p. 1736 - 1746
(2007/10/03)
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- Synthesis and biological evaluation of water soluble taxoids bearing sugar moieties
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Synthesis and biological evaluation of a variety of water soluble taxoids with sugar moieties are described.
- Mandai, Tadakatsu,Okumoto, Hiroshi,Oshitari, Tetsuta,Nakanishi, Katsuyoshi,Mikuni, Katsuhiko,Hara, Ko-ji,Hara, Ko-zo,Iwatani, Wakao,Amano, Tetsuya,Nakamura, Kosho,Tsuchiya, Yoshinori
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p. 561 - 566
(2007/10/03)
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- Chemoenzymatic synthesis of the C-13 side chain of paclitaxel (Taxol) and docetaxel (Taxotere)
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Reduction of methyl 3-chloro-2-oxo-3-phenylpropanoate with various reducing agents gave syn- and anti-3-chloro-2-hydroxy-3-phenylpropanoates 3, which underwent an efficient lipase-catalyzed resolution. All four diastereomers were subsequently converted to N-benzoyl-(2R,3S)-3-phenylisoserine methyl ester, C-13 side chain analogues of paclitaxel (Taxol).
- Hamamoto, Hiromi,Mamedov, Vakhid A.,Kitamoto, Makiko,Hayashi, Nobuyuki,Tsuboi, Sadao
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p. 4485 - 4497
(2007/10/03)
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- Baker's Yeast-Mediated Reductions of α-Keto Esters and an α-Keto-β-Lactam. Two Routes to the Paclitaxel Side Chain
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Baker's yeast (Saccharomyces cerevisiae) has been used to reduce a series of alkyl esters derived from pyruvate and benzoylformate. Both the yield and enantioselectivities of these reductions were maximized when methyl esters were used, and the (R)-alcohols were isolated in all instances. Yeast-mediated ester hydrolysis was a significant side reaction for products derived from long-chain alcohols. In the case of ethyl benzoylformate, the addition of methyl vinyl ketone increased the enantioselectivity of the reduction. These reductions were applied to two syntheses of the paclitaxel C13 side chain [(2R,3S)-N-benzoyl-3-phenylisoserine]. In the first, a racemic α-keto-β-azido ester was reduced by whole cells of Baker's yeast to afford a diastereomeric mixture in which the desired product predominated and could be isolated chromatographically. In the second, an easily synthesized α-keto-β-lactam was reduced by yeast cells to afford the desired eis isomer as well as the undesired trans diastereomer. Substituting a yeast strain deficient in fatty acid synthase in this reduction suppressed formation of the trans diastereomer. These results suggest that a single enzyme is responsible for both the D- and L-cis-alcohols resulting from reduction of the α-keto-β-lactam. All of the yeast strains used in this project are available commercially, and these biocatalytic reductions require only common laboratory equipment.
- Kayser, Margaret M.,Mihovilovic, Marko D.,Kearns, Jeff,Feicht, Anton,Stewart, Jon D.
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p. 6603 - 6608
(2007/10/03)
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- Synthesis of taxoids 4. Novel and versatile methods for preparation of new taxoids by employing cis- or trans-phenyl glycidic acid
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A novel route to the synthesis of docetaxel using esterification of (2R,3R)-or (2R,3S)-glycidic acid with 7,10-bis-O-(2,2,2- trichloroethoxycarbonyl)-10-deacetylbaccatin III is described. Related novel taxoids which have new side chains were synthesized from these synthetic intermediates.
- Yamaguchi, Tetsuo,Harada, Naoyuki,Ozaki, Kunihiko,Hayashi, Masahito,Arakawa, Hiroaki,Hashiyama, Tomiki
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p. 1005 - 1016
(2007/10/03)
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- Lipase-catalyzed transesterification as a practical route to homochiral syn-1,2-diols. The synthesis of the taxol side chain
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syn-2,3-Dihydoxy-3-phenyl-propanoic acid methyl ester (1a) and its simple derivatives (1b-e) are efficiently resolved in LPS-catalyzed transesterification, leading to the synthesis of the taxol side chain and analogs from both resolved enantiomers.
