- Synthetic method of paclitaxel side chain
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The invention discloses a synthetic method of a paclitaxel side chain. The method comprises the steps of taking (2R, 3S)-3-phenyl isoserine hydrochloride as a raw material; carrying out esterificationreaction under the participation of methanol and thionyl chloride to obtain (2R, 3S)-phenyl isoserine methyl ester; then preparing (2R, 3S)-N-benzoyl-phenyl isoserine methyl ester through a benzoylation reaction; preparing (4S, 5R)-5-methoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-3-benzoyl-1,3-oxazolidine through a cyclization protection reaction; finally, obtaining a paclitaxel side chain crude product through hydrolysis, and further purifying the paclitaxel side chain crude product through recrystallization to obtain a paclitaxel side chain finished product. The method is simple and easy to operate, short in production period, low in cost, high in purification efficiency and suitable for industrial application and market popularization.
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Paragraph 0010-0012
(2020/10/21)
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- Synthesis method of paclitaxel side chain and analogs thereof (by machine translation)
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The invention discloses a synthesis method of a taxol side chain ((4S, 5R) -3 - benzoyl -2 - (4 - methoxyphenyl) -4 - phenyl -5 - oxazoline carboxylic acid) shown as a formula (f) and a series of reactions such as epoxidation, methyl esterification, ammonolysis, ester hydrolysis, condensation, configuration overturning, condensation and hydrolysis as well as analogues thereof. The invention discloses a synthesis method of the taxol side chain ((4S 5R) -3 -benzoyl -2 - (4 - methoxyphenyl) -4 - phenyl -5 - oxazoline carboxylic acid) and the like. The method has the advantages of short reaction time, high yield, good chiral selectivity, suitability for industrial production and the like. (by machine translation)
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Paragraph 0053; 0079-0082
(2020/10/14)
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- 3-phenylisoserine derivative production method
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The present invention provides a 3-phenylisoserine derivative production method for obtaining 3-phenylisoserine derivatives represented by formula (2) (in the formula, R1 represents a phenyl group or a phenyl group having a substituent group; R3 represents a hydrogen atom, a methyl group, a benzyl group, a p-methoxybenzyl group, a tert-butly group, a methoxymethyl group, a 2-tetrahydropyranyl group, an ethoxyethyl group, an acetyl group, a pivoloyl group, a benzoyl group, a trimethylsilyl group, a triethylsilyl group, or a tert-butyldimethylsilyl group; R4 represents a formyl group, an acetyl group, a benzoyl group, a tert-butoxycarbonyl group, or a benzyloxycarbonyl group; and R5 represents a C1-4 alkyl group) by protecting, in water or a mixed solvent containing water, the amino group of a compound represented by formula (1) (in the formula, R1 represents a phenyl group or a phenyl group having a substituent group; R2 represents an alkali metal, an alkaline earth metal, or a nitrogenous base; and R3 represents a hydrogen atom, a methly group, a benzyl group, a p-methoxybenzyl group, a tert-butyl group, a methoxymethyl group, a 2-tetrahydropyranyl group, an ethoxymethly group, an acetyl group, a pivoloyl group, a benzoyl group, a trimethylsilyl group, a triethylsilyl group, or a tert-butyldimethylsilyl group), and when a specific compound has been obtained, extracting the compound using a C4 ether solvent, and while removing the C4 ether solvent and moisture content, replacing at least some of the C4 ether solvent with a C1-4 aliphatic alcohol and implementing an esterification reaction, and then isolating the 3-phenylisoserine derivative at 0-30 DEG C. The 3-phenylisoserine derivative production method enables the production of 3-phenylisoserine derivatives having at least 99% purity.
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Paragraph 0102; 0103; 0104; 0105; 0127
(2017/12/27)
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- Chemoselective esterification of α-hydroxyacids catalyzed by salicylaldehyde through induced intramolecularity
-
A new, direct and chemoselective esterification of α-hydroxyacids was developed using a reversible covalent-binding strategy. By taking advantage of acetal chemistry, simple aldehydes can be used to efficiently catalyze the esterification of α-hydroxy carboxylic acids in the presence of β-hydroxyacid moieties or other carboxylic acids in amounts equal to or in excess of the alcohols. A diverse array of α-aryl, α-alkyl, α-heteroaryl, and functionalized α-hydroxyacids were smoothly esterified with 1° and 2° alcohols catalyzed by 10 mol% inexpensive and commercially available salicylaldehyde, furnishing the resultant esterification products in 83-95% yields after a simple basic aqueous workup to remove the unreacted hydroxyacids. In addition, the salicylaldehyde can be recovered through vacuum distillation or silica gel purification, thereby meeting the standards of green chemistry. A mechanistic study proved that the formation of covalent adduct III during our proposed catalytic cycle (Scheme 1A) is responsible for the real catalysis.
