- Iterative Alanine Scanning Mutagenesis Confers Aromatic Ketone Specificity and Activity of L-Amine Dehydrogenases
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Direct reductive amination of prochiral ketones catalyzed by amine dehydrogenases is attractive in the synthesis of active pharmaceutical ingredients. Here, we report the protein engineering of L-Bacillus cereus amine dehydrogenase to allow reactivity on synthetically useful aromatic ketone substrates using an iterative, multiple-site alanine scanning mutagenesis approach. Mutagenesis libraries based on molecular docking, iterative alanine scanning, and double-proximity filter approach significantly expand the scope of active pharmaceutical ingredients relevant building blocks. The eventual quintuple mutant (A115G/T136A/L42A/V296A/V293A) showed reactivity toward aromatic ketones 12 a (5-phenyl-pentan-2-one) and 13 a (6-phenyl-hexan-2-one), which have not been reported to serve as targets of reductive amination by currently available amine dehydrogenases. Docking simulation and tunnel analysis provided valuable insights into the source of the acquired specificity and activity.
- Mu, Xiaoqing,Wu, Tao,Mao, Yong,Zhao, Yilei,Xu, Yan,Nie, Yao
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p. 5243 - 5253
(2021/11/16)
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- Development of an engineered thermostable amine dehydrogenase for the synthesis of structurally diverse chiral amines
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Amine dehydrogenases (AmDHs) are emerging as a class of attractive biocatalysts for synthesizing chiral amines via asymmetric reductive amination of ketones with inexpensive ammonia as an amino donor. However, the AmDHs developed to date exhibit limited substrate scope. Here, using directed evolution, we engineered a GkAmDH based on a thermostable phenylalanine dehydrogenase from Geobacillus kaustophilus. The newly developed AmDH is able to catalyze reductive amination of a diverse set of ketones and functionalized hydroxy ketones with ammonia or primary amines with up to >99% conversion, thus accessing structurally diverse chiral primary and secondary amines and chiral vicinal amino alcohols, with excellent enantioselectivity (up to >99% ee) and releasing water as the sole by-product.
- Chen, Fei-Fei,Chen, Qi,Liu, Lei,Wang, Dong-Hao,Wang, Zhi-Long,Xu, Jian-He,Zhang, Zhi-Jun,Zheng, Gao-Wei
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p. 2353 - 2358
(2020/05/13)
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- Addition of Highly Polarized Organometallic Compounds to N-tert-Butanesulfinyl Imines in Deep Eutectic Solvents under Air: Preparation of Chiral Amines of Pharmaceutical Interest
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Highly polarized organometallic compounds of s-block elements are added smoothly to chiral N-tert-butanesulfinyl imines in the biodegradable d-sorbitol/choline chloride eutectic mixture, thereby granting access to enantioenriched primary amines after quantitatively removing the sulfinyl group. The practicality of the method is further highlighted by proceeding at ambient temperature and under air, with very short reaction times (2 min), enabling the preparation of diastereoisomeric sulfinamides in very good yields (74–98 %) and with a broad substrate scope, and the possibility of scaling up the process. The method is demonstrated in the asymmetric syntheses of both the chiral amine side-chain of (R,R)-Formoterol (96 % ee) and the pharmaceutically relevant (R)-Cinacalcet (98 % ee).
