- Preparation of fluoxetine by multiple flow processing steps
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Microflow technology is established as a modern and fashionable tool in synthetic organic chemistry, bringing great improvement and potential, on account of a series of advantages over flask methods. The study presented here focuses on the application of flow chemistry process in performing an efficient multiple step syntheses of (±)-fluoxetine as an alternative to conventional synthetic methods, and one of the few examples of total synthesis accomplished by flow technique.
- Ahmed-Omer, Batoul,Sanderson, Adam J.
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Read Online
- Production of chiral compound using recombinant Escherichia coli cells co-expressing reductase and glucose dehydrogenase in an ionic liquid/water two phase system
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(S)-3-Chloro-1-phenyl-1-propanol ((S)-CPPO) is a useful chiral building block for the synthesis of anti-depressant drugs. The yeast reductase, YOL151W, evidences enantioselective reduction activity, converting 3-chloro-1-phenyl-1- propanone (3-CPP) into (
- Choi, Hye Jeong,Uhm, Ki-Nam,Kim, Hyung-Kwoun
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Read Online
- Asymmetric reduction of ketones by employing Rhodotorula sp. AS2.2241 and synthesis of the β-blocker (R)-nifenalol
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A broad range of prochiral ketones were efficiently reduced to the corresponding optically active secondary alcohols using resting cells of Rhodotorula sp. AS2.2241. The microbial reduction system exhibited high activity and enantioselectivity in the reduction of various aromatic ketones and acetylpyridines (>97% ee), but moderate to high enantioselectivity in the reduction of α- and β-keto esters. (R)-Nifenalol, a β-adrenergic blocker, was also synthesized using 2-bromo-1(R)-(4-nitrophenyl)ethanol (97% ee) which was prepared through the asymmetric reduction of 2-bromo-1-(4-nitrophenyl)ethanone employing Rhodotorula sp. AS2.2241. The simple preparation and the high activity of the biocatalyst turned this system into a versatile tool for organic synthesis.
- Yang, Wei,Xu, Jian-He,Xie, Yan,Xu, Yi,Zhao, Gang,Lin, Guo-Qiang
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Read Online
- Total Synthesis of Meayamycin B
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Meayamycin B is currently the most potent modulator of the splicing factor 3b subunit 1 and used by dozens of research groups. However, current supply for this natural product analogue is limited because of the lengthy synthetic scheme. Here, we report a more concise, more cost-effective, and greener synthesis of this compound by developing and employing a novel asymmetric reduction of a prochiral enone to afford an allylic alcohol with high enantioselectivity. In addition to this reaction, this synthesis highlights a scalable Mukaiyama aldol reaction, Nicolaou-type epoxide opening reaction, stereoselective Corey-Chaykovsky-type reaction, and a modified Horner-Wadsworth-Emmons Z-selective olefination. We also discuss a Z-E isomerization during the α,β-unsaturated amide formation. The new synthesis of meayamycin B consists of 11 steps in the longest linear sequence and 24 total steps.
- Basu, Upamanyu,Bressin, Robert K.,Koide, Kazunori,Osman, Sami,Pohorilets, Ivanna
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supporting information
p. 4637 - 4647
(2020/05/01)
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- Efficient Synthesis of (R)-2-Chloro-1-(2,4-dichlorophenyl)ethanol with a Ketoreductase from Scheffersomyces stipitis CBS 6045
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By enzyme screening, a ketoreductase cloned from Scheffersomyces stipitis CBS 6045 and named SsCR was identified that could catalyze the asymmetric hydrogenation of a variety of aromatic ketones. SsCR exhibited a specific activity of 65 U mg?1p
- Shang, Yue-Peng,Chen, Qi,Kong, Xu-Dong,Zhang, Yu-Jun,Xu, Jian-He,Yu, Hui-Lei
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supporting information
p. 426 - 431
(2017/02/10)
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- Nearly aqueous-like activity of lipoprotein lipase treated with glucose-headed surfactant in organic solvent
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In this work, we explored the activation of a lipoprotein lipase from Burkholderia species by glucose-headed surfactants (GHSs) for enhancing its catalytic activity in organic solvent. Three GHSs were prepared and then tested as the additives for inducing the activation of lipoprotein lipase. The kinetic parameters of GHS-treated lipoprotein lipase were determined for the hydrolysis or alcoholysis of p-nitrophenyl acetate. It was found that GHS-treated lipoprotein lipase was 4 to 5 orders of magnitude more active than its native counterpart in organic solvent. Such a dramatic activity enhancement was largely the result of a huge increase in the turnover frequency kcat. Surprisingly, the kcat values in organic solvent were one order of magnitude greater than their aqueous counterparts. As a result, the kcat/Km of GHS-treated lipoprotein lipase in organic solvent became comparable to the aqueous level within one order of magnitude. We thus have demonstrated for the first time that a lipase can display nearly aqueous-like activity in organic solvent. As an illustrative application of GHS-treated lipoprotein lipase, we performed the dynamic kinetic resolution of two secondary alcohols, which provided the products of high enantiopurity (98–99%ee) with high yields (90–91%).
