- Formation of Quasi-racemic Diastereoisomeric Salts as a Structural Cause for Efficient Optical Resolution
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During optical resolutions, when the resolving agent is structurally similar to the racemate, very efficient resolution can be achieved, because of the formation of quasi-racemic diastereoisomeric salts, in which the enantiomers have opposite configuration.
- Fogassy, Elemer,Kozma, David
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Read Online
- The Methyl Ester of α-Aminophenylacetic Acid: pH-Dependence and Phosphate Catalysis of Hydrolysis
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The dependence of the rate of spontaneous (non-enzymic) hydrolysis of α-aminophenylacetic acid methyl ester on the acidity of a medium was studied over the pH range 0.95-11.6.The mono- and dianion of phosphate was found to have a catalytic effect on this reaction, according to the mechanism of general base catalysis.Catalysis of the protonated substrate from hydrolysis by different phosphate ions, the second molecule of water, and the hydroxide ion follows the Broensted catalysis law with the slope 0.60.At a strong alkaline pH, phosphate slows down the ester hydrolysis, probably due to the formation of an ester-phosphate complex; the calculated dissociation constant is 4.2xE-3M, while the ratio of the hydrolysis rate constants for free ester and its phosphate complex is 7.7.
- Blinkovsky, Alexander M.,Galaev, Igor Yu.,Svedas, Vytas K.
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Read Online
- Highly Stable Zr(IV)-Based Metal-Organic Frameworks for Chiral Separation in Reversed-Phase Liquid Chromatography
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Separation of racemic mixtures is of great importance and interest in chemistry and pharmacology. Porous materials including metal-organic frameworks (MOFs) have been widely explored as chiral stationary phases (CSPs) in chiral resolution. However, it remains a challenge to develop new CSPs for reversed-phase high-performance liquid chromatography (RP-HPLC), which is the most popular chromatographic mode and accounts for over 90% of all separations. Here we demonstrated for the first time that highly stable Zr-based MOFs can be efficient CSPs for RP-HPLC. By elaborately designing and synthesizing three tetracarboxylate ligands of enantiopure 1,1′-biphenyl-20-crown-6, we prepared three chiral porous Zr(IV)-MOFs with the framework formula [Zr6O4(OH)8(H2O)4(L)2]. They share the same flu topological structure but channels of different sizes and display excellent tolerance to water, acid, and base. Chiral crown ether moieties are periodically aligned within the framework channels, allowing for stereoselective recognition of guest molecules via supramolecular interactions. Under acidic aqueous eluent conditions, the Zr-MOF-packed HPLC columns provide high resolution, selectivity, and durability for the separation of a variety of model racemates, including unprotected and protected amino acids and N-containing drugs, which are comparable to or even superior to several commercial chiral columns for HPLC separation. DFT calculations suggest that the Zr-MOF provides a confined microenvironment for chiral crown ethers that dictates the separation selectivity.
- Jiang, Hong,Yang, Kuiwei,Zhao, Xiangxiang,Zhang, Wenqiang,Liu, Yan,Jiang, Jianwen,Cui, Yong
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supporting information
p. 390 - 398
(2021/01/13)
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- D-Phenylglycine aminotransferase (d-PhgAT)-substrate scope and structural insights of a stereo-inverting biocatalyst used in the preparation of aromatic amino acids
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Enantiopure amines are key building blocks in the synthesis of many pharmaceuticals, so a route to their production is a current goal for biocatalysis. The stereo-inverting d-phenylglycine aminotransferase (d-PhgAT), isolated from Pseudomonas stutzeri ST-201, catalyses the reversible transamination from l-glutamic acid to benzoylformate, yielding α-ketoglutarate and d-phenylglycine (d-Phg). Detailed kinetic analysis revealed a range of amine donor and acceptor substrates that allowed the synthesis of enantiopure aromatic d-amino acids at a preparative scale. We also determined the first X-ray crystal structure of d-PhgAT with its bound pyridoxal 5′-phosphate (PLP) cofactor at 2.25 ? resolution. A combination of structural analysis and site-directed mutagenesis of this class III aminotransferase revealed key residues that are potentially involved in the dual substrate recognition, as well as controlling the stereo-inverting behaviour of d-PhgAT. Two arginine residues (Arg34 and Arg407) are involved in substrate recognition within P and O binding pockets respectively. These studies lay the foundation for further enzyme engineering and promote d-PhgAT as a useful biocatalyst for the sustainable production of high value, aromatic d-amino acids. This journal is
- Akhtar, M. Kalim,Campopiano, Dominic J.,De Cesare, Silvia,Loake, Gary J.,Marles-Wright, Jon,Serpico, Annabel
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p. 6533 - 6543
(2020/11/13)
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- Ultrasound-Controlled Chiral Separation of Four Amino Acids and 2,2,2-Trifluoro-1-(9-anthryl)ethanol
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Chiral separation of 4-hydroxyphenylglycine, phenylglycine, tryptophan, methionine, and 2,2,2-trifluoro-1-(9-anthryl)ethanol (TFAE) was performed under ultrasound reduction at room temperature and high temperature (50 °C). At high temperature (50 °C), both α and Rs were improved slightly under ultrasound reduction as compared to those under non-ultrasonic and ultrasonic irradiation (50 watt/L) conditions. Even at low temperatures, the largest α was observed under ultrasound reduction conditions, except in the case of methionine. However, at low temperature, Rs was reduced under ultrasound (50 watt/L) irradiation, but was improved under ultrasound reduction rather than under the continuous ultrasonic irradiation. Similar to the fact that gradient elution (based on solvent polarity) can improve α, ultrasound reduction can improve α and Rs. Ultrasound reduction is demonstrated to aid the rapid separation of chiral compounds with improved resolution, especially, at high temperatures. Although chromatographic separation using ultrasound has been rarely dealt with until now, ultrasound can be used as an external field in chromatography.
