- Optically active 2-amino-4-alkoxypyrimidnes derivatives as 5-HT2C agonists
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The present invention provides an optically active 2-amino-4-alkoxy pyrimidine derivative that has excellent performance as a 5-HT2C agonist but has high selectivity to 2A and 2B. The present invention provides the optically active 2-amino-4-alkoxy pyrimidine derivative having a structure of chemical formula 1.COPYRIGHT KIPO 2020
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Paragraph 0122; 0123
(2019/12/25)
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- Synthesis and biological evaluation of disubstituted pyrimidines as selective 5-HT2C agonists
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Here, we describe the synthesis of disubstituted pyrimidine derivatives and their biological evaluation as selective 5-HT2C agonists. To improve selectivity for 5-HT2C over other subtypes, we synthesized two series of disubstituted pyrimidines with fluorophenylalkoxy groups at either the 5-position or 4-position and varying cyclic amines at the 2-position. The in vitro cell-based assay and binding assay identified compounds 10a and 10f as potent 5-HT2C agonists. Further studies on selectivity to 5-HT subtypes and drug-like properties indicated that 2,4-disubstituted pyrimidine 10a showed a highly agonistic effect on the 5-HT2C receptor, with excellent selectivity, as well as exceptional drug-like properties, including high plasma and microsomal stability, along with low CYP inhibition. Thus, pyrimidine 10a could be considered a viable lead compound as a 5-HT2C selective agonist.
- Kim, Juhyeon,Kim, Yoon Jung,Londhe, Ashwini M.,Pae, Ae Nim,Choo, Hyunah,Kim, Hak Joong,Min, Sun-Joon
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- Base-Free Dynamic Kinetic Resolution of Secondary Alcohols with a Ruthenium-Lipase Couple
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We report the dynamic kinetic resolution (DKR) of various secondary alcohols by the combination of a ruthenium catalyst and an anionic surfactant-activated lipoprotein lipase. The DKR reactions performed under totally base-free conditions at room temperature provided the products of excellent enantiopurities (91-99% ee or greater) in high yields (92-99%). More importantly, the DKR of α-arylallyl alcohols was achieved for the first time with high yields (87-91%).
- Yun, Inyeol,Park, Jin Yong,Park, Jaiwook,Kim, Mahn-Joo
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p. 16293 - 16298
(2019/12/27)
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- Asymmetric Chemoenzymatic Reductive Acylation of Ketones by a Combined Iron-Catalyzed Hydrogenation–Racemization and Enzymatic Resolution Cascade
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A general and practical process for the conversion of prochiral ketones into the corresponding chiral acetates has been realized. An iron carbonyl complex is reported to catalyze the hydrogenation–dehydrogenation–hydrogenation of prochiral ketones. By merging the iron-catalyzed redox reactions with enantioselective enzymatic acylations a wide range of benzylic, aliphatic and (hetero)aromatic ketones, as well as diketones, were reductively acylated. The corresponding products were isolated with high yields and enantioselectivities. The use of an iron catalyst together with molecular hydrogen as the hydrogen donor and readily available ethyl acetate as acyl donor make this cascade process highly interesting in terms of both economic value and environmental credentials.
- El-Sepelgy, Osama,Brzozowska, Aleksandra,Rueping, Magnus
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p. 1664 - 1668
(2017/04/27)
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- Merging Iron Catalysis and Biocatalysis—Iron Carbonyl Complexes as Efficient Hydrogen Autotransfer Catalysts in Dynamic Kinetic Resolutions
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A dual catalytic iron/lipase system has been developed and applied in the dynamic kinetic resolution of benzylic and aliphatic secondary alcohols. A detailed study of the Kn?lker-type iron complexes demonstrated the hydrogen autotransfer of alcohols to proceed under mild reaction conditions and allowed the combination with the enzymatic resolution. Different racemic alcohols were efficiently converted to chiral acetates in good yields and with excellent enantioselectivities.