- Weng, Shiue-Shien,Li, Hsin-Chun,Yang, Teng-Mao
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p. 1976 - 1986
(2013/03/13)
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- Regio- and stereoselective methods for the conversion of (2S,3R)-β-phenylglycidic acid esters to taxoids and other enantiopure (2R,3S)-phenylisoserine esters
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A novel efficient method was proposed for the synthesis of enantiopure precursors of taxane-containing cytostatics, i.e., methyl esters of (2R,3S)- and (2S,3R)-N-benzoylphenylisoserine and similar taxoid esters. The method is based on the regio- and stereoselective hydrobromolysis of the corresponding trans-β-phenyl glycidate enatiomers, consecutive reactions of O-acylcarbamoylation of the obtained 3-bromohydrins, intramolecular cyclization to 4-phenyloxazolidin-2-one-5-carboxylic acid derivatives, and oxazolidinone ring opening.
- Afon'Kin,Kostrikin,Shumeiko,Popov,Matveev,Matvienko,Zabudkin
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p. 2149 - 2162
(2013/10/01)
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- A CATALYTIC ASYMMETRIC METHOD FOR THE PREPARATION OF THE PACLITAXEL (TAXOL) C-13 SIDE-CHAIN DERIVATIVES AND ITS USE IN THE PREPARATION OF TAXANE DERIVATIVES
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A new catalytic asymmetric two-step or one-pot method for the preparation of the C-13 side-chain of paclitaxel (Taxol) and derivatives of the general formula (I) in the form of an acid, salt or ester, in which R represents an aryl group or alkyl group, R1 represents an aryl group or alkyl group, Y represents O, H or alkyl, and X1 represent -CH2-Ph, alkyl, aryl, SiR3 (where the silyl group is a common protective group) or other suitable protective group.
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Page/Page column 19
(2010/06/17)
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- Highly enantioselective organocatalytic addition of aldehydes to N-(Phenylmethylene)benzamides: Asymmetric synthesis of the paclitaxel side chain and its analogues
-
A simple highly enantioselective organocatalytic addition of aldehydes to N-(phenylmethylene)benzamides is presented. The application of (R)-proline as the catalyst and subsequent oxidation of the protected α-hydroxy-β- benzoylami-noaldehydes (92-99% ee) gives access to esterification-ready phenylisoserine derivatives such as the protected paclitaxel (taxol) side chain. Esterification of these derivatives with baccatin III gives access to the cancer chemotherapeutic substance paclitaxel and its analogues that do not exist in nature.
- Dziedzic, Pawel,Schyman, Patrie,Kullberg, Martin,Cordova, Armando
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supporting information; experimental part
p. 4044 - 4048
(2009/12/01)
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- Highly diastereoselective enolate addition of O-protected α-hydroxyacetate to (SR)-tert-butanesulfmylimines: Synthesis of taxol side chain
-
The taxol side chain (sR,2R,3-5)-N-tert-butanesulfinyl-O-Boc-3- phenylisoserine benzyl ester 4c was synthesized through a lithium enolate addition of O-Boc-α-hydroxyacetate benzyl ester 5c to benzylidene (S R)-tert-butanesulfinamide 6a in excellent yield and diastereoselectivity. By similar approach, a series of enantiopure 3-substituted isoserine benzyl esters 4 useful for the semi-syntheses of taxol derivatives were also prepared in high to excellent yields and diastereoselectivities. The diastereoselective addition mechanism was discussed on the basis of the experimental observation.