- Lee, Jae Hwan,Ryoo, Jae Jeong
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p. 146 - 149
(2019/02/07)
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- Deracemization and stereoinversion to aromatic d-amino acid derivatives with ancestral l-amino acid oxidase
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Enantiomerically pure amino acid derivatives could be foundational compounds for peptide drugs. Deracemization of racemates to l-amino acid derivatives can be achieved through the reaction of evolved d-amino acid oxidase and chemical reductants, whereas deracemization to d-amino acid derivatives has not progressed due to the difficulty associated with the heterologous expression of l-amino acid oxidase (LAAO). In this study, we succeeded in developing an ancestral LAAO (AncLAAO) bearing broad substrate selectivity (13 l-amino acids) and high productivity through an Escherichia coli expression system (50.7 mg/L). AncLAAO can be applied to perform deracemization to d-amino acids in a similar way to deracemization to l-amino acids. In fact, full conversion (>99% ee, d-form) could be achieved for 16 racemates, including nine d,l-Phe derivatives, six d,l-Trp derivatives, and a d,l-phenylglycine. Taken together, we believe that AncLAAO could be a key enzyme to obtain optically pure d-amino acid derivatives in the future.
- Nakano, Shogo,Minamino, Yuki,Hasebe, Fumihito,Ito, Sohei
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p. 10152 - 10158
(2019/10/19)
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- Enantioselective synthesis of amines via reductive amination with a dehydrogenase mutant from Exigobacterium sibiricum: Substrate scope, co-solvent tolerance and biocatalyst immobilization
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In recent years, the reductive amination of ketones in the presence of amine dehydrogenases emerged as an attractive synthetic strategy for the enantioselective preparation of amines starting from ketones, an ammonia source, a reducing reagent and a cofactor, which is recycled in situ by means of a second enzyme. Current challenges in this field consists of providing a broad synthetic platform as well as process development including enzyme immobilization. In this contribution these issues are addressed. Utilizing the amine dehydrogenase EsLeuDH-DM as a mutant of the leucine dehydrogenase from Exigobacterium sibiricum, a range of aryl-substituted ketones were tested as substrates revealing a broad substrate tolerance. Kinetics as well as inhibition effects were also studied and the suitability of this method for synthetic purpose was demonstrated with acetophenone as a model substrate. Even at an elevated substrate concentration of 50 mM, excellent conversion was achieved. In addition, the impact of water-miscible co-solvents was examined, and good activities were found when using DMSO of up to 30% (v/v). Furthermore, a successful immobilization of the EsLeuDH-DM was demonstrated utilizing a hydrophobic support and a support for covalent binding, respectively, as a carrier.
- L?we, Jana,Ingram, Aaron A.,Gr?ger, Harald
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p. 1387 - 1392
(2018/03/21)
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- Structure-guided engineering of: Meso -diaminopimelate dehydrogenase for enantioselective reductive amination of sterically bulky 2-keto acids
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meso-Diaminopimelate dehydrogenase (DAPDH) and mutant enzymes are an excellent choice of biocatalysts for the conversion of 2-keto acids to the corresponding d-amino acids. However, their application in the enantioselective reductive amination of bulky 2-keto acids, such as phenylglyoxylic acid, 2-oxo-4-phenylbutyric acid, and indole-3-pyruvic acid, is still challenging. In this study, the structure-guided site-saturation mutagenesis of a Symbiobacterium thermophilum DAPDH (StDAPDH) gave rise to a double-site mutant W121L/H227I, which showed dramatically improved enzyme activities towards various 2-keto acids including these sterically bulky substrates. Several d-amino acids were prepared in optically pure form. The molecular docking of substrates into the active sites of wild-type and mutant W121L/H227I enzymes revealed that the substrate binding cavity of the mutant enzyme was reshaped to accommodate these bulky substrates, thus leading to higher enzyme activity. These results lay a foundation for further shaping the substrate binding pocket and manipulating the interactions between the substrate and binding sites to access highly active d-amino acid dehydrogenases for the preparation of synthetically challenging d-amino acids.
- Cheng, Xinkuan,Chen, Xi,Feng, Jinhui,Wu, Qiaqing,Zhu, Dunming
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p. 4994 - 5002
(2018/10/17)
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- RETRACTED ARTICLE: Chemoenzymatic Method for Enantioselective Synthesis of (R)-2-Phenylglycine and (R)-2-Phenylglycine Amide from Benzaldehyde and KCN Using Difference of Enzyme Affinity to the Enantiomers
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In general, enzymatic and chemoenzymatic methods for asymmetric synthesis of α-amino acids are performed using highly enantioselective enzymes. The enzymatic reactions using α-aminonitrile as a starting material have been performed using reaction conditions apart from the chemical Strecker synthesis. We developed a new chemoenzymatic method for the asymmetric synthesis of α-amino acids from aldehydes and KCN by performing Strecker synthesis and nitrilase reaction in the same reaction mixture. Nitrilase AY487533 that showed rather low enantioselectivity in hydrolysis of 2-phenylglycinonitrile (2PGN) to 2-phenylglycine (2PG) was utilized in the hydrolysis of aminonitrile formed from benzaldehyde and KCN via 2PGN by Strecker synthesis, preferentially synthesizing (R)-2PG with more than 95 % yield and enantiomeric excess (ee). The method was also utilized for the synthesis of (R)-2-phenylglycine amide ((R)-2PGNH2) from benzaldehyde and KCN by the chemoenzymatic reaction in the presence of a mutated nitrilase AY487533W186A, which catalyzes the conversion of 2PGN to 2PGNH2.