- El-Sepelgy, Osama,Alandini, Nurtalya,Rueping, Magnus
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supporting information
p. 13602 - 13605
(2016/10/21)
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- Mechanochemical Enzymatic Kinetic Resolution of Secondary Alcohols under Ball-Milling Conditions
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Mechanosynthesis is a valuable technique, offering attractive alternatives for the preparation of organic, inorganic, and organometallic products. Surprisingly, mechanochemical enzymatic transformations have only scarcely been studied until now. Here, we demonstrate the use of lipase B from Candida antarctica (CALB) in acylative kinetic resolutions of secondary alcohols in mixer and planetary mills. Despite the mechanical stress caused by the high-speed ball milling, the biocatalyst proved highly effective, stable, and, in part, recyclable under the applied mechanochemical conditions. Best milling practice: The compatibility of lipase B from Candida antarctica (CALB) in acylative kinetic resolutions of secondary alcohols in mixer and planetary mills has been explored. Despite the mechanical stress caused by the high-speed ball milling, the biocatalyst was found to be very effective, stable, and, in part, recyclable under the applied mechanochemical conditions.
- Hernández, José G.,Frings, Marcus,Bolm, Carsten
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p. 1769 - 1772
(2016/06/01)
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- Accessing N-Stereogenicity through a Double Aza-Michael Reaction: Mechanistic Insights
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Further development of the chemistry and applications of chiral compounds that possess configurationally stable stereogenic nitrogen atoms is hampered by the lack of efficient strategies to access such compounds in an enantiomerically pure form. Esters of propiolic acid and chiral alcohols were evaluated as cheap and readily available Michael acceptors in a diastereoselective synthesis of N-stereogenic compounds by means of a double aza-Michael conjugate addition. Diastereomeric ratios of up to 74:26 and high yields were achieved with (-)-menthyl propiolate as a substrate. Furthermore, a detailed mechanistic investigation was undertaken to shed some light on the course of this domino transformation. Kinetic studies revealed that the protic-solvent additive acts as a Bronsted acid and activates the ester toward the initial attack of the tetrahydrodiazocine partner. Conversely, acidic conditions proved unfavorable during the final cyclization step that provides the product.
- Kohrt, Sonja,Santschi, Nico,Cvengro, Jn
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p. 390 - 403
(2016/01/25)
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- Kinetic resolution of secondary alcohols with Burkholderia cepacia lipase immobilized on a biodegradable ternary blend polymer matrix as a highly efficient and heterogeneous recyclable biocatalyst
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The present work reports a highly efficient and biocatalytic heterogeneous protocol for kinetic resolution (KR) of racemic secondary alcohols with vinyl acetate as an acyl donor, using the biocatalyst Burkholderia cepacia lipase (BCL) immobilized on a biodegradable ternary blend support through polylactic acid (PLA)/polyvinyl alcohol (PVA)/chitosan (CHI); (PLA/PVA/CHI-BCL). The KR reaction with various substituted aromatic, heterocyclic racemic secondary alcohols gave enantiomerically pure alcohol and its enantioenriched acetate derivatives with high conversion (45-50%) and excellent enantiomeric excess (up to 99% ee) at optimized reaction conditions. The reaction works under mild conditions using simple and inexpensive starting materials such as racemic alcohols, vinyl acetate, and immobilized biocatalyst. The given protocol provides excellent recyclability with good yield and enantiomeric excess values up to the studied range of five cycles. The resultant products were characterized with the help of different analytical techniques such as 1H and 13C-NMR, chiral HPLC column, polarimeter, IR and GC-MS.
- More, Ganesh V.,Badgujar, Kirtikumar C.,Bhanage, Bhalchandra M.
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p. 4592 - 4598
(2015/02/19)
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- Chemoenzymatic approaches to obtain chiral-centered selenium compounds
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The synthesis of chiral-centered selenium compounds is presented. Enantioselective oxidations of these organoselenium compounds were performed using a wide range of biocatalysts, including Baeyer-Villiger monooxygenases, oxidoreductases-containing Aspergillus terreus and lipase (Cal-B) in the presence of oxidants. Finally, efficient synthesis of enantiopure organoselenium compounds using a kinetic resolution approach mediated by Cal-B was achieved.
