- Utilization of (18-Crown-6)-2,3,11,12-tetracarboxylic Acid as a Chiral NMR Solvating Agent for Diamines and β-Amino Acids
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The compound (18-crown-6)-2,3,11,12-tetracarboxylic acid was evaluated as a chiral nuclear magnetic resonance (NMR) solvating agent for a series of diamines and bicyclic β-amino acids. The amine must be protonated for strong association with the crown ether. An advantage of (18-crown-6)-2,3,11,12-tetracarboxylic acid over many other crown ethers is that it undergoes a neutralization reaction with neutral amines to form the protonated species needed for binding. Twelve primary diamines in neutral and protonated forms were evaluated. Diamines with aryl and aliphatic groups were examined. Some are atropisomers with equivalent amine groups. Others have two nonequivalent amine groups. Association equilibria for these systems are complex, given the potential formation of 2:1, 1:1, and 1:2 crown-amine complexes and given the various charged species in solution for mixtures of the crown ether with the neutral amine. The crown ether produced enantiomeric differentiation in the 1H NMR spectrum of one or more resonances for every diamine substrate. Also, a series of five bicyclic β-amino acids were examined and (18-crown-6)-2,3,11,12-tetracarboxylic acid caused enantiomeric differentiation in the 1H NMR spectrum of three or more resonances of each compound. Chirality 27:708-715, 2015.
- Rodriguez, Yolanda C.,Duarte, Tayla M.,Szakonyi, Zsolt,Forr?, Eniko,Fül?p, Ferenc,Wenzel, Thomas J.
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Read Online
- The N-Hydroxymethyl Group as a Traceless Activating Group for the CAL-B-Catalysed Ring Cleavage of β-Lactams: A Type of Two-Step Cascade Reaction
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An efficient enzymatic two-step cascade procedure has been devised for rapid access to diverse amino acids from N-hydroxymethyl-β-lactams; representative amino acids include the antifungal agent cispentacin, intermediates for the taxol side-chain, and assorted cathepsin inhibitors. When CAL-B-catalysed hydrolyses of racemic N-hydroxymethyl-β-lactams were performed with H2O (0.5 equiv.) in iPr2O at 60 °C, relatively quick (vs. non-activated counterparts) and enantioselective (E > 200) ring cleavage reactions took place. As the ring-opened amino acids formed, the hydroxymethyl group, as a traceless activating group, underwent spontaneous in situ degradation. Consequently, the desired β-amino acid and unreacted N-hydroxymethyl-β-lactam enantiomers (ee > 95 %) were formed. The formation of polymers, induced by liberation of formaldehyde, was successfully restricted by the addition of benzylamine as a capture agent, to the enzymatic reactions. An efficient enzymatic two-step cascade procedure was devised for CAL-B-catalysed hydrolysis of racemic N-hydroxymethyl-β-lactams. Conditions in which the hydroxymethyl group serves as a traceless activating group (E > 200), giving desired β-amino acid along with unreacted starting lactam enantiomers (ee > 95 %) were identified; polymerization was controlled by addition benzylamine addition.
- Forró, Enik?,Galla, Zsolt,Fül?p, Ferenc
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p. 2647 - 2652
(2016/06/09)
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- Enantioselective hydrolysis of 3,4-disubstituted β-lactams. An efficient enzymatic method for the preparation of a key Taxol side-chain intermediate
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3,4-Disubstituted β-lactams 3-benzyloxy-4-(4-chlorophenyl)azetidin-2-one [(3S?,4R?)-(±)-1], 3-benzyloxy-4-phenylazetidin-2-one [(3S?,4R?)-(±)-2] and 4-(4-chlorophenyl)-3-phenoxyazetidin-2-one [(3S?,4R?)-(±)-3] were resolved through immobilized CAL-B-catalysed ring-cleavage reactions. Excellent enantioselectivities (E > 200) were obtained for (3S?,4R?)-(±)-1 and (3S?,4R?)-(±)-2 when the reactions were performed with added H2O as nucleophile in tert-butyl methyl ether at 70 °C, whereas only moderate E (12) was achieved for (3S?,4R?)-(±)-3 under the same conditions but in diisopropyl ether. The resulting ring-opened β-amino acids [(2R,3S)-4 (ee > 98%), (2R,3S)-5 (ee > 98%) and (2R,3S)-6 (ee = 50%)] and the unreacted β-lactams [(3S,4R)-1-3] (ee > 98%) could be easily separated.