- Capriati, Vito,Cicco, Luciana,García-álvarez, Joaquín,González-Sabín, Javier,Perna, Filippo M.,Ríos-Lombardía, Nicolás,Salomone, Antonio,Vitale, Paola
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- Stereoselective Synthesis of 1-Arylpropan-2-amines from Allylbenzenes through a Wacker-Tsuji Oxidation-Biotransamination Sequential Process
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Herein, a sequential and selective chemoenzymatic approach is described involving the metal-catalysed Wacker-Tsuji oxidation of allylbenzenes followed by the amine transaminase-catalysed biotransamination of the resulting 1-arylpropan-2-ones. Thus, a series of nine optically active 1-arylpropan-2-amines were obtained with good to very high conversions (74–92%) and excellent selectivities (>99% enantiomeric excess) in aqueous medium. The Wacker-Tsuji reaction has been exhaustively optimised searching for compatible conditions with the biotransamination experiments, using palladium(II) complexes as catalysts and iron(III) salts as terminal oxidants in aqueous media. The compatibility of palladium/iron systems for the chemical oxidation with commercially available and made in house amine transaminases was analysed, finding ideal conditions for the development of a general and stereoselective cascade sequence. Depending on the selectivity displayed by selected amine transaminase, it was possible to produce both 1-arylpropan-2-amines enantiomers under mild reaction conditions, compounds that present therapeutic properties or can be employed as synthetic intermediates of chiral drugs from the amphetamine family. (Figure presented.).
- González-Martínez, Daniel,Gotor, Vicente,Gotor-Fernández, Vicente
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p. 2582 - 2593
(2019/05/15)
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- Upgraded Bioelectrocatalytic N2 Fixation: From N2 to Chiral Amine Intermediates
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Enantiomerically pure chiral amines are of increasing value in the preparation of bioactive compounds, pharmaceuticals, and agrochemicals. ω-Transaminase (ω-TA) is an ideal catalyst for asymmetric amination because of its excellent enantioselectivity and wide substrate scope. To shift the equilibrium of reactions catalyzed by ω-TA to the side of the amine product, an upgraded N2 fixation system based on bioelectrocatalysis was developed to realize the conversion from N2 to chiral amine intermediates. The produced NH3 was in situ reacted with l-alanine dehydrogenase to generate alanine with NADH as a coenzyme. ω-TA transferred the amino group from alanine to ketone substrates and finally produced the desired chiral amine intermediates. The cathode of the upgraded N2 fixation system supplied enough reducing power to synchronously realize the regeneration of reduced methyl viologen (MV?+) and NADH for the nitrogenase and l-alanine dehydrogenase. The coproduct, pyruvate, was consumed by l-alanine dehydrogenase to regenerate alanine and push the equilibrium to the side of amine. After 10 h of reaction, the concentration of 1-methyl-3-phenylpropylamine achieved 0.54 mM with the 27.6% highest faradaic efficiency and >99% enantiomeric excess (eep). Because of the wide substrate scope and excellent enantioselectivity of ω-TA, the upgraded N2 fixation system has great potential to produce a variety of chiral amine intermediates for pharmaceuticals and other applications.
- Chen, Hui,Cai, Rong,Patel, Janki,Dong, Fangyuan,Chen, Hsiaonung,Minteer, Shelley D.
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p. 4963 - 4971
(2019/03/26)
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- An Ammonium-Formate-Driven Trienzymatic Cascade for ω-Transaminase-Catalyzed (R)-Selective Amination
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(R)-Amination mediated by (R)-specific ω-transaminases generally requires costly d-alanine in excess to obtain the desired chiral amines in high yield. Herein, a one-pot, trienzymatic cascade comprising an (R)-specific ω-transaminase, an amine dehydrogenase, and a formate dehydrogenase was developed for the economical and eco-friendly synthesis of (R)-chiral amines. Using inexpensive ammonium formate as the sole sacrificial agent, the established cascade system enabled efficient ω-transaminase-mediated (R)-amination of various ketones, with high conversions and excellent ee (>99%); water and CO2 were the only waste products.
- Chen, Fei-Fei,Liu, Lei,Wu, Jian-Ping,Xu, Jian-He,Zhang, Yu-Hui,Zhang, Zhi-Jun,Zheng, Gao-Wei
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p. 14987 - 14993
(2019/12/02)
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- Improved synthetic method of (R)-1-aryl-2-propylamine
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The invention provides an improved synthetic method of (R)-1-aryl-2-propylamine. The improved synthetic method comprises the following steps of: adopting 1-arylacetone as a raw material, adding (R)-1-phenylethylamine, carrying out reductive amination reaction with hydrogen under a common action of a Lewis acid additive and a transitional metal hydrogenation catalyst; carrying out Pd/C catalytic hydrogenation on an obtained intermediate to remove phenethyl on nitrogen and thus obtaining (R)-1-aryl-2-propylamine. The improved synthetic method provided by the invention has the beneficial effectsthat the operation is simple, the adopted Lewis acid additive is low in cost and easy in obtaining, the yield and the enantioselectivity of a product are high, and the application value for industrialsynthesis of (R)-1-aryl-2-propylamine is very high.