- Brondani, Patricia B.,Guilmoto, Nathalie M. A. F.,Andrade, Leandro H.,Dudek, Hanna M.,Fraaije, Marco W.
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p. 10431 - 10436,6
(2012/12/12)
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- Chemoenzymatic approaches to obtain chiral-centered selenium compounds
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The synthesis of chiral-centered selenium compounds is presented. Enantioselective oxidations of these organoselenium compounds were performed using a wide range of biocatalysts, including Baeyer-Villiger monooxygenases, oxidoreductases-containing Aspergillus terreus and lipase (Cal-B) in the presence of oxidants. Finally, efficient synthesis of enantiopure organoselenium compounds using a kinetic resolution approach mediated by Cal-B was achieved.
- Brondani, Patrícia B.,Guilmoto, Nathalie M.A.F.,Dudek, Hanna M.,Fraaije, Marco W.,Andrade, Leandro H.
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p. 10431 - 10436
(2013/01/15)
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- Modular P-OP ligands in rhodium-mediated asymmetric hydrogenation: A comparative catalysis study
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Highly efficient and enantioselective hydrogenation reactions for α-(acylamino)acrylates, itaconic acid derivatives and analogues, α-substituted enol ester derivatives, and α-arylenamides (25 substrates) catalyzed by chiral cationic rhodium complexes of a set of P-OP ligands have been developed. The catalytic systems derived from these P-OP ligands provided a straightforward access to enantiomerically enriched α-amino acid, carboxylic acid, amine, and alcohol derivatives that are valuable chiral building blocks. Excellent efficiencies (full conversion in all cases) and extremely high enantiomeric excesses (94-99% ee) were achieved for a wide range of α-substituted enol ester derivatives, regardless of the substitution pattern. The R-oxy group of the ligand (methoxy or triphenylmethoxy) strongly influences the enantioselectivity and catalytic activity. Greater steric bulk around the metal centre correlated to greater (or similar) enantioselectivity, but also to slower hydrogenation. Furthermore, the hydrogenation rates observed with the four model substrates follow the same trend, independently of the R-oxy group of the ligand: methyl 2-acetamidoacrylate>dimethyl itaconate>1-phenylvinyl acetate>N-(1- phenylvinyl)acetamide. A substrate-to-catalyst ratio (S/C) of up to 10,000:1 was sufficient for total hydrogenation of a model substrate of intermediate reactivity (dimethyl itaconate), and did not imply any loss in conversion or enantioselectivity. Copyright
- Nunez-Rico, Jose L.,Etayo, Pablo,Fernandez-Perez, Hector,Vidal-Ferran, Anton
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supporting information
p. 3025 - 3035
(2013/01/15)
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- Dynamic kinetic resolution of a wide range of secondary alcohols: Cooperation of dicarbonylchlorido(pentabenzylcyclopentadienyl)ruthenium and CAL-B
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The substrate scope in the dynamic kinetic resolution ofsecondary alcohols was studied by using 31 structurallydifferent alcohols and isopropenyl acetate in the presence ofdicarbonylchlorido(pentabenzylcyclopentadienyl)rutheniumand Candida antarctica lipase B (Novozym 435, CAL-B) in toluene. The enzyme and the ruthenium complex were shown to function in a highly compatible manner allowing the conversion of the racemic alcohols into the (R)-acetates in practically theoretical yields and, in most cases, ee values exceeding 99%. The results are fully comparable to those published previously by using earlier reported, state-of-the-art ruthenium-based catalysts for the alcohol racemization. A clear benefit of the dicarbonylchlorido(pentabenzylcyclopentadienyl)ruthenium system, when compared to other (cyclopentadienyl)ruthenium racemization catalysts, is its simple and cost-efficient preparation. The substrate scope of 31 secondary alcohols was studied in the dynamic kinetic resolution by utilizing dicarbonylchlorido(pentabenzylcyclopentadienyl)rutheniumand Candida antarctica lipase B (CAL-B) in the acylation with isopropenyl acetate in toluene at room temperature. The secondary alcohols were transformed into highly enantiopure (R)-acetates (in most cases ee > 99%) in close to quantitative isolatedyields. Copyright
- Paeivioe, Mari,Mavrynsky, Denys,Leino, Reko,Kanerva, Liisa T.