- Galla, Zsolt,Beke, Ferenc,Forró, Eniko,Fül?p, Ferenc
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p. 107 - 112
(2015/12/01)
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- An investigation of nitrile transforming enzymes in the chemo-enzymatic synthesis of the taxol sidechain
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Paclitaxel (taxol) is an antimicrotubule agent widely used in the treatment of cancer. Taxol is prepared in a semisynthetic route by coupling the N-benzoyl-(2R,3S)-3-phenylisoserine sidechain to the baccatin III core structure. Precursors of the taxol sidechain have previously been prepared in chemoenzymatic approaches using acylases, lipases, and reductases, mostly featuring the enantioselective, enzymatic step early in the reaction pathway. Here, nitrile hydrolysing enzymes, namely nitrile hydratases and nitrilases, are investigated for the enzymatic hydrolysis of two different sidechain precursors. Both sidechain precursors, an openchain α-hydroxy-β-amino nitrile and a cyanodihydrooxazole, are suitable for coupling to baccatin III directly after the enzymatic step. An extensive set of nitrilases and nitrile hydratases was screened towards their activity and selectivity in the hydrolysis of two taxol sidechain precursors and their epimers. A number of nitrilases and nitrile hydratases converted both sidechain precursors and their epimers.
- Wilding, Birgit,Veselá, Alicja B.,Perry, Justin J. B.,Black, Gary W.,Zhang, Meng,Martínková, Ludmila,Klempier, Norbert
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p. 7803 - 7812
(2015/07/15)
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- New enzymatic two-step cascade reaction for the preparation of a key intermediate for the taxol side-chain
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Enzymatic strategies are reported for the synthesis of (2R, 3S)-3-amino-2-hydroxy-3-phenylpropionic acid (ee > 98%), a key intermediate of the side-chain of Taxolby enzymatic hydrolysis in organic media. The new enzymatic cascade reaction, which took place through Candida antarctica lipase B-catalysed deacylation followed by lactam ring-opening of racemic cis-3-acetoxy-4-phenylazetidin-2-one with H2O in iPr2O at: 60 °C, resulted in two different enantiopure products (ee ≥ 98%), one of them being the desired key intermediate for the side-chain of Taxol.
- Forro, Enikoe,Fueloep, Ferenc
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experimental part
p. 3074 - 3079
(2010/08/07)
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- A new enzymatic strategy for the preparation of (2R,3S)-3-phenylisoserine: a key intermediate for the Taxol side chain
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Burkholderia cepacia lipase PS-IM catalysed the hydrolysis of racemic ethyl 3-amino-3-phenyl-2-hydroxypropionate with excellent enantioselectivity (E >200), when the reaction was performed with added H2O as a nucleophile, in iPr2O, at 50 °C. The hydrolysis of the less reactive enantiomeric ethyl 3-amino-3-phenyl-2-hydroxypropionate with 18% HCl afforded the corresponding enantiomerically pure (2R,3S)-3-amino-3-phenyl-2-hydroxypropionic acid hydrochloride, a key intermediate for the Taxol side chain.
- Forro, Eniko,Fueloep, Ferenc
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scheme or table
p. 637 - 639
(2010/08/03)
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- Tachysan useful for synthesizing method for producing compd. homochiral
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A method is provided for processing a solution having optical isomers to obtain a (2R,3S) target isomer:wherein P1 is H or a hydroxyl protecting group, R1 is H, an alkyl group, an olefinic group or an aromatic group, and R2 is H or R3CO, where R3 is an alkyl group, an olefinic group, an aromatic group, an O-alkyl group, an O-olefinic group or an O-aromatic group, provided that Ris not H when Ris Ph and Pis H. The method includes passing the solution through a chromatographic stationary phase, such as S,S Whelk-O, that has a greater affinity for one of the target isomer and an optical isomer thereof. A portion of the solution with the target isomer is then collected. The solution may be a racemic mixture of (±)-N-CBZ-3-phenylisoserine ethyl ester.
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Page/Page column 16
(2008/06/13)
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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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- Chiral resolution method for producing compounds useful in the synthesis of taxanes
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A method is provided for processing a solution having optical isomers to obtain a (2R,3S) target isomer: wherein P1 is H or a hydroxyl protecting group, R1 is H, an alkyl group, an olefinic group or an aromatic group, and R2 is H or R3CO, where R3 is an alkyl group, an olefinic group, an aromatic group, an O-alkyl group, an O-olefinic group or an O-aromatic group, provided that R1 is not H when R3 is Ph and P1 is H. The method includes passing the solution through a chromatographic stationary phase, such as S,S Whelk-O, that has a greater affinity for one of the target isomer and an optical isomer thereof. A portion of the solution with the target isomer is then collected. The solution may be a racemic mixture of (±)-N-CBZ-3-phenylisoserine ethyl ester.
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- First one-pot copper-catalyzed synthesis of α-hydroxy-β-amino acids in water. A new protocol for preparation of optically active norstatines
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α-Hydroxy-β-amino acids were synthesized with excellent yields for the first time in water and by a simple procedure based on a copper catalytic cycle, which included the recovery and reuse of the catalyst and is possible to realize by using only water as reaction medium.
- Fringuelli, Francesco,Pizzo, Ferdinando,Rucci, Mauro,Vaccaro, Luigi
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p. 7041 - 7045
(2007/10/03)
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- N,N-dialkylhydrazones as the imine component in the Staudinger-like [2+2] cycloaddition to benzyloxyketene
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To overcome the limitations of using unstable imines in Staudinger cycloadditions to ketenes, aldehyde N,N-dialkylhydrazones 1 were used as stable imines. This strategy and a fine tuning of the auxiliary result in a straightforward synthesis of cycloadducts 2, deprotected β-lactams 3, and isoserines 4 (see scheme: a) Et3N, toluene, Δ; b) 1. magnesium monoperoxyphthalate, 2. H2, Pd/C; c) H+).