- Wang, Yin,He, Qin-Fei,Wang, Hao-Wei,Zhou, Xuan,Huang, Zhi-Yan,Qin, Yong
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p. 1588 - 1591
(2007/10/03)
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- Dynamic ligand exchange of the lanthanide complex leading to structural and functional transformation: One-pot sequential catalytic asymmetric epoxidation-regioselective epoxide-opening process
-
The characteristic property of the lanthanide complex, which easily undergoes a dynamic ligand exchange and alters its structure and function in situ, is described. After the completion of the catalytic asymmetric epoxidation of various α,β-unsaturated amides 2 in the presence of the Sm-(S)-BINOL-Ph3-As=O (1:1:1) complex 1 (2-10 mol %), the addition of Me3SiN3 directly to the reaction mixture led to smooth epoxide-opening at room temperature, affording the corresponding anti-β-azido-α-hydroxyamide 4 in excellent overall yield (up to 99%) with complete regioselectivity and excellent enantiomeric excess (up to >99%). The key to the success of the sequential process was the in situ generation of the highly reactive samarium azide complex through dynamic ligand exchange. In situ IR spectroscopy and other experiments provided strong evidence that the samarium azide complex was generated. In addition, the relatively high Lewis basicity of the amide moiety had a key role in the high reactivity of both the epoxidation and the epoxide-opening reactions. Examinations of other nucleophiles such as sulfur or carbon nucleophiles as well as transformations of epoxide-opened products are also described.
- Tosaki, Shin-Ya,Tsuji, Riichiro,Ohshima, Takashi,Shibasaki, Masakatsu
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p. 2147 - 2155
(2007/10/03)
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- Enantioselective synthesis of 1-aryl-2-propenylamines: A new approach to a stereoselective synthesis of the Taxol side chain
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A variety of substituted 1-aryl-2-propenylamines of high enantiomeric purity were prepared via lipase-catalysed resolution of the corresponding racemates. (R)-1-Phenyl-2-propenylamine was further synthesised into (2R,3S)-3-benzoylamino-2-hydroxy-3-phenylpropanoic acid methyl ester, the side chain of Taxol.
- Castagnolo, Daniele,Armaroli, Silvia,Corelli, Federico,Botta, Maurizio
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p. 941 - 949
(2007/10/03)
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- Transacylases of the paclitaxel biosynthetic pathway
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Transacylase enzymes and the use of such enzymes to produce paclitaxel and related taxoids, as well as intermediates in the paclitaxel biosynthetic pathway, are disclosed. Also disclosed are nucleic acid sequences encoding such transacylase enzymes such as (but without limitation) C-13 phenylpropanoid side chain-CoA acyltransferase and benzoyl-CoA:3′-N-debenzoyl-2′-deoxytaxol N-benzoyltransferase.
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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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- 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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- The design and synthesis of guanosine compounds with in vitro activity against the colon cancer cell line SW480: Non-taxane derived mimics of taxol?
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In the course of our investigation into the use of taxol as a lead compound to design new molecules with anti-cancer activity, we have synthesized four compounds based on protected guanosine coupled to taxol isoserine side-chain analogues. These analogues show in vitro anti-cancer activity against the colon cancer cell line SW480 that their constituent parts do not.
- Howarth, Joshua,Kenny, Padraic,McDonnell, Susan,O'Connor, Aine
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p. 2693 - 2697
(2007/10/03)
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- A practical diastereoselective synthesis of β-amino-α-hydroxy carboxylates
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Practical synthetic routes to β-amino-α-hydroxy carboxylates (AHC) have been developed from amino acids. Reduction of β-amino-α- keto esters 6 with NaBH4 was found to give anti-AHCs 7 in high de, which were efficiently converted to the corresponding syn-AHCs 8 via oxazolidine ring 10 formation.
- Lee, Jae-Mok,Lim, Hyun-Suk,Seo, Kyung-Chang,Chung, Sung-Kee
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p. 3639 - 3641
(2007/10/03)
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- A practical and stereoselective synthesis of taxol side chain
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Apractical and efficient synthesis of taxol C-13 side chain from cheap and easily available starting material is described.
- Zhou, Zhongqiang,Mei, Xingguo
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p. 723 - 728
(2007/10/03)
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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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- Asymmetric Sulfur Ylide Mediated Aziridination: Application in the Synthesis of the Side Chain of Taxol
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(Formula presented). Sulfur ylide methodology has been used to construct the Taxol side chain with a high degree of enantioselectivity via a trans-aziridine followed by stereospecific rearrangement of the trans-benzoylaziridine into a trans-oxazoline.