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- Direct Reductive Amination of Carbonyl Compounds with H2 Using Heterogeneous Catalysts in Continuous Flow as an Alternative to N-Alkylation with Alkyl Halides
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A general continuous-flow procedure for direct reductive amination of secondary and primary amines with aromatic and aliphatic aldehydes as well as ketones is reported. The use of hydrogen gas and commercially available Pt/C as a heterogeneous catalyst is a key. In addition to exhibiting an excellent functional group tolerance, this method allows the fast formation of C?N bonds without production of any hazardous chemical waste. Applications to the synthesis of key intermediates toward active pharmaceutical ingredients (Donepezil and Arformoterol/Tamsulosin) are also described. (Figure presented.).
- Laroche, Benjamin,Ishitani, Haruro,Kobayashi, Shū
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supporting information
p. 4699 - 4704
(2018/12/04)
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- Two-Enzyme Hydrogen-Borrowing Amination of Alcohols Enabled by a Cofactor-Switched Alcohol Dehydrogenase
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The NADPH-dependent secondary alcohol dehydrogenase from Thermoanaerobacter ethanolicus (TeSADH), displaying broad substrate specificity and low enantioselectivity, was engineered to accept NADH as a cofactor. The engineered TeSADH showed a >10 000-fold switch from NADPH towards NADH compared to the wildtype enzyme. This TeSADH variant was applied to a biocatalytic hydrogen-borrowing system that employed catalytic amounts of NAD+, ammonia, and an amine dehydrogenase, which thereby enabled the conversion a range of alcohols into chiral amines.
- Thompson, Matthew P.,Turner, Nicholas J.
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p. 3833 - 3836
(2017/09/25)
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- Amine dehydrogenases: Efficient biocatalysts for the reductive amination of carbonyl compounds
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Amines constitute the major targets for the production of a plethora of chemical compounds that have applications in the pharmaceutical, agrochemical and bulk chemical industries. However, the asymmetric synthesis of α-chiral amines with elevated catalytic efficiency and atom economy is still a very challenging synthetic problem. Here, we investigated the biocatalytic reductive amination of carbonyl compounds employing a rising class of enzymes for amine synthesis: amine dehydrogenases (AmDHs). The three AmDHs from this study-operating in tandem with a formate dehydrogenase from Candida boidinii (Cb-FDH) for the recycling of the nicotinamide coenzyme-performed the efficient amination of a range of diverse aromatic and aliphatic ketones and aldehydes with up to quantitative conversion and elevated turnover numbers (TONs). Moreover, the reductive amination of prochiral ketones proceeded with perfect stereoselectivity, always affording the (R)-configured amines with more than 99% enantiomeric excess. The most suitable amine dehydrogenase, the optimised catalyst loading and the required reaction time were determined for each substrate. The biocatalytic reductive amination with this dual-enzyme system (AmDH-Cb-FDH) possesses elevated atom efficiency as it utilizes the ammonium formate buffer as the source of both nitrogen and reducing equivalents. Inorganic carbonate is the sole by-product.
- Knaus, Tanja,B?hmer, Wesley,Mutti, Francesco G.