- Fernandez, Rosario,Ferrete, Ana,Lassaletta, Jose M.,Llera, Jose M.,Martin-Zamora, Eloisa
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p. 831 - 833
(2007/10/03)
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- Lipase-catalyzed transesterification of methyl 2-substituted 3-hydroxy-4-pentenoates and its synthetic application to the taxol side chain
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Syn-and anti-methyl 2-substituted 3-hydroxy-4-pentenoates were efficiently resolved in lipase-catalyzed transesterification. This protocol was successfully applied to the synthesis of the taxol side chain.
- Mandai, Tadakatsu,Oshitari, Tetsuta,Susowake, Masafumi
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p. 1665 - 1668
(2007/10/03)
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- Two step synthesis of D- and L- α-amino acids and D- and L- α-amino-aldehydes
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D- and L-α-amino acids and D- and L-α-amino aldehydes are synthesized from olefin substrates in two steps. The first step is a catalyzed asymmetric aminohydroxylation addition reaction to the olefin substrate. The addition reaction is catalyzed by osmium and is co-catalyzed by chiral ligands. The chiral ligands, in addition to being co-catalysts with the osmium, also serve to direct the addition reaction regioselectively and enantioselectively. Divalent ligands are preferred over monovalent ligands because of their enhance regio- and enantio-selectivity. As an oxidant nitrogen source for the addition reaction, either a carbamate or sulfonamide may be employed. If carbamate is employed as an oxidant nitrogen source, the resultant β-hydroxycarbamate is deprotected to yield the corresponding β-hydroxyamine. If sulfonamide is employed as an oxidant nitrogen source, the resultant β-hydroxysulfonamide is deprotected to yield the corresponding β-hydroxyamine. The resultant β-hydroxyamine is then selectively oxidized in a second synthetic step to produce the desired D- and L-α-amino acid or D- and L-α-amino aldehyde.
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- Catalytic asymmetric aminohydroxylation of olefins with sulfonamides
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β-Hydroxyamines and β-hydroxysulfonamides are synthesized from olefin substrates by means on a catalyzed asymmetric addition reaction. The addition reaction is catalyzed by osmium and is co-catalyzed by chiral ligands. The chiral ligands, in addition to being co-catalysts with the osmium, also serve to direct the addition reaction regioselectively and enantioselectively. Divalent ligands are preferred over monovalent ligands because of their enhance regio- and enantio-selectivity. Sulfonamides are employed as an oxidant nitrogen source for the production of β-hydroxysulfonamides. Excellent yields and enantiomeric efficiencies are achieved with co-solvents containing a 50/50 (v/v) mixtures of water and organic solvent. β-Hydroxyamines are obtained by deprotecting the corresponding β-hydroxysulfonamides.
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- Chiral catalysts and catalytic epoxidation catalyzed thereby
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Methods of using chiral catalysts for enantioselectively epoxidizing a prochiral olefin and for enantioselectively oxidizing a prochiral sulfide are disclosed. In accordance with one aspect of the invention, the catalyst used is a salen derivative which has the following general structure: STR1 In accordance with another aspect of the present invention is a method of producing an epoxychroman using a chiral catalyst. In accordance with this method, a chromene derivative, an oxygen atom source, and a chiral catalyst are reacted under such conditions and for such time as is needed to epoxidize said chromene derivative. In accordance with yet another aspect of this invention is a method of enantioselectively epoxidizing a cis-cinnamate derivative to make taxol or an analog thereof. In accordance with another aspect a method of disproportionation of hydrogen peroxide using the catalysts of the present invention is disclosed.
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- Catalytic asymmetric aminohydroxylation provides a short taxol side-chain synthesis.
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The p-toluenesulfonamide derivate of the C-13 side-chain of taxol was prepared on a one third mole scale in a single step from methyl cinnamate. The process employed is catalytic asymmetric aminohydroxylation (catalytic AA). In the present case, there is no work-up other than filtration of the pure product which is insoluble in the reaction mixture. The sulfonamide protecting group is removed by acidic hydrolysis.
- Li,Sharpless
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p. 649 - 651
(2007/10/03)
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- Katalytische asymmetrische Aminohydroxylierung (AA) von Olefinen
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Keywords: β-Aminoalkohole; Asymmetrische Aminohydroxylierung; Chloramin T; Osmiumverbindungen; Taxolseitenkette
- Li, Guigen,Chang, Han-Ting,Sharpless, K. Barry
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p. 449 - 452
(2007/10/03)
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- Process for the production of chiral hydroxy-β-lactams and hydroxyamino acids derived therefrom
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The reaction between a hydroxyacetic acid derivative bearing an oxygen protecting group and a chiral auxiliary group and an imine produces chiral β-lactams. Hydrolysis of the chiral β-lactams produces chiral amino acid analogs.
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