- Kawahara, Nobuhiro,Asano, Yasuhisa
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p. 5014 - 5020
(2018/10/20)
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- A high-throughput pH-based colorimetric assay: application focus on alpha/beta hydrolases
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Research involving α/β hydrolases, including α-amino acid ester hydrolase and cocaine esterase, has been limited by the lack of an online high throughput screening assay. The development of a high throughput screening assay capable of detecting α/β hydrolase activity toward specific substrates and/or chemical reactions (e.g., hydrolysis in lieu of amidase activity and/or synthesis instead of thioesterase activity) is of interest in a broad set of scientific questions and applications. Here we present a general framework for pH-based colorimetric assays, as well as the mathematical considerations necessary to estimate de novo the experimental response required to assign a ‘hit’ or a ‘miss,’ in the absence of experimental standard curves. This combination is valuable for screening the hydrolysis and synthesis activity of α/β hydrolases on a variety of substrates, and produces data comparable to the current standard technique involving High Performance Liquid Chromatography (HPLC). In contrast to HPLC, this assay enables screening experiments to be performed with greater efficiency.
- Paye, Mariétou F.,Rose, Harrison B.,Robbins, John M.,Yunda, Diana A.,Cho, Seonggeon,Bommarius, Andreas S.
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- One-Pot Enantioselective Synthesis of d-Phenylglycines from Racemic Mandelic Acids, Styrenes, or Biobased l-Phenylalanine via Cascade Biocatalysis
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Enantiopure d-phenylglycine and its derivatives are an important group of chiral amino acids with broad applications in thepharmaceutical industry. However, the existing synthetic methods for d-phenylglycine mainly rely on toxic cyanide chemistry and multistep processes. To provide green and safe alternatives, we envisaged cascade biocatalysis for the one-pot synthesis of d-phenylglycine from racemic mandelic acid, styrene, and biobased l-phenylalanine, respectively. Recombinant Escherichia coli (LZ110) was engineered to coexpress four enzymes to catalyze a 3-step reaction in one pot, transforming mandelic acid (210 mM) to give enantiopure d-phenylglycine in 29.5 g L?1 (195 mM) with 93% conversion. Using the same whole-cell catalyst, twelve other d-phenylglycine derivatives were also produced from the corresponding mandelic acid derivatives in high conversion (58–94%) and very high ee (93–99%). E. coli (LZ116) expressing seven enzymes was constructed for the transformation of styrene to enantiopure d-phenylglycine in 80% conversion via a one-pot 6-step cascade biotransformation. Twelve substituted d-phenylglycines were also produced from the corresponding styrene derivatives in high conversion (45–90%) and very high ee (92–99%) via the same cascade reactions. A nine-enzymeexpressing E. coli (LZ143) was engineered to transform biobased l-phenylalanine to enantiopure d-phenylglycine in 83% conversion via a one-pot 8-step transformation. Preparative biotransformations were also demonstrated. The high-yielding synthetic methods use cheap and green reagents (ammonia, glucose, and/or oxygen), and E. coli whole-cell catalysts, thus providing green and useful alternative methods for manufacturing d-phenylglycine. (Figure presented.).
- Zhou, Yi,Wu, Shuke,Li, Zhi
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supporting information
p. 4305 - 4316
(2017/11/21)
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- Chromatographic Resolution of α-Amino Acids by (R)-(3,3'-Halogen Substituted-1,1'-binaphthyl)-20-crown-6 Stationary Phase in HPLC
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Three new chiral stationary phases (CSPs) for high-performance liquid chromatography were prepared from R-(3,3'-halogen substituted-1,1'-binaphthyl)-20-crown-6 (halogen = Cl, Br and I). The experimental results showed that R-(3,3'-dibromo-1,1'-binaphthyl)-20-crown-6 (CSP-1) possesses more prominent enantioselectivity than the two other halogen-substituted crown ether derivatives. All twenty-one α-amino acids have different degrees of separation on R-(3,3'-dibromo-1,1'-binaphthyl)-20-crown-6-based CSP-1 at room temperature. The enantioselectivity of CSP-1 is also better than those of some commercial R-(1,1'-binaphthyl)-20-crown-6 derivatives. Both the separation factors (α) and the resolution (Rs) are better than those of commercial crown ether-based CSPs [CROWNPAK CR(+) from Daicel] under the same conditions for asparagine, threonine, proline, arginine, serine, histidine and valine, which cannot be separated by commercial CR(+). This study proves the commercial usefulness of the R-(3,3'-dibromo-1,1'-binaphthyl)-20-crown-6 chiral stationary phase.