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supporting information
p. 453 - 463
(2017/08/14)
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- Vicinal Diamines as Smart Cosubstrates in the Transaminase-Catalyzed Asymmetric Amination of Ketones
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Transaminases (TAs) have recently been established as catalysts for the asymmetric, reductive amination of prochiral ketones. Depending on the ketone substrate and the amine donor (the cosubstrate), equilibrium constants may limit high conversions; thus, methods to overcome this limitation are required. Removal of the co-product from the reaction equilibrium through spontaneous, intramolecular reactions has provided a successful solution to this problem; therefore, these amine donors have been named “smart cosubstrates”. Here, we present a comparison of various bifunctional amine donors including vicinal diamines as potential structural cosubstrate motifs. Upon TA-catalyzed deamination of 1,2-diamines, spontaneous dimerization of the resulting α-aminoketones and oxidation gave heteroaromatic pyrazines.
- Payer, Stefan E.,Schrittwieser, Joerg H.,Kroutil, Wolfgang
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supporting information
p. 2553 - 2559
(2017/05/12)
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- A stereoselective, catalytic strategy for the in-flow synthesis of advanced precursors of rasagiline and tamsulosin
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The diastereoselective, trichlorosilane-mediate reduction of imines, bearing different and removable chiral auxiliaries, in combination either with achiral bases or catalytic amounts of chiral Lewis bases, was investigated to afford immediate precursors of chiral APIs (Active Pharmaceutical Ingredients). The carbon-nitrogen double bond reduction was successfully performed in batch and in flow mode, in high yields and almost complete stereocontrol. By this metal-free approach, the formal synthesis of rasagiline and tamsulosin was successfully accomplished in micro(meso) flow reactors, under continuous flow conditions. The results of these explorative studies represent a new, important step towards the development of automated processes for the preparation of enantiopure biologically active compounds.
- Brenna, Davide,Pirola, Margherita,Raimondi, Laura,Burke, Anthony J.,Benaglia, Maurizio
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p. 6242 - 6247
(2017/09/30)
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- METHOD FOR PRODUCING NOVEL ORGANOMETALLIC COMPLEX AND AMINE COMPOUND
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The purpose of the invention is to provide a novel organometallic compound that can be utilized as a catalyst having high generality, high activity, and excellent functional group selectivity. The invention pertains to a novel organometallic compound represented by general formula (1) that catalyzes a reductive amination reaction.
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Paragraph 0192
(2016/03/19)
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- A novel series of tacrine-selegiline hybrids with cholinesterase and monoamine oxidase inhibition activities for the treatment of Alzheimer's disease
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A novel series of tacrine-selegiline hybrids was synthesised and evaluated for application as inhibitors of cholinesterase (AChE/BuChE) and monoamine oxidase (MAO-A/B). The results demonstrate that most of the synthesised compounds exhibit high inhibitory activity. Among these compounds, compound 8g provided a good balance of activity towards all targets (with IC50 values of 22.6 nM, 9.37 nM, 0.3724 μM, and 0.1810 μM for AChE, BuChE, MAO-A and MAO-B, respectively). These results indicated that 8g has the potential to be a multi-functional candidate for Alzheimer's disease.
- Lu, Chuanjun,Zhou, Qi,Yan, Jun,Du, Zhiyun,Huang, Ling,Li, Xingshu
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p. 745 - 753
(2013/05/22)
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- Investigation of one-enzyme systems in the ω-transaminase-catalyzed synthesis of chiral amines
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ω-Transaminase (TA) catalyzed asymmetric syntheses of amines were carried out in the one enzyme systems with wild-type enzymes (S)-TA from Pseudomonas aeruginosa, (S)-TA from Paracoccus denitrificans and (R)-TA from Aspergillus terreus. The scope of amine donors and aromatic carbonyl substrates was thoroughly explored. Among the range of potential amino donors, 2-propylamine, 2-butylamine and 1-phenylethylamine were found as promising candidates, which gave superior conversions in the amination reactions compared to other donors. Various prochiral aromatic ketones were accepted as substrates by the investigated enzymes. In most cases, good to excellent conversions (up to 98%) to the amine products with excellent e.e.-values (>99.9% for (S) or (R)) were obtained by the action of a single enzyme and an appropriate amino donor. (S)-TA from Paracoccus denitrificans was found to accept bulky ketones, e.g. 1-indanone, α- and β-tetralone or 2-acetonaphthone, in the asymmetric amination. In some cases the enantiomeric excesses in the amination reactions were dependent on the amino donor. More-over, the influence of the pH, temperature and cosolvents on the outcome of reactions was additionally investigated.