- Aggarwal, Varinder K.,Vasse, Jean-Luc
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p. 3987 - 3990
(2007/10/03)
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- Transacylases of the paclitaxel biosynthetic pathway
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Transacylase enzymes and the use of such enzymes to produce paclitaxel and related taxoids, as well as intermediates in the paclitaxel biosynthetic pathway, are disclosed. Also disclosed are nucleic acid sequences encoding such transacylase enzymes such as (but without limitation) C-13 phenylpropanoid side chain-CoA acyltransferase and benzoyl-CoA:3′-N-debenzoyl-2′-deoxytaxol N-benzoyltransferase.
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- Preparation of β-amino-α-mercapto acids and amides: Stereocontrolled syntheses of 2′-sulfur analogues of the taxol C-13 side chain, both syn and anti S-acetyl-N-benzoyl-3-phenylisocysteine
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Stereoselective syntheses of both syn and anti S-acetyl-N-benzoyl-3-phenylisocysteine as coupling-ready reagents via the ring-opening reactions of trans- and cis-oxazoline-5-carboxylates with thiolacetic acid were demonstrated. In addition, we report upon ring-opening reactions of oxazoline-5-carboxamides. Ab initio molecular calculations were used to explain the different reactivities of these oxazolines with respect to the ring-opening reaction.
- Lee, Sang-Hyeup,Qi, Xin,Yoon, Juyoung,Nakamura, Kensuke,Lee, Yoon-Sik
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p. 2777 - 2787
(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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- Efficient syntheses and ring-opening reactions of trans- and cis-Oxazoline-5-carboxylates
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cis- and trans-Oxazoline-5-carboxylates were synthesized effeciently from isopropyl trans-cinnamate utilizing the sharpless AA reaction. trans-Oxazoline was much more reactive than the cis-isomer toward ring opening reactions. From ab initio molecular calculation, the cis-isomer was predicted to be less reactive than the trans-isomer by 2.7 kcal/mol. Both syn and anti acetylthio ester and anti diamino ester were synthesized from these cis- and trans- oxazoline-5-carboxylates.
- Lee, Sang-Hyeup,Yoon, Juyoung,Nakamura, Kensuke,Lee, Yoon-Sik
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p. 1243 - 1246
(2007/10/03)
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- Total synthesis of the thiopeptide promothiocin A
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The thiopeptide (or thiostrepton) antibiotics are a class of sulfur-containing highly modified cyclic peptides with interesting biological activity. Described herein is the total synthesis of the thiopeptide antibiotic promothiocin A, which utilizes a mod
- Bagley, Mark C.,Bashford, Katherine E.,Hesketh, Claire L.,Moody, Christopher J.
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p. 3301 - 3313
(2007/10/03)
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- An enantiocontrolled synthesis of the masked taxol C-13 side chain, oxazoline carboxylic acid
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Oxazoline carboxylic acid 6 as the taxol side chain precursor has been efficiently synthesized via the intramolecular iodoamidation of allylic trichloroacetimidate derived from trans-olefinic diol 1.
- Kang, Sung Ho,Kim, Cheol Min,Youn, Joo-Hack
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p. 3581 - 3582
(2007/10/03)
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- Asymmetric total synthesis of Taxol
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The asymmetric total synthesis of Taxol was achieved by way of B to BC to ABC to ABCD ring construction. Optically active 8-membered ring enones 1 and 2 corresponding to the B ring of Taxol have been synthesized in high yields from the linear precursors 28 and 32, respectively, by intramolecular aldol cyclization using SmI2. The optically active linear polyoxy compounds 28 and 32 were obtained by way of diastereoselective aldol reaction between aldehyde 4 and ketene silyl acetal 8 catalyzed by MgBr2 · OEt2. The chiral pentanal 4 was synthesized either by asymmetric aldol reaction of achiral aldehyde 7 and ketene silyl acetal 8 by means of a chiral Lewis acid or by diastereoselective aldol reaction between the chiral aldehyde 16, derived from L-serine, and the lithium enolate derived from methyl isobutyrate. Optically active bicyclo[6.4.0]dodecanone 38β, corresponding to the BC ring system of Taxol, was prepared from 8-membered ring enone 2 in high yield by stereoselective Michael addition and successive intramolecular aldol cyclization. Furthermore, baccatin III, the ABCD ring system of Taxol, was efficiently synthesized from the BC ring system 38β by successive construction of the A and D rings by intramolecular pinacol coupling cyclization, introduction of the C-13 hydroxyl group and an oxetane-forming reaction. Finally, the total synthesis of Taxol was accomplished by dehydration condensation between a protected N-benzoylphenylisoserine 70 or 75 and 7-TES baccatin III, prepared from baccatin III. Taxol side chains 70, 73, 75, and 77, optically active protected N-benzoylphenylisoserines, were synthesized by enantioselective aldol reaction from two achiral starting materials, benzaldehyde and an enol silyl ether 65 derived from S-ethyl benzyloxyethanethioate.