- Wu, Peng,Wu, Yuping,Zhang, Junhui,Lu, Zhenyu,Zhang, Mei,Chen, Xuexian,Yuan, Liming
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supporting information
p. 1037 - 1042
(2017/07/25)
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- Highly efficient enantioselective liquid-liquid extraction of 1,2-amino-alcohols using SPINOL based phosphoric acid hosts
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Access to enantiopure compounds on large scale in an environmentally friendly and cost-efficient manner remains one of the greatest challenges in chemistry. Resolution of racemates using enantioselective liquid-liquid extraction has great potential to meet that challenge. However, a relatively feeble understanding of the chemical principles and physical properties behind this technique has hampered the development of hosts possessing sufficient resolving power for their application to large scale processes. Herein we present, employing the previously untested SPINOL based phosphoric acids host family, an in depths study of the parameters affecting the efficiency of the resolution of amino-alcohols in the optic of further understanding the core principles behind ELLE. We have systematically investigated the dependencies of the enantioselection by parameters such as the choice of solvent, the temperature, as well as the pH and bring to light many previously unsuspected and highly intriguing interactions. Furthermore, utilizing these new insights to our advantage, we developed novel, highly efficient, extraction and resolving protocols which provide remarkable levels of enantioselectivity. It was shown that the extraction is catalytic in host by demonstrating transport in a U-tube and finally it was demonstrated how the solvent dependency could be exploited in an unprecedented triphasic resolution system.
- Pinxterhuis, Erik B.,Gualtierotti, Jean-Baptiste,Heeres, Hero J.,De Vries, Johannes G.,Feringa, Ben L.
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p. 6409 - 6418
(2017/08/29)
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- Nitrilases
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The invention relates to nitrilases and to nucleic acids encoding the nitrilases. In addition, methods of designing new nitrilases and methods of use thereof are also provided. The nitrilases have increased activity and stability at increased pH and temperature.
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Paragraph 0495
(2015/09/22)
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- Nitrilases, nucleic acids encoding them and methods for making and using them
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The invention relates to nitrilases and to nucleic acids encoding the nitrilases. In addition methods of designing new nitrilases and method of use thereof are also provided. The nitrilases have increased activity and stability at increased pH and temperature.
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Page/Page column 50
(2016/01/09)
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- Kinetics of enantioselective liquid-liquid extraction of phenylglycine enantiomers using a BINAP-copper complex as chiral selector
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Kinetic study of reactive extraction of phenylglycine (PhgH) racemate with S-BINAP ((S)-(-)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene)- copper complex (BINAP-Cu) as the chiral selector was performed in a modified Lewis cell. The theory of extraction accompanied by a chemical reaction was applied to achieve insightful understanding of the extraction process. The effects of agitation speed, interface area, pH value of the aqueous phase, initial concentration of PhgH racemate, and initial concentration of BINAP-Cu on the specific rate of extraction were investigated. An extraction course was simulated based on the rate equations. The forward rate constants of 3.14 × 10-5 m3.4 mol-0.7 s-1 for R-PhgH and 4.03 × 10-5 m3.4 mol-0.7 s-1 for S-PhgH, respectively, were found. The modeled extraction course was in good agreement with the experimental one.
- Zhang, Pan-Liang,Luo, Jing-Jing,Tang, Ke-Wen,Yi, Jian-Min
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p. 1317 - 1324
(2014/07/21)
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- High yield synthesis of d-phenylglycine and its derivatives by nitrilase mediated dynamic kinetic resolution in aqueous-1-octanol biphasic system
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A strategy of nitrilase mediated dynamic kinetic resolution toward the synthesis of d-phenylglycine was developed, using aqueous-1-octanol biphasic system. Due to the efficient suppression of the decomposition of phenylglycinonitrile, a maximum yield of 81% is obtained. This result indicates that the nitrilase mediated dynamic kinetic resolution is a promising method toward the synthesis of d-phenylglycine and its derivatives.
- Qiu, Jian,Su, Erzheng,Wang, Wei,Wei, Dongzhi
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p. 1448 - 1451
(2014/03/21)
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- Large α-aminonitrilase activity screening of nitrilase superfamily members: Access to conversion and enantiospecificity by LC-MS
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A high-throughput screening for the identification of nitrilases demonstrating activity towards alpha-aminonitriles is reported. A LC-MS assay giving access to both conversion and enantiospecificity was developed. 588 candidate enzymes were screened as cell lysates against six alpha-aminonitriles in 96-well microplates. The candidate enzymes were selected following two criteria, their sequence identity with a set of known nitrilases or their phylogenetic position among the nitrilase superfamily. Five enzymes were identified and found to hydrolyse alpha-aminonitrile into the corresponding alpha-aminoacid. The substrate range was found to be very narrow as only two different alpha-aminonitriles, 2-aminovaleronitrile and 2-amino-2- phenylacetonitrile, were found to be substrates. The biocatalytic capabilities of three enzymes were further investigated and the best result was obtained with an enzyme from Burkholderia xenovorans catalysing the enantiospecific hydrolysis of 2-aminovaleronitrile into (S)-norvaline with excellent conversion and enantiomeric excess.
- Bordier, Franck,Stam, Mark,Darii, Ekaterina,Tricot, Sabine,Fossey, Aurelie,Rohault, Johanna,Debard, Adrien,Mariage, Aline,Pellouin, Virginie,Petit, Jean-Louis,Perret, Alain,Vallenet, David,Salanoubat, Marcel,Weissenbach, Jean,Vergne-Vaxelaire, Carine,De Berardinis, Veronique,Zaparucha, Anne
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- Deracemization of amino acids by coupling transaminases of opposite stereoselectivity
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Biocatalytic deracemization of amino acids without relying on oxidase-based deamination of an unwanted enantiomer was demonstrated by coupling a-and w-transaminases displaying opposite stereoselectivity. This strategy employs isopropylamine and a keto acid as cosubstrates and is free of generation of hydrogen peroxide which is troublesome in the conventional oxidase-based methods.