- Fesko, Kateryna,Steiner, Kerstin,Breinbauer, Rolf,Schwab, Helmut,Schuermann, Martin,Strohmeier, Gernot A.
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p. 103 - 110
(2013/10/22)
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- Stereoselectivity of four (R)-selective transaminases for the asymmetric amination of ketones
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Four (R)-ω-transaminases originating from Hyphomonas neptunium (HN-ωTA), Aspergillus terreus (AT-ωTA) and Arthrobacter sp. (ArR-ωTA), as well as an evolved transaminase (ArRmut11-ωTA) were successfully employed for the amination of prochiral ketones leading to optically pure (R)-amines. The first three transaminases displayed perfect stereoselectivity for the amination of all substrates tested (ee >99%). Furthermore, the transaminase AT-ωTA led in most cases to better conversion than ArR-ωTA and HN-ωTA using D-alanine as amine donor. α-Tetralone, which was the only substrate not accepted by HN-ωTA, ArR-ωTA, and AT-ωTA, was successfully transformed with perfect enantioselectivity (ee >99%) into the corresponding optically pure amine employing the variant ArRmut11-ωTA. Copyright
- Mutti, Francesco G.,Fuchs, Christine S.,Pressnitz, Desiree,Sattler, Johann H.,Kroutil, Wolfgang
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experimental part
p. 3227 - 3233
(2012/01/03)
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- Enzymatic enantiomeric resolution of phenylethylamines structurally related to amphetamine
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Both enantiomers of several phenylethylamines, structurally related to amphetamine, have been prepared in good yields and excellent enantiomeric purity by enzymatic kinetic resolution using CAL-B and ethyl methoxyacetate as the acyl donor. In the case of the 4-hydroxyderivative of amphetamine (compound 4i), the S enantiomer racemized possibly in a dynamic kinetic resolution (DKR) under the enzymatic conditions used. The Royal Society of Chemistry 2011.
- Munoz, Lourdes,Rodriguez, Anna M.,Rosell, Gloria,Bosch, M. Pilar,Guerrero, Angel
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p. 8171 - 8177
(2012/01/04)
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- Asymmetric synthesis of optically pure pharmacologically relevant amines employing ω-transaminases
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Various ω-transaminases were tested for the synthesis of enantiomerically pure amines from the corresponding ketones employing D- or L-alanine as amino donor and lactate dehydrogenase to remove the side-product pyruvate to shift the unfavourable reaction equilibrium to the product side. Both enantiomers, (R)- and (S)-amines, could be prepared with up to 99% ee and >99% conversions within 24 h at 50 mM substrate concentration. The activity and stereoselectivity of the amination reaction depended on the ω-transaminase and substrate employed; furthermore the co-solvent significantly influenced both the stereoselectivity and activity of the transaminases. Best results were obtained by employing ATA-117 to obtain the (R)-enantiomer and ATA-113 or ATA-103 to access the (S)-enantiomer with 15% v v-1 DMSO.
- Koszelewski, Dominik,Lavandera, Ivan,Clay, Dorina,Rozzell, David,Kroutil, Wolfgang
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scheme or table
p. 2761 - 2766
(2009/10/06)
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- PROCESS FOR PREPARING ISOMERS OF CARMOTEROL
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A process for preparing a compound of formula (III) comprising condensing an oxiranyl compound of formula (I) with an amine of formula (II) or a salt thereof wherein: R1 is a group selected from alkyl, aryl, allyl, alkoxy, cycloalkyl, heterocyclic, alkenyl, benzocycloalkyl, aralkyl, haloarylalkyl, heteroaralkyl, haloalkyl, alkoxyaralkyl, substituted silyl and benzyl; and R2 is hydrogen, optionally substituted silyl or optionally substituted benzyl. Formula (I), (II) and (III): There is also described a process for preparing (R,R)-carmoterol from compound (III).