- Oh, Yeonock,Choi, Yoon Kyung,Yun, Inyeol,Lee, Eungyeong,Kim, Kyungwoo,Kim, Mahn-Joo
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p. 148 - 153
(2016/11/04)
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- Method for preparation of optically active 3-amino-arylpropan-1-ol derivatives from 3-chloro-1-arylpropan-1-ol derivatives
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The present invention relates to a method for preparing an optically active 3-amino-1-arylpropan-1-ol derivative, including the step of making an optically active 3-chloro-1-arylpropan-1-ol compound react with an amine derivative. The method according to the present invention allows direct amination of an optically active 3-chloro-1-arylpropan-1-ol derivative through a single-step reaction. Thus, it is possible to provide a compound functioning as a key intermediate of various optically active molecules through a simple process with high yield, while maintaining the optical purity of the reactant. Therefore, the method may be used for preparing medicines, such as (S)-Duloxetin, (R)-Fluoxetine, (R)- Tomoxetine or (R)- Nisoxetine, with high optical purity by combining the method for preparing an optically active 3-chloro-1-arylpropan-1-ol derivative as a reactant of the method with an additional substitution reaction.(AA) Tomoxetine(BB) Fluoxetine(CC) 3-amino-1-propanol(DD) Nisoxetine(EE) DuloxetineCOPYRIGHT KIPO 2016
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Paragraph 0063-0066
(2016/12/01)
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- Synthesis of 3-Aryl-1-aminopropane Derivatives: Lithiation-Borylation-Ring-Opening of Azetidinium Ions
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In situ generated 2-phenyl-azetidinium ylides react with boronic esters to form acyclic γ-dimethylamino tertiary boronic esters. The transformation is believed to involve the formation of a zwitterionic boronate, which subsequently undergoes ring-opening 1,2-migration, which is promoted by the relief of ring strain. Owing to the configurational instability of the initially formed ylides, which appear to be in equilibrium with the open-chain carbene form, the reaction is not stereospecific. The C-B bond of the γ-dimethylamino tertiary boronic esters can be transformed into a variety of functional groups (C-OH, C-vinyl, C-H, C-BF3), thus giving a diverse selection of 3-aryl-1-aminopropanes, which represent a privileged motif among drug molecules.
- Casoni, Giorgia,Myers, Eddie L.,Aggarwal, Varinder K.
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p. 3241 - 3253
(2016/09/12)
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- A convenient enantioselective CBS-reduction of arylketones in flow-microreactor systems
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A convenient, versatile, and green CBS-asymmetric reduction of aryl and heteroaryl ketones has been developed by using the microreactor technology. The study demonstrates that it is possible to handle borane solution safely within microreactors and that the reaction performs well using 2-MeTHF as a greener solvent.
- De Angelis, Sonia,De Renzo, Maddalena,Carlucci, Claudia,Degennaro, Leonardo,Luisi, Renzo
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supporting information
p. 4304 - 4311
(2016/05/24)
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- Chiral N-heterocyclic carbene iridium catalyst for the enantioselective hydrosilane reduction of ketones
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Enantioselective reduction of ketones with (EtO)2MeSiH catalyzed by an in-situ generated N-heterocyclic carbene (NHC) Ir complex at room temperature has been developed. A series of benzimidazolium salts were synthesized and screened in the asymmetric hydrosilylation reaction. As a result, propiophenone was efficiently reduced by the combined catalytic system of [IrCl(cod)]2 and NHC-Ag complex derived from N-(1-naphthalenylmethyl)-substituted benzimidazolium salt L12, affording the corresponding alcohol in 92% yield and with 92% ee. Moreover, the evaluation of an Ir catalyst precursor showed that cationic [Ir(cod)2]BF4 complex could be used. Furthermore, the introduction of a chiral hydroxyamide side arm into the benzimidazolium salt was critical for the successful design of the NHC ligand.
- Manabe, Yoshiki,Shinohara, Kanako,Nakamura, Hanako,Teramoto, Hiro,Sakaguchi, Satoshi
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p. 138 - 145
(2016/06/15)
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- PEG600-carboxylates as efficient reusable reaction media and acylating agents for the resolution of sec-alcohols
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Herein is presented a simple, attractive, and reusable methodology for one-pot resolution/separation of free sec-alcohols with enantiomeric excess (ee) values over 90% by the combination of sustainable acylating agents/solvents (polyethylene glycol derivatives) and an easily available and common biocatalyst (Candida antarctica lipase B, or CAL B) under irreversible conditions, along with a separation process by extraction or distillation. A scale-up reaction was carried out with the Fluoxetine precursor with ee values close to 90% for the R enantiomer.
- Monteiro, Carlos M.,Lourenco, Nuno M. T.,Ferreira, Frederico C.,Afonso, Carlos A. M.
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- A method for preparing optically active 3-amino-1-phenylpropanol derivatives as an intermediate and a method for preparing optically active pharmaceutical products using the same
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The present invention relates to a method for preparing a 3-amino-1-phenylpropanol derivative having (R) or (S) optical activity with 80% or more of an enantiomeric excess (ee), which includes a step of performing an asymmetric reduction reaction in the presence of a spiroborate ester catalyst and a hydrogen donor. The invention also relates to a method for preparing an optically active pharmaceutical product, which includes a step of preparing a (R)- or (S)-3-amino-1-phenylpropanol derivative, that is an intermediate, by using the catalyst.(AA) 3-amino-1-phenylpropanol(BB) Tomoxetine(CC) Nisoxetine(DD) FluoxetineCOPYRIGHT KIPO 2016
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Paragraph 0176-0179
(2016/11/09)
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- Chiral terpene auxiliaries III: Spiroborate esters from (1R,2S,3R,5R)-3-amino-apopinan-2-ol as highly effective catalysts for asymmetric reduction of ketones with borane
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New spiroborate esters, derived from terpene amino alcohols, (S)-prolinol, and 2-aminoethanol, were employed as catalysts in the borane reduction of acetophenone and other aryl alkyl and halogenated ketones. The corresponding alcohols were obtained in high yields and with enantioselectivities up to 98% ee. The influence of the amino alcohol and the diol moieties of spiroborate on the reaction selectivity was examined. The catalyst load, the nature of the solvent, the borane source, and the reaction conditions were also investigated.
