- Asymmetric, catalytic phenyl transfer to imines: Highly enantioselective synthesis of diarylmethylamines
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Both planar and central chirality are not necessary in [2.2]paracyclophane-based N,O-ligands to achieve high enantioselectivity: diarylmethylamines are obtained in excellent yields and enantioselectivities up to 97% ee in the enantioselective transfer of a phenyl group from organozinc reagents to imines in the presence of catalytic amounts of ketimine L* (see scheme).
- Hermanns, Nina,Dahmen, Stefan,Bolm, Carsten,Braese, Stefan
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- A ligand-library approach to the highly efficient rhodium/phosphoramidite- catalyzed asymmetric arylation of N,N-dimethylsulfamoyl-protected aldimines
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(Chemical Equation Presented) Small but effective: The title reaction, after microwave-assisted removal of the N,N-dimethylsulfamoyl protecting group, leads to chiral diarylmethyl amines. The use of 1 mol% catalyst and 1.3 equivalents of aryl boronic acid results in excellent yields (up to 98%) and enantioselectivities (up to 95% ee) of the isolated products. acac = acetylacetonate; eth = ethylene.
- Jagt, Richard B. C.,Toullec, Patrick Y.,Geerdink, Danny,De Vries, Johannes G.,Feringa, Ben L.,Minnaard, Adriaan J.
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- Ruthenium-Catalyzed Direct Asymmetric Reductive Amination of Diaryl and Sterically Hindered Ketones with Ammonium Salts and H2
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A Ru-catalyzed direct asymmetric reductive amination of ortho-OH-substituted diaryl and sterically hindered ketones with ammonium salts is reported. This method represents a straightforward route toward the synthesis of synthetically useful chiral primary diarylmethylamines and sterically hindered benzylamines (up to 97 % yield, 93–>99 % ee). Elaborations of the chiral amine products into bioactive compounds and a chiral ligand were demonstrated through manipulation of the removable and convertible -OH group.
- Hu, Le' an,Zhang, Yao,Zhang, Qing-Wen,Yin, Qin,Zhang, Xumu
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p. 5321 - 5325
(2020/02/28)
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- Preparation method of levocetirizine
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The invention provides a preparation method of levocetirizine. The method comprises the following steps of: the step 1, carrying out a cyclization reaction on (R)-4-chlorodiphenyl methylamine and tris(2-chloroethyl)amine to obtain a compound represented by a formula (I); 2, performing condensation reaction of the compound shown in the formula (I) and 2-ethyl glycolate to obtain a compound shown ina formula (II); and the step 3, converting the compound shown in the formula (II) into levocetirizine. According to the preparation method, (R)-4-chlorodiphenyl methylamine and tris(2-chloroethyl)amine are taken as the initial raw materials, and cyclization reaction, condensation reaction and hydrolysis reaction are carried out so as to obtain levocetirizine. The synthetic route provided by the invention is short, the yield is high, and experimental results show that the yield of the levocetirizine prepared by the method provided by the invention can reach 47%, and the purity can reach 99.7%.
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- Isopropylamine as Amine Donor in Transaminase-Catalyzed Reactions: Better Acceptance through Reaction and Enzyme Engineering
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Amine transaminases (ATA) have now become frequently used biocatalysts in chemo-enzymatic syntheses including industrial applications. They catalyze the transfer of an amine group from a donor to an acceptor leading to an amine product with high enantiopurity. Hence, they represent an environmentally benign alternative for waste intensive chemical amine synthesis. Isopropylamine (IPA) is probably one of the most favored amine donors since it is cheap and achiral, but nevertheless there is no consistency in literature concerning reaction conditions when IPA is best to be used. At the same time there is still a poor understanding which structural properties in ATA are responsible for IPA acceptance. Herein, we demonstrate, on the basis of the 3FCR enzyme scaffold, a substantial improvement in catalytic activity towards IPA as the amine donor. The asymmetric synthesis of industrial relevant amines was used as model reaction. A systematic investigation of the pH-value as well as concentration effects using common benchmark substrates and several ATA indicates the necessity of a substrate- and ATA-dependent reaction engineering.