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supporting information; experimental part
p. 1452 - 1457
(2011/04/22)
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- Asymmetric transfer hydrogenation of ketones in aqueous solution catalyzed by rhodium(III) complexes with C2-symmetric fluorene-ligands containing chiral (1R,2R)-cyclohexane-1,2-diamine
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Two C2-symmetric bis(sulfonamide) ligands containing fluorene-chiral (1R,2R)-cyclohexane- 1,2-diamine were complexed to Rh III(Cp*) and used as catalyst to reduce aromatic ketones. The corresponding chiral secondary alcohols were obtained in 87-100percent ee and 85-99percent yield, under asymmetric transfer hydrogenation (ATH) conditions using aqueous sodium formate as the hydride source. With acetophenone, 94percent ee and 86-97percent yield was achieved with substrate/catalyst (S/C) ratio of 10,000.
- Montalvo-Gonza?lez, Rube?n,Cha?vez, Daniel,Aguirre, Gerardo,Parra-Hakea, Miguel,Somanathan, Ratnasamy
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experimental part
p. 431 - 435
(2010/07/16)
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- Synthesis of a novel ruthenium(I{cyrillic, ukrainian}I{cyrillic, ukrainian}) complex and its unique behaviors in enzymatic dynamic kinetic resolution of secondary alcohols
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A cyclopentadienyl benzoyl ruthenium(I{cyrillic, ukrainian}I{cyrillic, ukrainian}) complex 3 was first prepared as an efficient catalyst in Candida Antarctica lipase B (CALB) mediated dynamic kinetic resolution (DKR) of secondary alcohols. With the aid of this ruthenium complex 3, (S)-1-phenylethanol was completely racemized within 25 min, and in combination with CALB, series of secondary alcohols bearing various functional groups were resolved in an efficient DKR manner. A detailed mechanism involving the C-H bond activation was presented for the formation of complex 3 by capturing the crucial intermediate in this pathway. Related mechanistic studies were carried out to illustrate this type of DKR catalyst is based on the racemization of secondary alcohols. The novelty of its structure, its unique catalytic behavior as well as its wide scope of application of various substrates and its higher efficiency make complex 3 as an important alternative to those complexes, which are commonly used in DKR process.
- Chen, Qihui,Yuan, Chengye
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experimental part
p. 3707 - 3716
(2010/07/05)
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- Highly efficient dynamic kinetic resolution of secondary aromatic alcohols with low-cost and easily available acid resins as racemization catalysts
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A new and efficient dynamic kinetic resolution (DKR) process of secondary aromatic alcohols was developed with acid resins as racemization catalysts. Acid resin CD8604 was shown to have excellent racemization activity and good biocompatibility. When employing CD8604 and complex acyl donors as racemization catalyst and acyl donor, respectively, enantiomerically pure aromatic acetate was obtained with excellent yield and ee values through the DKR process. It is noteworthy that the system could be reused more than 10 times with little loss of yield and ee value.