- ?wiklińska, Marta,Krzemiński, Marek P.,Tafelska-Kaczmarek, Agnieszka
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p. 1453 - 1458
(2015/12/09)
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- Enantioselective reduction of propiophenone formed from 3-chloropropiophenone and stereoinversion of the resulting alcohols in selected yeast cultures
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Biotransformation of 3-chloro-1-phenylpropan-1-one 1 in sixteen selected cultures of yeast strains has been carried out. For most of the biocatalysts studied the substrate was fully consumed after 1-9 h of transformation, with the exception of the culture of Saccharomyces brasiliensis KCh 905, in which after 24 h trace amounts of the substrate were still visible (2%). However, apart from the expected enantiospecific reduction of the substrate to 3-chloro-1-phenylpropan-1-ol 3, the main biotransformation products comprised of a dehalogenation product - propiophenone 2 and the product of its reduction - 1-phenylpropan-1-ol 4. It was only in the cultures of five strains: Saccharomyces brasiliensis KCh 905, Rhodotorula marina KCh 77, Candida parapsilosis KCh 909, Candida viswanathii KCh 120, and Saccharomyces cerevisiae KCh 464 that 3-chloro-1-phenylpropan-1-ol 3 was observed in amounts of more than 10% of the product mixture. (S)-3-Chloro-1-phenylpropan-1-ol with ee = 91% was identified after 9 h of biotransformation in the culture of Candida viswanathii KCh 120, whereas (R)-3-chloro-1-phenylpropan-1-ol with ee = 28% was found in the culture of Aphanocladium album KCh 417. 1-Day biotransformation of propiophenone 2 in the cultures of Rhodotorula strains gave (S)-1-phenylpropan-1-ol 4 with a very high ee (95-99%) and 85-99% of substrate conversion, whereas transformation of this substrate in the cultures of Candida viswanathii KCh 120 and Candida parapsilosis KCh 909 led to (R)-1-phenylpropan-1-ol with ee = 98% and 97%, respectively. During biotransformation of propiophenone the percent composition of the reaction mixtures changed with time. Employment of the racemic mixture of 1-phenylpropan-1-ol 4 as a substrate for biotransformations allowed us to observe that the biocatalysts tested were capable of enantioselective oxidation of (S)-1-phenylpropan-1-ol. An exception was the culture of Rhodotorula glutinis KCh 242, in which after one day of biotransformation (S)-1-phenylpropan-1-ol was obtained with ee = 96%.
- Janeczko, Tomasz,Kostrzewa-Suslow, Edyta
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p. 1264 - 1269
(2015/01/16)
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- Asymmetric transfer hydrogenation of aromatic ketones catalyzed by new chiral C2-symmetric bis(sulfonyl) tetraaza ligands complexed with [Ru(η6-p-cymene)Cl2]2 in water
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In this report, a new series of C2-symmetric bis(sulfonyl) tetraaza ligands were synthesized from (1S,2S)-1,2-diarylethylenediamine analogues and tested in the asymmetric transfer hydrogenation (ATH) of aromatic ketones by complexing with [Ru(η6-p-cymene)Cl2]2 employing sodium formate as hydrogen source in neat water. A moderate to excellent conversion (~99.8 %) and overall satisfying enantioselectivity (~92.8 %) were obtained with varied electronic and steric effects of the substituents on ligands and substrates.
- Liu, Xungao,Zhang, Tian,Hu, Yingying,Shen, Liang
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p. 1289 - 1295
(2014/07/21)
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- Chemoenzymatic synthesis of fluoxetine precursors. Reduction of β-substituted propiophenones
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Five endophytic yeast strains isolated from edible plants were tested in the reduction β-chloro- and β-azidopropiophenone for the preparation of optically active fluoxetine precursors. The biotransformation rendered not only the corresponding chiral γ-substituted alcohols, but also unsubstituted alcohols and ketones. The product profile was studied and a plausible mechanism for the reductive elimination of the β-functional group is proposed.
- Coronel, Camila,Arce, Gabriel,Iglesias, Cesar,Noguera, Cynthia Magallanes,Bonnecarrere, Paula Rodriguez,Giordano, Sonia Rodriguez,Gonzalez, David
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- Copper(ii)-catalyzed enantioselective hydrosilylation of halo-substituted alkyl aryl and heteroaryl ketones: Asymmetric synthesis of (R)-fluoxetine and (S)-duloxetine
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A set of reaction conditions has been established to facilitate the non-precious copper-catalyzed enantioselective hydrosilylation of a number of structurally diverse β-, γ- or ε-halo-substituted alkyl aryl ketones and α-, β- or γ-halo-substituted alkyl heteroaryl ketones under air to afford a broad spectrum of halo alcohols in high yields and good to excellent enantioselectivities (up to 99% ee). The developed procedure has been successfully applied to the asymmetric synthesis of antidepressant drugs (R)-fluoxetine and (S)-duloxetine, which highlighted its synthetic utility.