- Lee, Donghyun,Kim, Mahn-Joo
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p. 2163 - 2166
(2007/10/03)
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- Synthesis of taxoids I. Regioselective Lewis acid-mediated ring-opening of aryl orthoacetates
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The reaction of aryl orthoacetates with acetyl bromide readily proceeded regioselectively to afford the desirable aryl bromides in the presence of tin(II) or zinc bromide as a catalyst. The synthesis of some docetaxel derivatives is also described by using this improved process.
- Harada, Naoyuki,Hashiyama, Tomiki,Ozaki, Kunihiko,Yamaguchi, Tetsuo,Ando, Akira,Tsujihara, Kenji
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p. 305 - 318
(2007/10/03)
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- Process for the enantioselective preparation of phenylisoserine derivatives
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Process for the enantioselective preparation of phenylisoserine derivatives of general formula (I), in which R represents a phenyl or tert-butoxy radical, R1 represents a hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms and R2 represents a hydrogen atom or a group protecting the alcohol function. STR1
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- Enantioselective synthesis of the taxol and taxotere side chains
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A new route to Taxol and Taxotere side chains via asymmetric dihydroxylation of both cis and transmethyl cinnamates is described.
- Koskinen,Karvinen,Siirila
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- Enantio- and stereo-selective route to the taxol side chain via asymmetric epoxidation of trans-cinnamyl alcohol and subsequent epoxide ring opening
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The first route to the side chain of Taxol and Taxotere, employing asymmetric epoxidation (AE) of trans-cinnamyl alcohol and a new highly regio- and stereo-selective opening of the epoxide ring with MgBr2, is described.
- Bonini,Righi
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p. 2767 - 2768
(2007/10/02)
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- Selective C-2 opening of 2,3-epoxyesters with HN3-amine system: A viable route to β-hdyroxy-α-amino acids
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The combination of hydrogen azide with amines has proven to effect the C-2 opening of 2,3-epoxyester with high regioselectivity uniformly for trans-epoxyesters and depending on their structures for cis-2,3-epoxyesters.
- Saito,Takahashi,Ishikawa,Moriwake
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p. 667 - 670
(2007/10/02)
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- Synthesis of all four homochiral stereoisomers of methyl 3-phenyl-1H-aziridine-2-carboxylate
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Sodium -E3-phenylglycidate (±)-2E was prepared using the Darzens' procedure. Classical resolution with 1-phenylethylamine afforded optically pure salts (+)-(2S,3R)-2E and (-)-(2R,3S)-2E. Alternatively, (±)-2E was converted into (±)-2Z by ring opening of ethyl ester (±)1E with hydrogen bromide, followed by recyclization and saponification. Classical resolution of (±)-2Z with ephedrine afforded optically pure salts (+)-(2S,3S)-2Z and (-)-(2R,3R)-2Z Treatment of the four sodium salts with sodium azide followed by esterification gave hydroxy azido esters 3, which were finally converted into the four homochiral stereoisomers of methyl 3-phenyl-1H-aziridine-2-carboxylate 5 in a reaction with triphenylphosphine and subsequent heating of the initially formed oxazaphospholidines 4.
- Thijs, Lambertus,Orskamp Jos,Adriaan,Marielle,Eenstra, Rolf W.,Legters, Johan,Zwanenburg, Binne
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p. 2611 - 2622
(2007/10/02)
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- An Efficient, Enantioselective Synthesis of the Taxol Side Chain
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An asymmetric epoxidation (70-80percent ee) and a highly regioselective epoxide cleavage have been used as the key reactions in the synthesis of the taxol side chain methyl ester (2; 95percent ee, 23percent overall yield from phenylacetylene.Transesterifications of 2 (in four steps) have been effected and are exemplified with (-)-isopinocampheol (8), 1,2;3,4-di-O-isopropylidene-D-galactopyranose (9), and methyl gibberellate (10).
- Denis, Jean-Noel,Greene, Andrew E.,Serra, A. Aarao,Luche, Marie-Jacqueline
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