- Mukaiyama, Teruaki,Shiina, Isamu,Iwadare, Hayato,Saitoh, Masahiro,Nishimura, Toshihiro,Ohkawa, Naoto,Sakoh, Hiroki,Nishimura, Koji,Tani, Yu-Ichirou,Hasegawa, Masatoshi,Yamada, Koji,Saitoh, Katsuyuki
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p. 121 - 161
(2007/10/03)
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- Stereocontrolled Synthesis of the Taxol C-13 Side Chain: Methyl (2R,3S)-3-Benzoylamino-2-hydroxy-3-phenylpropanoate
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Addition of lithiated methoxyallene 5 to literature-known amino aldehyde 3 followed by ozonolysis provided syn-configurated α-hydroxy-β-amino ester 6 in moderate overall yield and with an ee of 90%. The predominant formation of syn-compounds may be due to a chelate controlled addition step.
- Schade, Wolfgang,Reissig, Hans-Ulrich
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p. 685 - 686
(2007/10/03)
-
- Process for the production β-amino-α-hydroxycarboxylic acids and derivatives thereof
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Disclosed is a process for producing β-amino-α-hydroxycarboxylic acid derivatives of general formula (2R,3S)- or (2S,3E)-N-(X,Y)-3-amino-2-hydroxy-3-phenyl propionic acid-Z of Formula I, STR1 e.g. of (2E,3S)-3-amino-2-hydroxy-3-phenyl propionic acid or (2R,3S)-N-benzoyl-3-amino-2-hydroxy-3-phenyl propionic acid methylester. Compounds of type I are valuable intermediates in the total synthesis of Taxols which can be used in the treatment of various forms of cancer.
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- Total asymmetric synthesis of taxol by dehydration condensation between 7-TES baccatin III and protected N-benzoylphenylisoserines prepared by enantioselective aldol reaction
-
Total asymmetric synthesis of Taxol was completed by dehydration condensation between a protected N-benzoylphenylisoserine 4 or 9 and 7-TES baccatin in which was prepared from 8-membered ring enone. Taxol side chains 4, 7, 9 and 11, optically active protected N-benzoylphenylisoserines, were successfully synthesized by enantioselective aldol reaction from two achiral starting materials, benzaldehyde and an enol silyl ether derived from S-ethyl benzyloxyethanethioate.
- Shiina, Isamu,Saitoh, Katsuyuki,Frechard-Ortuno, Isabelle,Mukaiyama, Teruaki
-
-
- Lipase-catalyzed transesterification as a practical route to homochiral syn-1,2-diols. The synthesis of the taxol side chain
-
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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- Paclitaxel stability in solution
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Research in this laboratory has focused on the cytokinetic effect of taxanes on nonmammalian systems. Taxanes are a class of natural products that includes the well-known anticancer compound, paclitaxel (Taxol). Our methodology for the study of fungal growth in liquid medium amended with paclitaxel included membrane solid phase extraction (SPE) of the fungal broth. This was followed by elution of paclitaxel from the SPE membrane using methanol. The methanolic solution was evaporated under relatively mild conditions, namely 41-43°C and approximately 85 kPag. Analysis of the concentrated solution indicated that it contained a considerable quantity of 7-epi-taxol and smaller quantities of 7-epi-10-deacetyltaxol, 10-deacetyltaxol, and baccatin III, in addition to paclitaxel, even in those cases where the medium had not been inoculated with fungus. Obviously, fungal metabolism could not account for these observations. Although epimerization in solution at carbon 7 in the C ring of the taxane core has been observed and reported previously, no detailed study of the solution kinetics of paclitaxel degradation, including epimerization, is available. We report here our investigation of the stability of paclitaxel in several solvent systems at various temperatures and pressures. The investigations indicate that the apparent activation energy barrier (Ea) for paclitaxel degradation is highly dependent on experimental conditions. These stability studies emphasize the need to demonstrate explicitly that all taxane degradation, including epimerization, observed during in vitro studies is not an artifact of the analytical methodology employed.