- Zhou, Ji-Ning,Fang, Qiang,Hu, Yi-Hu,Yang, Li-Yao,Wu, Fei-Fei,Xie, Lin-Jie,Wu, Jing,Li, Shijun
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p. 1009 - 1017
(2014/02/14)
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- Mesoporous silica KIT-6 supported superparamagnetic CuFe2O 4 nanoparticles for catalytic asymmetric hydrosilylation of ketones in air
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A diverse range of prochiral ketones were reduced in air with high yields and good-to-excellent enantioselectivities (up to 97% ee) in the presence of a heterogeneous catalyst system, which was in situ formed from catalytic amounts of superparamagnetic CuFe2O4 nanoparticles supported on mesoporous silica KIT-6 and non-racemic dipyridylphosphine ligand, the stoichiometric hydride donor polymethylhydrosiloxane (PMHS) as well as certain amounts of additives. The magnetically separable catalysts could be efficiently reused 4 times without apparent loss of both the activity and enantioselectivity. the Partner Organisations 2014.
- Li, Min,Li, Bin,Xia, Hong-Feng,Ye, Danru,Wu, Jing,Shi, Yifeng
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p. 2680 - 2688
(2014/05/06)
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- Harnessing the ortho-directing ability of the azetidine ring for the regioselective and exhaustive functionalization of arenes
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This work demonstrates how the directing ability of the azetidine ring could be useful for regioselective ortho-C-H functionalization of aryl compounds. Robust polar organometallic (lithiated) intermediates are involved in this synthetic strategy. The reagent n-hexyllithium emerged as a safer, yet still effective, basic reagent for the hydrogen/lithium permutation relative to the widely used reagent nBuLi. Two different reaction protocols were discovered for regioselective lithiation at the ortho positions adjacent to the azetidine ring, which served as a toolbox when other competing directing groups were installed on the aromatic ring. The coordinating ability of the azetidine nitrogen atom, as well as the involvement of dynamic phenomena related to the preferential conformations of 2-arylazetidine derivatives, were recognized to be responsible for the observed reactivity and regioselectivity. A site-selective functionalization of the aromatic ring was achieved for aryl azetidines with either coordinatively competent groups (e.g. methoxy) or inductively electron-withdrawing substituents (e.g. chlorine and fluorine). By fine-tuning the reaction conditions, regioselective introduction of several substituents on the aromatic ring could be realized. Several substitution patterns were accomplished, which included 1,2,3-trisubstitution, 1,2,3,4-tetrasubstitution, and 1,2,3,4,5-pentasubstitution, up to the exhaustive substitution of the aromatic ring.
- Zenzola, Marina,Degennaro, Leonardo,Trinchera, Piera,Carroccia, Laura,Giovine, Arianna,Romanazzi, Giuseppe,Mastrorilli, Piero,Rizzi, Rosanna,Pisano, Luisa,Luisi, Renzo
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p. 12190 - 12200
(2015/03/31)
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- Candida tenuis xylose reductase catalyzed reduction of aryl ketones for enantioselective synthesis of active oxetine derivatives
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Candida tenuis xylose reductase shows high catalytic efficiencies in carbonyl reduction of acetophenone and 1-phenyl-1-propanone derivatives. The quite low substrate solubility in aqueous buffer systems is circumvented by addition of methanol or by two-phase solvent systems. In the latter, methanol improves the substrate phase transfer as solvent mediator and leads to reasonable space/time yields. Resulting enantiomerically pure chiral alcohols are key intermediates for synthesis of active pharmaceutical ingredients. (R)-Atomoxetine is exemplarily synthesized in four steps, and the further use for generation of other oxetine derivatives and a polo-like kinase 1 inhibitor are discussed. Copyright
- Vogl, Michael,Brecker, Lothar,Kratzer, Regina,Nidetzky, Bernd
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p. 847 - 853,7
(2020/07/31)
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- Asymmetric total synthesis of (S)-dapoxetine
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A concise asymmetric total synthesis of (S)-dapoxetine from commercially available 3-chloropropiophenone is described. The key step includes a highly stereoselective amination of chiral benzylic ether, with the retention of stereochemistry, using chlorosu
- Kim, Sun Joo,Jeon, Tae Hong,Min, Im Sook,Kim, In Su,Jung, Young Hoon
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supporting information; experimental part
p. 3680 - 3682
(2012/09/25)
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- Corey-itsuno reduction of ketones: A development of safe and inexpensive process for synthesis of some API intermediates
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A safe and inexpensive procedure for asymmetric reduction of ketones using in situ prepared N,N-diethylaniline borane (DEANB) and oxazaborolidine catalyst from sodium borohydride, N,N-diethylaniline hydrochloride and (S)-α,α-diphenylprolinol is described. This protocol is demonstrated successfully to manufacture enantiopure dapoxetine at the plant scale.
- Mahale, Rajendra D.,Chaskar, Sudhir P.,Patil, Kiran E.,Maikap, Golak C.,Gurjar, Mukund K.