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- Assymetric formal synthesis of (-)-formoterol and (-)-tamsulosin
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Biologically important (2R)-2-amino-3-phenylpropanes consisted in commercial drugs including (R,R)-formoterol, and (R)-tamsulosin were prepared from chiral (2R)-aziridine-2-carboxylate without any chromatographic separation. Key reactions include regio- and stereoselective ring opening reaction of aziridin-2-yl-phenylmethanol and subsequent cyclization toward enantiopure 4,5-disubastitued oxazolidin-2-ones as synthetic intermediates.
- Kim, Yongeun,Kang, Lae-Sung,Ha, Hyun-Joon,Ko, Seung Whan,Lee, Won Koo
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p. 2243 - 2248
(2008/09/17)
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- An efficient enantioselective synthesis of (R,R)-formoterol, a potent bronchodilator, using lipases
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The potent β2-adrenergic receptor agonist formoterol (R,R)-1 has been obtained in enantiomerically pure form by a convenient chemoenzymatic approach by coupling of epoxide (R)-6 with the unprotected primary amine (R)-9. Both chiral precursors have been prepared by enantiodifferentiation processes involving Pseudomonas cepacia (lipase PS) and Candida antarctica lipase (CALB), respectively. For the resolution of amine 9, we have found that utilization of triethylamine as non-reactive base enhances the reaction rate and the enantioselectivity of the process. The key coupling reaction of (R)-6 and (R)-9 has been conducted through derivatization of the amine with the labile trimethylsilyl group, which liberates the amino group of the resulting amino alcohol (R,R)-11 upon column chromatography purification. In this way, the overall approach is shorter than others previously described. Copyright (C) 2000 Elsevier Science Ltd.
- Campos, Francisco,Bosch, M. Pilar,Guerrero, Angel
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p. 2705 - 2717
(2007/10/03)
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- SULFONIC, PHOSPHONIC OR PHOSPHINIIC ACID BETA-3 AGONIST DERIVATIVES
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Compounds of the formula STR1 and pharmaceutically acceptable salts thereof wherein: A is a bond or--OCH 2--, where the oxygen is linked to R 1 ;B is--CH 2--or when R 3 is hydrogen, B may be--CH 2 O--where the oxygen is linked to the phenyl ring;R 1 is an aryl group; R 2 is hydrogen or lower alkyl;R 3 is hydrogen; or R 2 and R 3 together form the group--CH 2 CH 2--; andR 4 is--SO 3 H,--P(O 2 H) R 5,--P(O 2 R 5')R 5,--PO 3 H 2,--PO 3 HR. sup.5' or--PO 3 (R 5') 2 where R 5 and R 5' are independently lower alkyl. These compounds are beta 3 adrenergic receptor agonists and are useful, for example, in the treatment of diabetes, obesity, achalasia, and gastrointestinal diseases.
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- Bronchodilating 8-hydroxy-5-{(1R)-1-hydroxy-2-[N-((1R)-2-(p-methoxyphenyl)-1-methylethyl)-amino]ethyl} carbostyril
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A novel carbostyril derivative of the formula: STR1 or a pharmaceutically acceptable acid addition salt thereof, and a process for preparing same. The compound (I) shows potent bronchodilating activity and is useful as a bronchodilator.
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- Asymmetric synthesis of phenylisopropylamines
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The synthesis of enantiomers of a series of methoxy- and alkyl- substituted phenylisopropylamines is described. The synthesis comprises reducing the imines, formed by the reaction of appropriate phenylacetones with either (+)- or (-)-α-methylbenzylamine, by low-pressure reduction techniques, and subsequently subjecting the optically active N-(α-phenethyl)phenylisopropylamine derivative to hydrogenolysis. The hydrogenolysis products are characterized by enantiomeric purities in the range of 96 - 99%. Yields of products are approximately 60%.
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