- Dawood, Ayad W. H.,Wei?, Martin S.,Schulz, Christian,Pavlidis, Ioannis V.,Iding, Hans,de Souza, Rodrigo O. M. A.,Bornscheuer, Uwe T.
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p. 3943 - 3949
(2018/07/31)
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- Expansion of the Substrate Specificity of Porcine Kidney D-Amino Acid Oxidase for S-Stereoselective Oxidation of 4-Cl-Benzhydrylamine
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Discovery and development of enzymes for the synthesis of chiral amines have been a hot topic for basic and applied aspects of biocatalysts. Based on our X-ray crystallographic analyses of porcine kidney D-amino acid oxidase (pkDAO) and its variants, we rationally designed a new variant that catalyzed the oxidation of (S)-4-Cl-benzhydrylamine (CBHA) from pkDAO and obtained it by functional high-throughput screening with colorimetric assay. The variant I230A/R283G was constructed from the variant R283G which had completely lost the activity for D-amino acids, further gaining new activity toward (S)-chiral amines with the bulky substituents. The variant enzyme (I230A/R283G) was characterized to have a catalytic efficiency of 1.85 s?1 for (S)-CBHA, while that for (R)-1-phenylethylamine was diminished 10-fold as compared with the Y228L/R283G variant. The variant was efficiently used for the synthesis of (R)-CBHA in 96 % ee from racemic CBHA by the deracemization reaction in the presence of reducing agent such as NaBH4 in water. Furthermore, X-ray crystallographic analysis of the new variant complexed with (S)-CBHA, together with modelling study clearly showed the basis of understanding the structure-activity relationship of pkDAO.
- Yasukawa, Kazuyuki,Motojima, Fumihiro,Ono, Atsushi,Asano, Yasuhisa
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p. 3500 - 3505
(2018/08/06)
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- Simultaneous engineering of an enzyme's entrance tunnel and active site: The case of monoamine oxidase MAO-N
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A new directed evolution approach is presented to enhance the activity of an enzyme and to manipulate stereoselectivity by focusing iterative saturation mutagenesis (ISM) simultaneously on residues lining the entrance tunnel and the binding pocket. This combined mutagenesis strategy was applied successfully to the monoamine oxidase from Aspergillus Niger (MAO-N) in the reaction of sterically demanding substrates which are of interest in the synthesis of chiral pharmaceuticals based on the benzo-piperidine scaffold. Reversal of enantioselectivity of Turner-type deracemization was achieved in the synthesis of (S)-1,2,3,4-tetrahydro-1-methyl-isoquinoline, (S)-1,2,3,4-tetrahydro-1-ethylisoquinoline and (S)-1,2,3,4-tetrahydro-1-isopropylisoquinoline. Extensive molecular dynamics simulations indicate that the altered catalytic profile is due to increased hydrophobicity of the entrance tunnel acting in concert with the altered shape of the binding pocket.
- Li, Guangyue,Yao, Peiyuan,Gong, Rui,Li, Jinlong,Liu, Pi,Lonsdale, Richard,Wu, Qiaqing,Lin, Jianping,Zhu, Dunming,Reetz, Manfred T.
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p. 4093 - 4099
(2017/07/10)
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- Highly Enantioselective Arylation of N,N-Dimethylsulfamoyl-Protected Aldimines Using Simple Sulfur-Olefin Ligands: Access to Solifenacin and (S)-(+)-Cryptostyline II
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With the use of a simple sulfur-olefin ligand, a highly enantioselective rhodium-catalyzed addition of arylboroxines to N,N-dimethylsulfamoyl-protected aldimines has been achieved, allowing access to a broad range of chiral diarylmethylamines in high yields (up to 98%) with uniformly excellent enantioselectivities (up to 99% ee). This catalyst system is also applicable to the arylation of N-tosyl arylimines. By utilizing this method, some biologically active molecules possessing a chiral 1-aryl-1,2,3,4-tetrahydroisoquinoline core such as Solifenacin and (S)-(+)-Cryptostyline II are facilely constructed.