- Park, Eul-Soo,Shin, Jong-Shik
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p. 3505 - 3509
(2015/02/19)
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- Biocatalytic asymmetric synthesis of unnatural amino acids through the cascade transfer of amino groups from primary amines onto keto acids
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Flee to the hills: An unfavorable equilibrium in the amino group transfer between amino acids and keto acids catalyzed by α-transaminases was successfully overcome by coupling with a ω-transaminase reaction as an equilibrium shifter, leading to efficient asymmetric synthesis of diverse unnatural amino acids, including L-tert-leucine and D-phenylglycine. Copyright
- Park, Eul-Soo,Dong, Joo-Young,Shin, Jong-Shik
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p. 3538 - 3542
(2014/01/06)
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- SEPARATING AGENT FOR CHROMATOGRAPHY
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A separating agent for chromatography is provided that is useful for the separation of specific compounds, e.g., for the optical resolution of amino acids. This separating agent for chromatography provides a higher productivity and contains a crown ether-like cyclic structure and optically active binaphthyl. This separating agent for chromatography containing a crown ether-like cyclic structure and optically active binaphthyl is provided by introducing a substitution group for binding to carrier into a specific commercially available 1,1′-binaphthyl derivative that has substituents at the 2, 2′, 3, and 3′ positions, then introducing a crown ether-like cyclic structure, and subsequently chemically bonding the binaphthyl derivative to the carrier through the substitution group for binding to carrier.
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Paragraph 0074; 0075
(2013/08/15)
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- Enzymatic synthesis of chiral phenylalanine derivatives by a dynamic kinetic resolution of corresponding amide and nitrile substrates with a multi-enzyme system
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Mutant α-amino-ε-caprolactam (ACL) racemase (L19V/L78T) from Achromobacter obae with improved substrate specificity toward phenylalaninamide was obtained by directed evolution. The mutant ACL racemase and thermostable mutant D-amino acid amidase (DaaA) from Ochrobactrum anthropi SV3 co-expressed in Escherichia coli (pACLmut/pDBFB40) were utilized for synthesis of (R)-phenylalanine and non-natural (R)-phenylalanine derivatives (4-OH, 4-F, 3-F, and 2-F-Phe) by dynamic kinetic resolution (DKR). Recombinant E. coli with DaaA and mutant ACL racemase genes catalyzed the synthesis of (R)-phenylalanine with 84% yield and 99% ee from (RS)-phenylalaninamide (400 mM) in 22 h. (R)-Tyrosine and 4-fluoro-(R)-phenylalanine were also efficiently synthesized from the corresponding amide compounds. We also co-expresed two genes encoding mutant ACL racemase and L-amino acid amidase from Brevundimonas diminuta in E. coli and performed the efficient production of various (S)-phenylalanine derivatives. Moreover, 2-aminophenylpropionitrile was converted to (R)-phenylalanine by DKR using a combination of the non-stereoselective nitrile hydratase from recombinamt E. coli and mutant ACL racemase and DaaA from E. coli encoding mutant ACL racemase and DaaA genes. Copyright
- Yasukawa, Kazuyuki,Asano, Yasuhisa
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p. 3327 - 3332
(2013/01/15)
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- Enantioselective hydrocyanation of N-protected aldimines
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Enantioselective hydrocyanation of N-benzyloxycarbonyl aldimines catalyzed by a Ru[(S)-phgly]2[(S)-binap]/C6H5OLi system or a bimetallic complex [Li{Ru[(S)-phgly]2[(S)-binap]}]Cl affords the amino nitriles in 92 - 99% ee. The reaction is carried out in tert-C 4H9OCH3 with a substrate-to-catalyst molar ratio in the range of 500 - 5000 at -20 to 0°C. Primary, secondary, and tertiary alkyl imines as well as the aryl and heteroaryl substrates are smoothly cyanated to produce the desired products in high yield.
- Uemura, Masato,Kurono, Nobuhito,Ohkuma, Takeshi
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supporting information; experimental part
p. 882 - 885
(2012/04/05)
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- Preparation of cross-linked enzyme aggregates of l-aminoacylase via co-aggregation with polyethyleneimine
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l-Aminoacylase from Aspergillus melleus was co-aggregated with polyethyleneimine and subsequently cross-linked with glutaraldehyde to obtain aminoacylase-polyethyleneimine cross-linked enzyme aggregates (termed as AP-CLEA). Under the optimum conditions, AP-CLEA expressed 74.9% activity recovery and 81.2% aggregation yield. The said method of co-aggregation and cross-linking significantly improved the catalytic stability of l-aminoacylase with respect to temperature and storage. AP-CLEA were employed for enantioselective synthesis of three unnatural amino acids (namely: phenylglycine, homophenylalanine and 2-naphthylalanine) via chiral resolution of their ester-, amide- and N-acetyl derivatives. The enantioselectivity of AP-CLEA was the highest for hydrolysis of amino acid amides; was moderate for hydrolysis of N-acetyl amino acids and was the least for hydrolysis of amino acid esters. Furthermore, AP-CLEA were found to retain more than 92% of the initial activity after five consecutive batches of (RS)-homophenylalanine hydrolysis suggesting an adequate operational stability of the biocatalyst.
- Vaidya, Bhalchandra K.,Kuwar, Suyog S.,Golegaonkar, Sandeep B.,Nene, Sanjay N.