- Cheng, Yongmei,Xu, Gang,Wu, Jianping,Zhang, Chensheng,Yang, Lirong
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experimental part
p. 2366 - 2369
(2010/06/13)
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- Synthesis of chiral aromatic alcohols: Use of new C2-symmetric RhIIICp*, RuII(cymene), or RuII(benzene) complexes containing chiral diaminocyclohexane ligand as asymmetric transfer hydrogenation catalyst
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Twelve chiral secondary alcohols were synthesized by asymmetric transfer hydrogenation (ATH) using C2-symmetric bis(sulfonamide) ligand (2) derived from (1R,2R)-cyclohexane-1,2-diamine and complexed with [RhCl 2CP*]2, [RuCl2(cymene)] 2, or [RuCl2(benzene)]2 and then used in situ in the reduction of prochiral ketones. The alcohols were obtained in 85-99% yield and 90-99% enantioselectivity with isopropanol as the hydrogen source. Two-fold rate enhancement and better yields were achieved (88-99%) with 80-99% enantioselectivity using the complex [RhCl2CP*] 2 and aqueous sodium formate as the hydrogen source.
- Montalvo-Gonzalez, Ruben,Chavez, Daniel,Aguirre, Gerardo,Parra-Hake, Miguel,Somanathan, Ratnasamy
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experimental part
p. 2737 - 2746
(2009/12/06)
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- An unexpected ruthenium complex and its unique behavior as catalyst in dynamic kinetic resolution of secondary alcohols
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A ruthenium complex was accidentally synthesized and its unique catalytic behavior in dynamic kinetic resolution of various types of secondary alcohols, particularly for those bearing additional functional groups, is described. The Royal Society of Chemis
- Chen, Qihui,Yuan, Chengye
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supporting information; experimental part
p. 5333 - 5335
(2009/03/11)
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- High-yielding metalloenzymatic dynamic kinetic resolution of fluorinated aryl alcohols
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Dynamic kinetic resolution (DKR) of various fluorinated aryl alcohols by a combination of lipase-catalyzed enzymatic resolution with in situ ruthenium-catalyzed alcohol racemization is described. (R)-Selective Candida antarctica lipase B (CALB) was employed for transesterification of different fluoroaryl alcohols in DKR reactions delivering the corresponding acetates in high yield (≥97%) with excellent enantiomeric excess (≥98%).
- Bogár, Krisztián,B?ckvall, Jan-E.
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p. 5471 - 5474
(2008/02/10)
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- Asymmetric transesterification of secondary alcohols catalyzed by feruloyl esterase from Humicola insolens
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A new asymmetric transesterification of secondary alcohols catalyzed by feruloyl esterase from Humicola insolens has been found. Although alcohols are not the natural substrates for this enzyme, a high R enantioselectivity was observed. Stereochemical studies showed that variations in substrate structure lead to strong variations in enantioselectivity. The highest enantioselectivities are obtained when the β-carbon of the secondary alcohol is tertiary or quaternary.
- Hatzakis, Nikos S.,Smonou, Ioulia
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p. 325 - 337
(2007/10/03)
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- Practical P-chiral phosphane ligand for Rh-catalyzed asymmetric hydrogenation
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A highly electron-donating and conformationally rigid P-chiral bis(trialkylphospholane) ligand 2 (DuanPhos) has been prepared in both enantiomeric forms through a concise synthesis. Rh-2 complex has exhibited remarkably high enantio-selectivities (up to >99% ee) and reactivities (up to 10,000 TON) for the hydrogenation of a wide variety of functionalized prochiral alkenes (5 different types), which provides a very practical catalytic system for the preparation of various synthetically useful chiral compounds. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005.
- Liu, Duan,Zhang, Xumu
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p. 646 - 649
(2007/10/03)
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- Asymmetric hydrogenation of itaconic acid and enol acetate derivatives with the Rh-TangPhos catalyst
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(Matrix presented) The Rh-TangPhos catalyst has been used for asymmetric hydrogenation of itaconic acid and enol acetate derivatives. A variety of chiral 2-substituted succinic acids and chiral acetates have been obtained in excellent ee values (up to 99% ee).
- Tang, Wenjun,Liu, Duan,Zhang, Xumu
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p. 205 - 207
(2007/10/03)
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- One-pot lipase-catalyzed synthesis of enantiopure secondary alcohols from carbonyl compounds: A new protocol for lipase-mediated resolution
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Reduction of acetophenones with sodium borohydride in the presence of neutral alumina in hexane followed by enantioselective acylation catalyzed by Pseudomonas cepacia lipase has been achieved in one-pot. Further, immobilized lipase offered a high degree of selectivity with spontaneity.