- Jiang, Tao,Chen, Wen-Wen,Xu, Ming-Hua
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p. 2138 - 2141
(2017/04/27)
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- Copper(I)-Catalyzed Asymmetric Pinacolboryl Addition of N-Boc-imines Using a Chiral Sulfoxide - Phosphine Ligand
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Highly efficient and enantioselective copper(I)-catalyzed pinacolboryl addition of N-Boc-imines is reported. By using a single chiral sulfoxide-(dialkyl)phosphine (SOP) ligand, both enantiomeric isomers of α-amino boronic esters were obtained through an achiral counteranion switch.
- Wang, Ding,Cao, Peng,Wang, Bing,Jia, Tao,Lou, Yazhou,Wang, Min,Liao, Jian
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p. 2420 - 2423
(2015/05/27)
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- Engineering an enantioselective amine oxidase for the synthesis of pharmaceutical building blocks and alkaloid natural products
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The development of cost-effective and sustainable catalytic methods for the production of enantiomerically pure chiral amines is a key challenge facing the pharmaceutical and fine chemical industries. This challenge is highlighted by the estimate that 40-45% of drug candidates contain a chiral amine, fueling a demand for broadly applicable synthetic methods that deliver target structures in high yield and enantiomeric excess. Herein we describe the development and application of a "toolbox" of monoamine oxidase variants from Aspergillus niger (MAO-N) which display remarkable substrate scope and tolerance for sterically demanding motifs, including a new variant, which exhibits high activity and enantioselectivity toward substrates containing the aminodiphenylmethane (benzhydrylamine) template. By combining rational structure-guided engineering with high-throughput screening, it has been possible to expand the substrate scope of MAO-N to accommodate amine substrates containing bulky aryl substituents. These engineered MAO-N biocatalysts have been applied in deracemization reactions for the efficient asymmetric synthesis of the generic active pharmaceutical ingredients Solifenacin and Levocetirizine as well as the natural products (R)-coniine, (R)-eleagnine, and (R)-leptaflorine. We also report a novel MAO-N mediated asymmetric oxidative Pictet-Spengler approach to the synthesis of (R)-harmicine.
- Ghislieri, Diego,Green, Anthony P.,Pontini, Marta,Willies, Simon C.,Rowles, Ian,Frank, Annika,Grogan, Gideon,Turner, Nicholas J.
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supporting information
p. 10863 - 10869
(2013/08/23)
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- N-(Alkylsulfamoyl)aldimines: Easily deprotected precursors for diarylmethylamine synthesis
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The sequential reaction of chlorosulfonyl isocyanate with t-BuOH, t-BuNH2 and TFA allows formation of H2NSO 2NHBut. Condensation of the latter with Ar1CHO in the presence of Ti(OEt)4 provides the activated imines Ar 1CHNSO2NHBut (59-89%). Commercially available boronic acids add to these imines with good stereoselectivity (76-98% ee) using readily available diene ligands. Simple deprotection with 5% w/w water in pyridine affords free Ar1CHNH2Ar2.
- Crampton, Rosemary H.,Fox, Martin,Woodward, Simon
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p. 599 - 605
(2013/06/27)
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- Chiral phosphoric acid catalyzed enantioselective transfer hydrogenation of ortho-hydroxybenzophenone N-H ketimines and applications
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Unprotected synthesis: The first enantioselective chiral phosphoric acid catalyzed transfer hydrogenation of unprotected ortho-hydroxybenzophenone N-H imines by using a Hantzsch ester as the hydrogen source afforded the corresponding chiral N,O-unprotected ortho-hydroxydiarylmethylamines in high yields with excellent enantioselectivities (see scheme).
- Nguyen, Thanh Binh,Wang, Qian,Gueritte, Franioise
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p. 9576 - 9580
(2011/10/02)
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- Bis-sulfamyl imines: Potent substrates for asymmetric additions of arylboroxines under rhodium catalysis
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Bis-sulfamyl imines are shown to be potentially ideal substrates for rhodium-catalysed asymmetric additions of arylboron nucleophiles as they show: (i) near perfect enantioselectivities (11 examples, 98-99+% ee), (ii) good to excellent diastereoselectivities (10-32:1 rac:meso), and (iii) high functional group tolerance in removal of the low molecular weight protecting group via mild heating in aqueous pyridine.