- MacEachern-Keith,Butterfield, L. J. Wagner,Mattina, M. J. Incorvia
-
-
- Asymmetric synthesis of taxol and taxotere side chains by enolate hydroxylation
-
We report an asymmetric synthesis of the taxol and taxotere side chains by hydroxylation of enolates derived from N-substituted methyl 3-amino-3-phenyl propionate with the oxodiperoxymolybdenum (pyridine) (hexamethyl phosphoric triamide) complex (MoOPH). We report an asymmetric synthesis of the taxol and taxotere side chains by hydroxylation of enolates derived from N-substituted methyl 3-amino-3-phenyl propionate with the oxodiperoxymolybdenum (pyridine) (hexamethyl phosphoric triamide) complex (MoOPH).
- Hanessian,Sanceau
-
p. 621 - 624
(2007/10/03)
-
- 4-Isopropyl-2-oxazolin-5-one anion as masked umpoled synthon for both formyl and hydroxycarbonyl anions: Generation, reactivity and synthetic applications
-
The anion of the title compound, simply generated in the presence of catalytic amount of triethylamine, reacts with both common electrophilic olefins and aldehydes to give moderate to good yield of Michael or aldol adducts respectively. Mild acid treatment of these adducts at ambient temperature serves to demask the aldehyde function, allowing one to consider the anion of 1 as a nucleophilic acylating equivalent of formaldehyde. On the other hand, the same anion of 1 may act as a masked umpoled synthon for a hydroxycarbonyl anion since its aldol adducts with aldehydes undersent concomitant isomerization and ring cleavage under mild basic conditions producing dipeptides which could be hydrolyzed to give the corresponding carboxylic acids. Synthetic applications of this chemistry in the area of sugar, aminosugar and non-proteinogenic aminoacid derivatives are discussed.
- Barco, Achille,Benetti, Simonetta,De Risi, Carmela,Pollini, Gian P.,Spalluto, Giampiero,Zanirato, Vinicio
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p. 4719 - 4734
(2007/10/03)
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- Semisynthese von Taxol: eine hochenantio- und -diastereoselektive Synthese der Seitenkette und eine neue Methode zur Esterbildung an C13 unter Verwendung von Thioestern
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Keywords: Asymmetrische Synthesen; Enolate; Imine; Taxol; Thioester
- Gennari, Cesare,Vulpetti, Anna,Donghi, Monica,Mongelli, Nicola,Vanotti, Ermes
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p. 1809 - 1812
(2007/10/03)
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- N-Benzoyl-(2R,3S)-3-Phenylisoserine Methyl Ester; A Facile and Convenient Synthesis and Resolution by Entrainment
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The importance of N-benzoyl (2R,3S)-phenylisoserine (3), also known as the "taxol side chain", for the strong antitumor activity of taxol (1), a potent anticancer drug, has prompted numerous efforts towards the development of a practical taxol side chain synthesis.Here we describe a highly practical and inexpensive synthesis of the taxol side chain methyl ester 4 and resolution via entrainment based on the observation that compound 4 exhibits conglomerate crystal structure.
- Srivastava, Ranjan P.,Zjawiony, Jordan K.,Peterson, John R.,McChesney, James D.