- Kamal, Ahmed,Sandbhor, Mahendra,Ramana
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p. 815 - 820
(2007/10/03)
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- Selection of enantioselective acyl transfer catalysts from a pooled peptide library through a fluorescence-based activity assay: An approach to kinetic resolution of secondary alcohols of broad structural scope
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An assay employing a fluorescently labeled split and pool peptide library has been applied to the discovery of a new class of octapeptide catalysts for the kinetic resolution of secondary alcohols. A highly diverse library of peptide-based catalysts was synthesized on solid-phase synthesis beads such that each individual bead was co-functionalized with (i) a uniform loading of a pH-sensitive fluorophore and (ii) a unique peptidebased catalyst. The library was then screened for activity in acylation reactions employing (±)-sec-phenylethanol as the substrate and acetic anhydride as the acylation agent. From the most active catalysts, a lead peptide (4) was identified that provides a selectivity-factor (krel) of 8.2 upon resynthesis and evaluation under homogeneous conditions. A "directed" second-generation split and pool peptide library was synthesized such that the new peptide sequences in the library were biased toward the lead structure. Random samples of the second generation library were screened in single bead assays that revealed several new peptide-based catalysts that afford improved selectivities in kinetic resolutions. Peptide catalyst 13 proves effective for the kinetic resolution of sec-phenylethanol (krel = 20), as well as eight other secondary alcohols of a broad substrate scope (krel = 4 to > 50).
- Copeland,Miller
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p. 6496 - 6502
(2007/10/03)
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- Enantioselective acylation of primary and secondary alcohols catalyzed by lipase QL from Alcaligenes sp.: A predictive active site model for lipase QL to identify which enantiomer of an alcohol reacts faster in this acylation
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Lipase QL (from Alcaligenes sp.)-catalyzed acylation of alcohols using isopropenyl acetate as the acylating agent in diisopropyl ether converted preferentially primary alcohols with an S configuration and secondary alcohols with an R configuration into the corresponding homochiral acetates. On the basis of observed enantiomer selectivities, a predictive active site model for lipase QL is proposed for identifying which enantiomer of a primary or a secondary alcohol reacts faster in this acylation. Copyright (C) 1996 Published by Elsevier Science Ltd.
- Naemura, Koichiro,Murata, Masaki,Tanaka, Rie,Yano, Masashi,Hirose, Keiji,Tobe, Yoshito
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p. 3285 - 3294
(2007/10/03)
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- Enantioselective acylation of alcohols catalyzed by lipase QL from Alcaligenes sp.: A predictive active site model for lipase QL to identify the faster reacting enantiomer of an alcohol in this acylation
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Lipase QL-catalyzed acylation of secondary alcohols using isopropenyl acetate as the acylating agent in diisopropyl ether gave preferentially the corresponding acetate with an R configuration. On the basis of the results, a predictive active site model for lipase QL is proposed for identifying which enantiomer of a secondary alcohol reacts faster in this reaction.
- Naemura,Murata,Tanaka,Yano,Hirose,Tobe
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p. 1581 - 1584
(2007/10/03)
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- Lipase-catalyzed enantioselective acylation of alcohols: A predictive active site model for lipase YS to identify which enantiomer of an alcohol reacts faster in this acylation
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Primary alcohols having a hydroxymethyl group at an S sterogemic center and secondary alcohols with an R configuration are preferentially acylated to give the corresponding acetates by lipase YS (from Pseudomonas fluorescens)-catalyzed acylation using isopropenyl acetate as the acylating agent in diisopropyl ether. On the basis of enantiomer selectivities observed, a predictive active site model for lipase YS is proposed for identifying which enantiomer of a primary or a secondary alcohol reacts faster in this acylation.
- Naemura,Fukuda,Murata,Konishi,Hirose,Tobe
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p. 2385 - 2394
(2007/10/03)
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