- Crampton, Rosemary,Woodward, Simon,Fox, Martin
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supporting information; experimental part
p. 903 - 906
(2011/06/19)
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- Synthesis and applications of chiral organoboranes generated from sulfonium ylides
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The reactions of aryl-stabilized sulfonium ylides with trialkyl/triarylboranes have been investigated. Clean monohomologation of the boranes with only a small amount of the higher homologation products (2O2/NaOH) and amines (treatment with NH2OSO3H). Although the reactions were conveniently conducted at 5 °C, the ylide reaction with tributylborane was very fast even at -78 °C (complete after 15 min). Use of chiral sulfides rendered the reactions asymmetric, and high enantioselectivity (>95% ee) was observed in all cases. The ylide-borane reaction was applied to short syntheses of the anti-inflammatory agents neobenodine and cetirizine, both of which contain a chiral diarylmethylalkoxy and diarylmethylamino moiety, respectively. Copyright
- Aggarwal, Varinder K.,Guang, Yu Fang,Schmidt, Andreas T.
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p. 1642 - 1643
(2007/10/03)
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- Asymmetric synthesis of diarylmethyl amines by rhodium-catalyzed asymmetric addition of aryl titanium reagents to imines
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A rational tuning of the arene sulfonamide moiety (by introducing isopropyl groups onto the phenyl ring) brought about high enantioselectivity in the asymmetric synthesis of diarylmethyl amines by the title reaction (see scheme). Ar1 = 4-CF3C6H4, 4-ClC 6H4, 4-FC6H4, 3-MeOC 6H4, 4-MeOC6H4, 2-MeC 6H4, 1-naphthyl, Ph; Ar2 = Ph, 4-FC 6H4, 3-MeOC6H4, 4-MeOC 6H4.
- Hayashi, Tamio,Kawai, Masahiro,Tokunaga, Norihito
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p. 6125 - 6128
(2007/10/03)
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- Effective tuning of the arene and alkanesulfinamides for highly enantioselective synthesis of (S)-4-chlorophenylphenylmethylamine, a key intermediate for antihistamic (S)-cetirizine
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High diastereoselectivity (>94%) has been achieved in the phenylMgBr addition process to chlorophenyl aldimine derived from the new and sterically hindered triisopropylbenzene sulfinamide (TIPBSA) in the synthesis of a key intermediate of (S)-Cetirizine. Surprisingly, under the same reaction conditions, toluenesulfinamide derived chlorophenyl aldimine provided only 10% ee.
- Han, Zhengxu,Krishnamurthy, Dhileepkumar,Grover, Paul,Fang, Q. Kevin,Pflum, Derek A.,Senanayake, Chris H.
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p. 4195 - 4197
(2007/10/03)
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- Asymmetric synthesis of cetirizine dihydrochloride
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Practical route technology for the preparation of (S)-cetirizine·2HCl via diastereoselective organometallic addition to N-tert-butanesulfinyl aldimines is disclosed.
- Pflum, Derek A,Krishnamurthy, Dhileepkumar,Han, Zhengxu,Wald, Stephen A,Senanayake, Chris H
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p. 923 - 926
(2007/10/03)
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- A practical synthesis of para di- and mono-substituted benzhydrylamines from benzhydrol precursors
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A series of para-substituted benzhydrylamines 6 were obtained by substitution of the corresponding benzhydrol precursors 1 with phenyl carbamate 2 under acidic conditions, followed by basic hydrolysis of the carbamate intermediates 3. One unsymmetrical intermediate 3i has been resolved by preparative chiral chromatography. Subsequent deprotection of the carbamate function led to the recovery of enantiomerically pure (+)- and (-)- 4-chlorobenzhydryl amines.
- Laurent, Mathieu,Marchand-Brynaert, Jacqueline
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p. 667 - 672
(2007/10/03)
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