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experimental part
p. 710 - 713
(2012/07/27)
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- Lipase-catalyzed synthesis of both enantiomers of 3-chloro-1-arylpropan-1- ols
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The lipase-catalyzed synthesis of both enantiomers of 3-chloro-1-(4- fluorophenyl)propan-1-ol, 3-chloro-1-(4-iodophenyl)propan-1-ol, and 3-chloro-1-phenylpropan-1-ol is described. The procedure is based on the enantiomer-selective acylation of the racemic alcohols in presence of lipase from Pseudomonas fluorescens (LAK) followed by the lipase from Candida rugosa (CRL) mediated hydrolysis of previously obtained enantiomerically enriched 1-aryl-3-chloropropyl esters. For the production of enantiopure (S)-1-aryl-3-chloropropan-1-ols (99% ee, 34-42% yield) the reactions were stopped at higher conversions than the theoretical optimum of 50%, while for enantiopure (R)-1-aryl-3-chloropropyl acetates (99% ee) the reactions were stopped at lower conversions. The latter compounds were enzymatically hydrolyzed into the corresponding (R)-1-aryl-3-chloropropan-1-ols (97-99% ee, 18-24% yield). The absolute configuration of the resolution products was determined by VCD measurements combined with quantum chemical calculations. Georg Thieme Verlag Stuttgart - New York.
- Pop, Laura Ancua,Czompa, Andrea,Paizs, Csaba,Toa, Monica Ioana,Vass, Elemer,Matyus, Peter,Irimie, Florin-Dan
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experimental part
p. 2921 - 2928
(2011/10/13)
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- Copper(II)-catalyzed hydrosilylation of ketones using chiral dipyridylphosphane ligands: Highly enantioselective synthesis of valuable alcohols
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In the presence of PhSiH3 as the reductant, the combination of enantiomeric dipyridylphosphane ligands and Cu(OAc)2·H 2O, which is an easy-to-handle and inexpensive copper salt, led to a remarkably practical and versatile chiral catalyst system. The stereoselective formation of a selection of synthetically interesting β-, γ- or δ-halo alcohols bearing high degrees of enantiopurity (up to 99.9 % enantiomeric excess (ee)) was realized with a substrate-to-ligand molar ratio (S/L) of up to 10 000. The present protocol also allowed the hydrosilylation of a diverse spectrum of alkyl aryl ketones with excellent enantioselectivities (up to 98 % ee) and exceedingly high turn-over rates (up to 50 000 S/L molar ratio in 50 min reaction time) in air, under very mild conditions, which offers great opportunities for the preparation of various physiologically active targets. The synthetic utility of the chiral products obtained was highlighted by the efficient conversion of optically enriched β-halo alcohols into the corresponding styrene oxide, β-amino alcohol, and β-azido alcohol, respectively.
- Yu, Feng,Zhou, Ji-Ning,Zhang, Xi-Chang,Sui, Yao-Zong,Wu, Fei-Fei,Xie, Lin-Jie,S. C. Chan, Albert,Wu, Jing
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supporting information; scheme or table
p. 14234 - 14240
(2012/01/12)
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- Enzymatic production of l-menthol by a high substrate concentration tolerable esterase from newly isolated Bacillus subtilis ECU0554
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Enzymatic preparation of l-menthol has been attracting much attention in the flavor and fragrance industry. A new ideal strain, Bacillus subtilis ECU0554, which exhibited high hydrolytic activity and excellent enantioselectivity towards l-menthyl ester, has been successfully isolated from soil samples through enrichment culture and identified as Bacillus subtilis by 16S rDNA gene sequencing. The esterase extracted from B. subtilis ECU0554 (BSE) showed the best catalytic properties (E > 200) for dl-menthyl acetate among the five menthyl esters examined. Enantioselective hydrolysis of 100 mM dl-menthyl acetate at 30°C and pH 7.0, using crude BSE as biocatalyst and 10% ethanol (v/v) as cosolvent, resulted in 49.0% conversion (3 h) and 98.0% ee for the l-menthol produced, which were much better than those using commercial enzymes tested. Moreover, BSE exhibited strong tolerance against high substrate concentration (up to 500 mM), and the concentration of l-menthol produced could reach as high as 182 mM, and more importantly, the optical purity of l-menthol produced was kept above 97% ee, which were not found in previous reports. These results imply that BSE is a potentially promising bio-catalyst for the large-scale enzymatic preparation of l-menthol. Using this excellent biocatalyst, the enzymatic production of l-menthol will become a mild, efficient, inexpensive and easy-to-use "green chemistry" methodology.
- Zheng, Gao-Wei,Yu, Hui-Lei,Zhang, Jian-Dong,Xu, Jian-He
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experimental part
p. 405 - 414
(2009/11/30)
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- Organic metal compound and process for preparing optically-active alcohols using the same
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The present invention provides an asymmetric reduction catalyst effective in preparing optically-active alcohol compounds having various functional groups, and a process for preparing optically-active alcohol compounds using said asymmetric reduction catalyst. The organic metal compound of the present invention is represented by the following general formula (1): wherein R1 and R2 may be mutually identical or different, and are an alkyl group, a phenyl group, a naphthyl group, a cycloalkyl group, or an alicyclic ring formed by binding R1 and R2, which may have a substituent; R3 is a hydrogen atom or an alkyl group; Cp is a cyclopentadienyl group, which may have a substituent, bound to M1 via a π bond; X1 is a halogen atom or a hydrido group; M1 is rhodium or iridium; and * denotes asymmetric carbon.