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experimental part
p. 184 - 191
(2012/03/22)
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- Chiral imprinting with amino acids of ordered mesoporous silica exhibiting enantioselectivity after calcination
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Chiral ordered mesoporous silica (COMS) was synthesized in basic media by combining tetraethyl orthosilicate and quaternized aminosilane (with a templating role) silica sources together with four different standard amino acids (arginine, histidine, isoleucine, and proline). Besides the hexagonal MCM-41-type structure, narrow pore size distribution, and high specific surface area, it was found that these solids have potential for enantiomeric separation because of the transference of chirality from the amino acid to the silica. This is illustrated by the resolution of several racemic mixtures (those of proline, isoleucine, trans-4-hydroxyproline, pipecolic acid, valine, leucine, and phenylglycine) with the calcined COMS prepared with l-proline. The opposite behavior observed in induced circular dichroism experiments with calcined COMS, obtained using both enantiomers of proline, confirmed their chiral nature. The high number and variety of existing amino acids, and chiral organic compounds in general, makes these ordered silicas attractive for the production of enantiopure substances.(Figure Presented)
- Lacasta, Susana,Sebastian, Victor,Casado, Clara,Mayoral, Alvaro,Romero, Pilar,Larrea, Angel,Vispe, Eugenio,Lopez-Ram-De-Viu, Pilar,Uriel, Santiago,Coronas, Joaquin
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scheme or table
p. 1280 - 1287
(2012/02/15)
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- Totally diastereoselective addition of aryl Grignard reagents to the nitrone-based chiral glycine equivalent MiPNO
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The reaction of the chiral nitrone MiPNO (2-isopropyl-2,3-dimethyl-1-oxy-2, 3-dihydro-imidazol-4-one) with Grignard reagents is totally diastereoselective. Using simple and functionalized arylmagnesium reagents, enantiopure hydroxylamines were obtained in fair to good yields, which in turn could be easily transformed into new chiral ketonitrones. The preparation of enantiopure l-phenylglycine derivatives is also described.
- Thiverny, Maryse,Farran, Daniel,Philouze, Christian,Blandin, Veronique,Chavant, Pierre Y.
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p. 1274 - 1281
(2011/11/28)
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- Amino ester hydrolase from Xanthomonas campestris pv. campestris, ATCC 33913 for enzymatic synthesis of ampicillin
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α-Amino ester hydrolases (AEH) are a small class of proteins, which are highly specific for hydrolysis or synthesis of α-amino containing amides and esters including β-lactam antibiotics such as ampicillin, amoxicillin, and cephalexin. A BLAST search revealed the sequence of a putative glutaryl 7-aminocephalosporanic acid (GL-7-ACA) acylase 93% identical to a known AEH from Xanthomonas citri. The gene, termed gaa, was cloned from the genomic DNA of Xanthomonas campestris pv. campestris sp. strain ATCC 33913 and the corresponding protein was expressed into Escherichia coli. The purified protein was able to perform both hydrolysis and synthesis of a variety of α-amino β-lactam antibiotics including (R)-ampicillin and cephalexin, with optimal ampicillin hydrolytic activity at 25 °C and pH 6.8, with kinetic parameters of kcat of 72.5 s-1 and KM of 1.1 mM. The synthesis parameters α, βo, and γ for ampicillin, determined here first for this class of proteins, are α = 0.25, βo = 42.8 M-1, and γ = 0.23, and demonstrate the excellent synthetic potential of these enzymes. An extensive study of site-directed mutations around the binding pocket of X. campestris pv. campestris AEH strongly suggests that mutation of almost any first-shell amino acid residues around the active site leads to inactive enzyme, including Y82, Y175, D207, D208, W209, Y222, and E309, in addition to those residues forming the catalytic triad, S174, H340, and D307.
- Blum, Janna K.,Bommarius, Andreas S.
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supporting information; scheme or table
p. 21 - 28
(2010/12/19)
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- Chiral separation of underivatized amino acids by reactive extraction with palladium-BINAP complexes
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(Figure Presented) In answer to the need for a more economic technology for the separation of racemates, a novel system for reactive enantioselective liquid-liquid extraction (ELLE) is introduced. Palladium (S)-BINAP complexes are employed as hosts in the separation of underivatized amino acids. The system shows the highest selectivity for the ELLE of tryptophan with metal complexes as hosts reported to date and shows a good selectivity toward a range of natural and unnatural amino acids. Furthermore, the host can be prepared in situ from commerically available compounds. Bulk-membrane transport in the form of U-tube experiments demonstrates the enantioselective and catalytic nature of the transport. The dependency of the system on parameters such as pH, organic solvent, and host-substrate ratio has been established. 31P NMR spectroscopy has been used to confirm the preferred enantiomer in the extraction experiments. The intrinsic selectivity was deduced by determination of the association constants of the palladium complex with the tryptophan enantiomers.
- Verkuijl, Bastiaan J. V.,Minnaard, Adriaan J.,De Vries, Johannes G.,Feringa, Ben L.
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experimental part
p. 6526 - 6533
(2010/03/01)
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- Using ionic liquid [EMIM][CH3COO] as an enzyme-'friendly' co-solvent for resolution of amino acids
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An ionic liquid (IL), 1-ethyl-3-methylimidazolium acetate [EMIM][CH3COO], was used in 0-4.0 M (～60% IL, v/v), as a nonvolatile organic medium for the enzymatic resolution of amino acids. When dl-phenylalanine methyl ester was studied as a model substrate, high enantiomeric excesses (ee) of l-amino acid were obtained in all ionic concentrations; however, lower yields were observed at high IL concentrations. This IL is more enzyme-'friendly' than the hydrophilic organic solvent acetonitrile and those ILs containing chaotropic anions (such as [EMIM][OTs]). Among three proteases and two lipases investigated, lyophilized Bacillus licheniformis protease exhibited the best enantioselectivity and activity. Highly enantioselective resolutions were also produced for several other amino acids in 2.0 M IL. Interestingly, high ee were also found in deuterium oxide (D2O) rather than in ordinary water, and a further enhancement was achieved with the co-existence of [EMIM][CH3COO]. The heavy water effect was explained in terms of protein stabilization by D2O. The secondary structural changes of enzyme in various media were interpreted by the second derivatives of FT-IR spectra.