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p. 1683 - 1688
(2007/10/02)
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- Asymmetric Synthesis of the Taxol and Taxotere C-13 Side Chains
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A practical and efficient asymmetric synthesis of the 3-benzoylamino-2-hydroxy-3-phenylpropionic acid derived side chain of the important anticancer agent taxol is described.The pivotal synthetic transformation relies upon the highly diastereoselective tandem lithium amide conjugate addition-electrophilic hydroxylation of tert-butyl cinnamate 4.The resultant anti β-amino-α-hydroxy acid derivative is readily converted to the anti diastereomer of the taxol side chain methyl ester, from which the naturally occuring syn configuration is secured by a simple Mitsunobu inversion sequence via a dihydrooxazole intermediate.Under optimal conditions, this straightforward approach provides the taxol side chain methyl ester (-)-15 (natural enantiomer) in four steps and 60percent yield from tert-butyl cinnamate 4.The protocol is applied to the preparation of all four taxol side chain stereoisomers and is extended to allow for the synthesis of the side chain of taxotere, a potent taxol analogue.
- Bunnage, Mark E.,Davies, Stephen G.,Goodwin, Christopher J.
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p. 2385 - 2392
(2007/10/02)
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- Practical preparation of α-hydroxy-β-amino ester units; Stereoselective synthesis of taxol side chain and norstatine
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An asymmetric reaction of chiral imines with α-silyloxy ketene acetals mediated by chiral boron reagents is described. The key to its success is the use of the chiral boron complex prepared in situ from (R)- or (S)-binaphthol and B(OPh)3. Both diastereomers of α-hydroxy-β-amino ester units are successfully prepared with high selectivities by the chiral boron reagents depending on the geometry of the silyl ketene acetals. The optically pure anti α-hydroxy-β-amino ester is obtained from (E)-silyl ketene acetal, while the corresponding syn α-hydroxy-β-amino ester is obtained from (Z)- silyl ketene acetal. The method can be efficiently applied to the stereoselective synthesis of taxol C-13 side chain and the norstatine family.
- Hattori, Kouji,Yamamoto, Hisashi
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p. 2785 - 2792
(2007/10/02)
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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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- 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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- Application of Yeast-Catalyzed Reductions to Synthesis of (2R,3S)-Phenylisoserine
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A simple synthesis of (2R,3S)-phenylisoserine, a precursor of the C-13 side chain of Taxol (paclitaxel), utilising yeast-catalyzed reduction to generate a second chiral centre is reported.This short enantioselective series of transformations can be readily adapted to large scale production of a variety of N-substituted paclitaxel analogues.
- Kearns, Jeff,Kayser, Margaret
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p. 2845 - 2848
(2007/10/02)
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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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- Chemie und Biologie von Taxol
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Die Pflanzen koennten als Quelle von Verbindungen betrachtet werden, aus denen sich der Chemiker solche mit besonderen Eigenschaften heraussuchen kann.Taxol, ein komplexes, polyoxygeniertes Diterpen aus der Pazifischen Eibe, Taxus brevifolia, wurde in den spaeten sechziger Jahren bei einer umfassenden Untersuchung pflanzlicher Stoffe auf antineoplastische Wirkstoffe entdeckt.In den vergangenen zwei Jahrzehnten sind das Interesse an Taxol und die damit verbundenen Forschungsarbeiten langsam an dem Punkt angelangt, an dem es scheint, dass die Medien aufmerksam geworden sind und jede neue Entwicklung gespannt erwarten.Das, was einstmals eine weitgehend unbekannte Verbindung war, an der nur die masochistischsten unter den Synthesechemikern und eine ebenso kleine Zahl von Zellbiologen Interesse zeigten, ist heute eine der wenigen organischen Substanzen, die - wie etwa Benzol oder Aspirin - auch dem Durchschnittsbuerger dem Namen nach bekannt sind.Die wissenschaftlichen Untersuchungen von Taxol haben sich in dieser Zeit enorm ausgeweitet: Aerzte erforschen zur Zeit seine Wirkung auf nahezu jedes bekannte Neoplasma; Biologen untersuchen die Wechselwirkungen zwischen Taxol und Zellskelettsystemen, um auf diese Weise die Mechanismen zu ergruenden, nach denen Zellen funktionieren; Synthesechemiker, die von der einzigartigen und empfindlichen Struktur sowie von der Funktionalitaet des Taxols gefesselt sind, arbeiten intensiv daran, einen synthetischen Zugang zu ihm zu finden.Die Nachfrage nach Taxol ist in der Tat in den letzten fuenf Jahren so stark gestiegen, dass intensiv nach Quellen alternativ zur Extraktion von T. brevifolia gesucht wird.Da bei den vielfaeltigen Arbeiten ueber Taxol der Wissensumfang schnell zunimmt, mag es fuer den in diesem Gebiet Interessierten schwierig sein, sich ein angemessenes Grundwissen anzueignen.Wir wollen in diesem Beitrag daher erstmalig versuchen, einen Ueberblick sowohl ueber die Chemie als auch ueber die Biochemie dieser einzigartigen Verbindung zu geben.