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Page/Page column 7; 14
(2009/04/24)
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- Enantioselective, ketoreductase-based entry into pharmaceutical building blocks: Ethanol as tunable nicotinamide reductant
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(Chemical Equation Presented) The use of NADH- and NADPH-dependent ketoreductases to access enantioenriched pharmaceutical building blocks is reported. Seven structurally diverse synthons are obtained, including those for atomoxetine (KRED 132), talampanel (RSt-ADH and CPADH), Dolastatin (KRED 132), and fluoxetine (KRED 108/132). Ethanol may be used as stoichiometric reductant, regenerating both nicotinamide cofactors, particularly under four-electron redox conditions. Its favorable thermodynamic and economic profile, coupled with its advantageous dual cosolvent role, suggests a new application for biomass-derived ethanol.
- Broussy, Sylvain,Cheloha, Ross W.,Berkowitz, David B.
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supporting information; experimental part
p. 305 - 308
(2009/07/18)
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- Synthesis and activity of 1-(3-amino-1-phenylpropyl)indolin-2-ones: A new class of selective norepinephrine reuptake inhibitors
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Norepinephrine and serotonin play an important role in a wide variety of biological processes and are implicated in a number of neurological disorders. A novel class of 1-(3-amino-1-phenylpropyl)indolin-2-ones was designed and synthesized that displays po
- McComas, Casey C.,Vu, An T.,Mahaney, Paige E.,Cohn, Stephen T.,Fensome, Andrew,Marella, Michael A.,Nogle, Lisa,Trybulski, Eugene J.,Ye, Fei,Zhang, Puwen,Alfinito, Peter,Bray, Jenifer,Johnston, Grace,Koury, Elizabeth,Deecher, Darlene C.
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scheme or table
p. 4929 - 4931
(2009/05/07)
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- Enantioselective reduction of prochiral ketones using spiroborate esters as catalysts
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Novel spiroborate esters derived nonracemic 1,2-aminoalcohols and ethylene glycol are reported as highly effective catalysts for the asymmetric borane reduction of a variety of prochiral ketones with borane-dimethyl sulfide complex at room temperature. Optically active alcohols were obtained in excellent chemical yields using 0.1-10 mol % of catalysts with up to 99% ee.
- Stepanenko, Viatcheslav,Jesús, Melvin De,Correa, Wildeliz,Guzmán, Irisbel,Vázquez, Cindybeth,de la Cruz, Wilanet,Ortiz-Marciales, Margarita,Barnes, Charles L.
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p. 5799 - 5802
(2008/02/09)
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- Applications of asymmetric hydrosilylations mediated by catalytic (DTBM-SEGPHOS)CuH
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Several aryl ketone precursors useful in the synthesis of known physiologically active compounds have been reduced to the corresponding nonracemic alcohols. The previously reported combination of a catalytic quantity of (R)-(-)-DTBM-SEGPHOS-ligated CuH an
- Lipshutz, Bruce H.,Lower, Asher,Kucejko, Robert J.,Noson, Kevin
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p. 2969 - 2972
(2007/10/03)
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- Asymmetric reduction of prochiral ketones using in situ generated oxazaborolidine derived from (1S,2S,3R,4R)-3-amino-7,7-dimethoxynorbornan-2-ol. An efficient synthesis of enantiopure (R)-tomoxetine
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In this work, we report our results on the asymmetric reduction of prochiral aromatic and aliphatic ketones 3, 5-8 catalyzed by the novel in situ generated oxazaborolidine 2 derived from (1S,2S,3R,4R)-3-amino-7,7- dimethoxybornan-2-ol (1) and BH3?Me2S. This methodology was applied to the synthesis of the anti-depressant drug (R)-tomoxetine in three steps and 47% overall yield from 3-chloropropiophenone (3h). Catalytic asymmetric reduction of prochiral ketones was examined in the presence of chiral oxazaborolidine catalyst 2 prepared in situ from (1S,2S,3R,4R)-3-amino-7,7-dimethoxynorbornan-2-ol (1). The optically active secondary alcohols were generally obtained in moderate to high enantiomeric excesses (ee 43-95%) and good yields (75-94%), except for ketones bearing electron-withdrawing groups. The methodology was applied to the synthesis of enantiopure (R)-tomoxetine, a potent anti-depressant drug.
- Lapis, Alexandre A. M.,De Fátima, ?ngelo,Martins, José E. D.,Costa, Valentim E. U.,Pilli, Ronaldo A.
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p. 495 - 498
(2007/10/03)
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- New atropisomeric biaryl derivatives of 4-aminopyridine - Identification of an improved nucleophilic catalyst for asymmetric acylation of sec-alcohols
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The synthesis, CSP-HPLC resolution, and absolute configuration assignment of a series of 4-dialkylaminopyridine-based atropisomeric biaryls are described. Screening of these enantiomerically pure catalysts, which differ only in the nature of the 4-dialkylamino substituent, for the kinetic resolution of 1-(1-naphthyl)ethanol reveals the importance of this group on the selectivity of catalysis. The di-n-butylamino derivative displays the most favourable catalytic profile. The utility of this catalyst for the kinetic resolution of a selection of sec-alcohols, including a precursor for the synthesis of the antidepressant fluoxetine hydrochloride (Prozac) are reported. The possible role of the dialkylamino group in chirality transfer is discussed.