- Zhao, Hua,Jackson, Lee,Song, Zhiyan,Olubajo, Olarongbe
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p. 2491 - 2498
(2007/10/03)
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- Synthesis of optically active α-methylamino acids and amides through biocatalytic kinetic resolution of amides
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Catalyzed by Rhodococcus sp. AJ270, a nitrile hydratase and amidase containing microbial whole-cell catalyst, under very mild conditions, a number of racemic α-methylamino amides were resolved into the corresponding optically active (S)-(+)-α-methylamino acids and (R)-(-)-α- methylamino amides. The steric requirement of the amidase against α-amino phenylacetamides bearing methyl group(s) at α-amino nitrogen and/or α-carbon was also studied. Coupled with the chemical hydrolysis of amide, the biotransformation process provided a direct synthesis of α-methylamino acids in both enantiomeric forms from readily available racemic amides.
- Wang, Mei-Xiang,Liu, Jun,Wang, De-Xian,Zheng, Qi-Yu
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p. 2409 - 2416
(2007/10/03)
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- An 'easy-on, easy-off' protecting group for the enzymatic resolution of (±)-1-phenylethylamine in an aqueous medium
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A new approach has been developed for the biocatalytic resolution of (±)-1-phenylethylamine in 100% aqueous medium based on two integrated enzymatic steps: protection and deprotection of the reactive amine enantiomer catalyzed by the same enzyme-penicillin acylase from Alcaligenes faecalis. An 'easy-on, easy-off' protecting group has been introduced using (R)-phenylglycine amide as the acyl donor. (R)-Phenylglycyl-substituted (R)-1-phenylethylamine was poorly soluble and precipitated at enzymatic acylation in an alkaline medium (pH 10-11), driving the synthesis towards high yields. Conversely at pH 7.5, its solubility was continuously increasing, which rendered the subsequent deacylation by the same enzyme highly efficient. In contrast to the resolutions, which employ one biocatalytic step, the new approach made it possible to exploit two sequential enantioselective enzymatic reactions implementing a double enantioselectivity control. Effective enzymatic resolution of (±)-1-phenylethylamine in an aqueous medium was performed with (R)-phenylglycine amide as an acyl donor using the suggested approach.
- Guranda, Dorel T.,Khimiuk, Andrey I.,Van Langen, Luuk M.,Van Rantwijk, Fred,Sheldon, Roger A.,Svedas, Vytas K.
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p. 2901 - 2906
(2007/10/03)
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- Chemoenzymatic approaches to the dynamic kinetic asymmetric synthesis of aromatic amino acids
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Enzymatic approaches for the production of amino acids by nitrilases are described. Dynamic kinetic asymmetric synthesis conditions were established for the aromatic aminonitriles, phenylglycinonitrile and 4- fluorophenylglycinonitrile, at high pH to produce the corresponding amino acid products in high enantiomeric excess. N-Acylation of aromatic aminonitriles led to spontaneous racemization at pH 8, allowing preferential enzymatic hydrolysis of the (R)-enantiomer to afford the product N-acylamino acids in up to 99% enantiomeric excess (ee).
- Chaplin, Jennifer A.,Levin, Michael D.,Morgan, Brian,Farid, Nancy,Li, Jen,Zhu, Zuolin,McQuaid, Jeff,Nicholson, Lawrence W.,Rand, Cynthia A.,Burk, Mark J.
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p. 2793 - 2796
(2007/10/03)
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- Polymeric and dendrimeric pyridoxal enzyme mimics
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Pyridoxal was covalently attached to polyethylenimine polymers, but the resulting materials were found to degrade rapidly. In comparison, the dendrimeric pyridoxals, which possess only one pyridoxal unit at the core of every dendrimer molecule were found to be relatively stable compounds. A total of 12 poly(amidoamine) type dendrimers were synthesized. They range from G1 to G6 with either NMe2 or NHAc termini. The NMe2-terminated pyridoxal dendrimers racemize α-amino acids 50-100 times faster than does simple pyridoxal, while the NHAc-terminated pyridoxal dendrimers racemize α-amino acids only 3-5 times faster than does simple pyridoxal. Both the NMe2- and NHAc-terminated pyridoxal dendrimers decarboxylate 2-amino-2-phenyl-propionic acid 1-3 times faster than simple pyridoxal. The interior polarity in the pyridoxal dendrimers is similar to that of 85:15 water-DMF solution. Furthermore, we successfully incorporated eight lauryl groups to the G5 pyridoxal dendrimer at known positions. The laurylated dendrimer exhibits lower racemization and decarboxylation rates than do the unlaurylated ones, in contrast to the positive rate effects of laurylation in polyethylenimine-pyridoxamines in our previous transamination studies.
- Liu, Lei,Breslow, Ronald
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p. 3277 - 3287
(2007/10/03)
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- 3-oxopropane-1-sulphonic acids and sulphonates
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The invention relates to 1,3-disubstituted-3-oxopropane-1-sulfonic acids and sulfonates and enantiomerically inriched forms thereof. The invention further relates to the use of these enantiomerically inriched compounds to resolve mixtures of enantiomers, in particular mixtures of enantiomers of amino-functionalized compounds.