- Nicolaou, Kyriacos Costa,Dai, Wei-Min,Guy, Rodney Kiplin
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- THE CHEMISTRY OF TAXANES: REACTIONS OF TAXOL AND BACCATIN DERIVATIVES WITH LEWIS ACIDS IN APROTIC AND PROTIC MEDIA
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Several Lewis acids were shown to cleanyl open the oxetane ring of taxol and baccatin derivatives.The reaction is shown to proceed via anchimeric assistance by the C-4 acetate group.Several minor products, including a novel derivative possessing a bridged C-ring, were also isolated.A mechanistric rationale is provides for all compounds formed.When taxol derivatives were treated with Lewis acids in methanol, ester cleavage reactions were observed.We provide conditions that are selective for C-10 acetate cleavage and for C-13 side-chain methanolysis.
- Chen, Shu-Hui,Huang, Stella,Wei, Jianmei,Farina, Vittorio
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p. 2805 - 2828
(2007/10/02)
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- Highly stereocontrolled asymmetric syntheses of taxol and taxotere C-13 side chain analogues
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Asymmetric aldol reaction of (+)-tricarbonyl(η6-2-trimethylsilylbenzaldehyde)chromium(0) complex (4) with titanium enolate of S-tert-butyl benzyloxyethanethioate (10) provided, after consecutive desilylation and decomplexation, anti-aldol product 15 in a highly stereo selective manner. Anti-product 15 was subsequently converted to (2R,3S)-N-benzoyl- and N-tert-butoxycarbonyl-3-phenylisoserine methyl esters (23 and 24), C-13 side chain analogues of taxol (1) and taxotere (2).
- Mukai, Chisato,Kim, In Jong,Furu, Etsuko,Hanaoka, Miyoji
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p. 8323 - 8336
(2007/10/02)
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- Chiral Auxiliary-Mediated Asymmetric Induction in a Thermal Inverse Electron Demand Hetero-Diels-Alder Reaction. Enantioselective Synthesis of the Taxol A-Ring Side Chain
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Chiral auxiliary-modified ketene acetal 5g and N-benzoylbenzaldimine (4) engage in an endo and ?-facially selective thermal inverse electron demand hetero-Diels-Alder reaction that is the key step in a synthesis of enantiomerically pure taxol A-ring side-chain methyl ester 9.
- Swindell, Charles S.,Tao, Ming
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p. 5889 - 5891
(2007/10/02)
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- Chemoenzymatic Synthesis of the C-13 Side Chain of Taxol: Optically Active 3-Hydroxy-4-phenyl β-Lactam Derivatives
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Enantiomerically pure 3-hydroxy-4-phenyl β-lactam derivatives have been successfully prepared via enantioselective hydrolyses and transesterifications of racemic esters and alcohols respectivily catalyzed by bacterial lipases.These lipases also catalyzed highly enantioselective cleavage of the β-lactam ring of (+/-)-10 to yield derivatives of (2R,3S)-phenylisoserine in high enantiomeric excess.The resolved enantiomers are important intermediates in the synthesis of the C-13 side chain of taxol.
- Brieva, Rosario,Crich, Joyce Z.,Sih, Charles J.
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p. 1068 - 1075
(2007/10/02)
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- Asymmetric Synthesis of Sulfinimines: Applications to the Synthesis of Nonracemic β-Amino Acids and α-Hydroxy-β-amino Acids
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Asymmetric oxidation of sulfenimines 1 affords sulfinimines 2 (88-90percent ee) which are chiral ammonia imine synthons useful in the enantioselective synthesis of β-amino acids and α-hydroxy-β-amino acids such as the C-13 side chain of taxol (2R,3S)-7.
- Davis, Franklin A.,Reddy, R. Thimma,Reddy, Rajarathnam E.
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p. 6387 - 6389
(2007/10/02)
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