- Spivey, Alan C.,Leese, David P.,Zhu, Fujiang,Davey, Stephen G.,Jarvest, Richard L.
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p. 4513 - 4525
(2007/10/03)
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- Aminocyclopentadienyl Ruthenium Complexes as Racemization Catalysts for Dynamic Kinetic Resolution of Secondary Alcohols at Ambient Temperature
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Aminocyclopentadienyl ruthenium complexes, which can be used as room-temperature racemization catalysts with lipases in the dynamic kinetic resolution (DKR) of secondary alcohols, were synthesized from cyclopenta-2,4-dienimines, Ru3(CO)12, and CHCl 3: [2,3,4,5-Ph4(η5-C 4CNHR)]Ru-(CO)2Cl (4: R = i-Pr; 5: R = n-Pr; 6: R = t-Bu), [2,5-Me2-3,4-Ph2(η5-C 4CNHR)]Ru(CO)2Cl (7: R = i-Pr; 8: R = Ph), and [2,3,4,5-Ph4(η5-C4CNHAr)]Ru(CO) 2Cl (9: Ar =p-NO2C6H4; 10: Ar = p-ClC6H4; 11: Ar = Ph; 12: Ar = p-OMeC6H 4; 13: Ar = p-NMe2C6H4). The tests in the racemization of (S)-4-phenyl-2-butanol showed that 7 is the most active catalyst, although the difference decreased in the DKR. Complex 4 was used in the DKR of various alcohols; at room temperature, not only simple alcohols but also functionalized ones such as allylic alcohols, alkynyl alcohols, diols, hydroxyl esters, and chlorohydrins were successfully transformed to chiral acetates. In mechanistic studies for the catalytic racemization, ruthenium hydride 14 appeared to be a key species. It was the major organometallic species in the racemization of (S)-1-phenylethanol with 4 and potassium tert-butoxide. In a separate experiment, (S)-1-phenylethanol was racemized catalytically by 14 in the presence of acetophenone.
- Choi, Jun Ho,Choi, Yoon Kyung,Kim, Yu Hwan,Park, Eun Sil,Kim, Eun Jung,Kim, Mahn-Joo,Park, Jaiwook
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p. 1972 - 1977
(2007/10/03)
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- A new catalytic enantioselective reducing reagent system from (-)-α,α-diphenylpyrrolidinemethanol and 9-borabicyclo[3.3.1]nonane, especially effective for hindered and substituted aralkylketones
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New catalytic enantioselective reduction systems were prepared from aminoalcohols and dialkylboranes, for the enantioselective reductions of prochiral aromatic ketones. Among these, the system prepared from (-)-α,α-diphenylpyrrolidinemethanol with 9-borabicyclo[3.3.1]nonane proved especially promising for such reductions. This complex catalyzes the reduction of prochiral aralkyl ketones to the corresponding alcohols with BH3-THF, with enantioselectivities 82-99.2%. Also, this catalyst is particularly effective for the more hindered and substituted aralkyl ketones. Various modifications in this new catalytic reduction system, such as changing reaction conditions, reducing agent and dialkylborane, were also examined.
- Kanth, Josyula V.B.,Brown, Herbert C.
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p. 1069 - 1074
(2007/10/03)
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- Asymmetric reduction of ketones via whole cell bioconversions and transfer hydrogenation: Complementary approaches
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Prochiral aryl and dialkyl ketones were enantioselectively reduced to the corresponding alcohols using whole cells of the white-rot fungus Merulius tremellosus ono991 as a biocatalytic reduction system and ruthenium(II)-amino alcohol and iridium(I)-amino sulfide complexes as metal catalysts in asymmetric transfer hydrogenation. Comparison of the results showed that the corresponding chiral alcohols could be obtained with moderate to high enantioselectivities (e.e.s of up to 98%). The biocatalytic and transfer hydrogenation approaches appear to be complementary. The biocatalytic approach is the most suitable for the enantioselective reduction of chloro-substituted (aryl) ketones, whereas in the reduction of α,β-unsaturated compounds excellent results were obtained using the catalytic hydrogenation protocol.
- Hage, Annemarie,Petra, Danielle G.I.,Field, Jim A.,Schipper, Dick,Wijnberg, Joannes B.P.A.,Kamer, Paul C.J.,Reek, Joost N.H.,Van Leeuwen, Piet W.N.M.,Wever, Ron,Schoemaker, Hans E.
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p. 1025 - 1034
(2007/10/03)
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- Catalytic enantioselective synthesis of secondary alcohols using C2-symmetric diamino diol ligands
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A new class of diamino diols was evaluated as catalytic ligands in the enantioselective borane reduction of aromatic ketones and the enantioselective ethylation of arylaldehydes with diethylzinc. By variation of the substitution pattern on the ketone, e.e.s of up to 94% could be obtained by in situ borane reduction using 0.025 equiv. of the ligand at 35°C in THF. N,N,N′,N′-Tetramethyldiamino diol and N,N′-dialkyl diamino diol were used as promoters for the enantioselective addition of diethylzinc reagent to the arylaldehyde, where use of 0.1 equiv. of N,N,N′,N′-tetramethyl diamino diol as catalyst in the addition of diethylzinc to arylaldehyde achieved e.e.s of up to 98%.
- Jiang, Biao,Feng, Yan,Hang, Jian-Feng
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p. 2323 - 2329
(2007/10/03)
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- Chemoenzymatic synthesis of the non-tricyclic antidepressants Fluoxetine, Tomoxetine and Nisoxetine
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3-Chloro-1-phenylpropan-1-ol and the corresponding butanoate, 3-chloro-1-phenyl-1-propyl butanoate, were kinetically resolved using lipase B from Candida antarctica catalysis by transesterification and hydrolysis respectively. The resulting chiral building blocks (S)- and (R)-3-chloro-1-phenylpropanol were converted into both enantiomers of the antidepressant drugs, Fluoxetine, Tomoxetine and Nisoxetine. The Royal Society of Chemistry 2000.
- Liu, Hui-Ling,Hoff, Bard Helge,Anthonsen, Thorleif
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p. 1767 - 1769
(2007/10/03)
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- Lipase Catalyzed Kinetic Resolution of Pharmaceutically Useful Chloro Alcohols in Heptane
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Pharmaceutrically useful chloro alcohols, 3-chloro-1-phenyl-1-propanol (1), 1-chloro-3-(1-naphthyloxy)-2-propanol (2) and 4-chloro-1-(4-tert-butylphenyl)-1-butanol (3), are prepared in enantiomerically pure form by an efficient lipase PS catalyzed transesterification in heptane.The effect of organic solvent nature on enzyme activity was also studied.
- Raju, S. Bhaskar,Chiou, Tzyy-Wen,Tai, Dar-Fu
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p. 1519 - 1520
(2007/10/02)
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- Hydrolases in organic synthesis: Preparation of enantiomerically pure compounds
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Esterhydrolases (Esterases, Lipases) are highly (chemo-, regio- and enantio-) selective biocatalysts for the transformation of racemic and achiral substrates into enantiomerically pure compounds.Numerous examples for their application in the preparation of synthetically useful chiral auxiliaries and building blocks for flavour compounds, pheromones and several pharmaceuticals including β-adrenergic blockers, antidepressants and ACE inhibitors are presented.
- Ader, U,Andersch, P,Berger, M,Goergens, U,Seemayer, R,Schneider, M
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p. 145 - 150
(2007/10/02)
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- Diphenyloxazaborolidine a new catalyst for enantioselective reduction of ketones
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A variety of ketones can be reduced in high enantioselectivity with the oxazaborolidines derived from commercially available erythro aminodiphenylethanol.
- Quallich, George J.,Woodall, Teresa M.
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p. 4145 - 4148
(2007/10/02)
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- An efficient route to enantiomerically pure antidepressants: Tomoxetine, nisoxetine and fluoxetine
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Both enantiomers (R)- and (S)-3-chloro-1-phenyl-1-propanol can be obtained conveniently by an efficient enzymatic resolution process. They can be converted via enantioconvergent routes into all enantiomers of the important antidepressants (R)- and (S)-Tomoxetine, Fluoxetine and Nisoxetine.
- Schneider,Goergens
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p. 525 - 528
(2007/10/02)
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- Novel process of producing phenyl or substituted phenylalkylamine pharmaceutical agents and novel chiral intermediates of high enantiomeric purity useful therein
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A process for producing the optically pure (+)- or (-) isomer of a phenyl- or substituted- phenylalkanolamine compounds having pharmacologic activity without the need for resoltuion processes ad novel intermediates useful in the process including optically pure haloalcohols are provided.
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- Chiral Synthesis via Organoboranes. 18. Selective Reductions. 43. Diisopinocampheylchloroborane as an Excellent Chiral Reducing Reagent for the Synthesis of Halo Alcohols of High Enantiomeric Purity. A Highly Enantioselective Synthesis of Both Optical Isomers of Tomoxetine, Fluoxetine, a
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Diisopinocampheylchloroborane, dIpc2BCl, reduces ring and chain sustituted haloaralkyl ketones to the corresponding halo alcohols in excellent enantiomeric excess.In certain cases these alcohols can be upgraded by simple methods to essentially 100percent ee.For instance, (+)- or (-)-3-chloro-1-phenyl-1-propanol is initially obtained in 97percent ee.Simple recrystallisation then furnishes the pure enantiomers.These chiral halo alcohols are highly versatile intermediates.They can be readily cyclized to oxiranes and 2-substituted tetrahydrofurans with retention of chirality.Utilizing this methodology, we have developed an efficient, highly enantioselective synthesis of both optical isomers of the antidepressant drugs, Tomoxetine, Fluoxetine, and Nisoxetine, from the common intermediates (+)-or (-)-3-chloro-1-phenyl-1-propanol.
- Srebnik, Morris,Ramachandran, P.V.,Brown, Herbert C.
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p. 2916 - 2920
(2007/10/02)
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- Asymmetric Synthesis of 2-Aryl Substituted Oxetanes by Enantioselective Reduction of β-Halogenoketones using Lithium Borohydride modified with N,N'-Dibenzoylcystine
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Optically active 2-aryl substituted oxetanes are synthesised in high enantiomeric excesses (up to 89percent e.e.) via enantioselective reduction of β-halogenoketones with lithium borohydride using (R,R')-N,N'-dibenzoylcystine and t-butyl alcohols as ligands.
- Soai, Kenso,Niwa, Seiji,Yamanoi, Takashi,Hikima, Hitoshi,Ishizaki, Miyuki
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p. 1018 - 1019
(2007/10/02)
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