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-
Page/Page column 12-13
(2008/06/13)
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- Novel enantioselective synthesis of both enantiomers of furan-2-yl amines and amino acids
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A new enantioselective synthesis of furan-2-yl amines and amino acids is described, in which the key step is the oxazaborolidine-catalyzed enantioselective reduction of O-benzyl (E)- and (Z)-furan-2-yl ketone oximes to the corresponding chiral amines. The chirality of the furan-2-yl amines is fully controlled by the appropriate choice of the geometrical isomer of the O-benzyl oxime. Oxidation of the furan ring furnished amino acids in high yields.
- Demir, Ayhan S.,Sesenoglu, Oezge,Uelkue, Dincer,Arici, Cengiz
-
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- Penicillin Acylase Catalysed Synthesis of Ampicillin in Hydrophilic Organic Solvents
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Penicillin acylase (EC 3.5.1.11) from Alcaligenes faecalis, immobilised as a cross-linked enzyme aggregate (CLEA), catalysed the synthesis of ampicillin in water-miscible organic solvents at low water concentrations. Below 4% water (v/v) no reaction was observed, showing the crucial role of water in maintaining the activity of penicillin acylase. The initial value of S/H was strongly affected by the nature of the solvent, but the effect of the water content was slight in the studied range of 4 to 15%. A reaction in acetonitrile containing 8% water afforded ampicillin in up to 86% yield.
- Van Langen, Luuk M.,Oosthoek, Natasja H. P.,Van Rantwijk, Fred,Sheldon, Roger A.
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p. 797 - 801
(2007/10/03)
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- Glutaryl Acylases: One-Reaction Enzymes or Versatile Enantioselective Biocatalysts?
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A significant broad substrate specificity, that crosses over the usual β-lactam derivatives, has been observed with an industrial glutaryl-7-aminocephalosporanic acid acylase (GA). This enzyme possesses significant enantioselective amidase and even esterase activity, with a stereopreference for the S-enantiomer. The easy separation of products from unreacted reagents, possessing different physical-chemical properties, is achieved by solvent extraction, avoiding chromatography or distillation during reaction work-up.
- Raimondi, Stefano,Monti, Daniela,Pagnoni, Ugo Maria,Riva, Sergio
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p. 783 - 789
(2007/10/03)
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- Stereoselective hydration of (RS)-phenylglycine nitrile by new whole cell biocatalysts
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Five new bacterial isolates with stereoselective nitrile hydratase activity against (RS)-2-phenylpropionitrile and (RS)-phenylglycine nitrile were investigated. The permeabilized whole cell isolates selectively hydrate the (S)-enantiomer of phenylglycine nitrile with E values of 1.2-5.4. One isolate, which was identified as Pantoea endophytica, produced pure (S)-phenylglycine (>99% ee) as a result of hydrolysis of (S)-phenylglycine amide by an (S)-specific amidase. Surprisingly, in the hydrolysis of (RS)-phenylglycine nitrile, it was found that the (R)-amide was accumulated in excess (21% ee) despite the nitrile hydratase produced by Pantoea endophytica was (S)-selective. The synthesis of pure (R)-phenylglycine (>99% ee) was achieved in time course studies using another Pantoea sp. with (R)-selective amidase. In the case of Nocardioides sp. the intermediate product, (S)-phenylglycine amide, could be produced (52% ee) without its subsequent hydrolysis into the acid due to the apparent absence of any amidase activity.
- Hensel, Martina,Lutz-Wahl, Sabine,Fischer, Lutz
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p. 2629 - 2633
(2007/10/03)
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- Practical and convenient enzymatic synthesis of enantiopure α-amino acids and amides
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Catalyzed by the nitrile hydratase and the amidease in Rhodococcus sp. AJ270 cells under very mild conditions, a number of α-aryl- and α-alkyl-substituted DL-glycine nitriles 1 rapidly underwent a highly enantioselective hydrolysis to afford D-(-)-α-amino acid amides 2 and L-(+)-α-amino acids 3 in high yields with excellent enantiomeric excesses in most cases. The overall enantioselectivity of the biotransformations of nitriles originated from the combined effects of a high L-enantioselective amidase and a low enantioselective nitrile hydratase. The influence of the substrates on both reaction efficiency and enantioselectivity was also discussed in terms of steric and electronic effects. Coupled with chemical hydrolysis of D-(-)-α-phenylglycine amide, biotransformation of DL-phenylglycine nitrile was applied in practical scale to produce both D- and L-phenylglycines in high optical purity.
- Wang, Mei-Xiang,Lin, Shuang-Jun
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p. 6542 - 6545
(2007/10/03)
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- Highly efficient and enantioselective synthesis of L-arylglycines and D-arylglycine amides from biotransformations of nitriles
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Under very mild conditions, the Rhodococcus sp. AJ270-catalysed biotransformation of arylglycine nitriles 1, prepared easily from the reaction of substituted benzaldehydes, ammonium chloride and potassium cyanide, proceeded efficiently to produce optically active D-arylglycine amides 2 and L-arylglycines 3 in excellent yields with enantiomeric excesses higher than 99%.
- Wang, Mei-Xiang,Lin, Shuang-Jun
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p. 6925 - 6927
(2007/10/03)
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- A practical asymmetric synthesis of homochiral α-arylglycines
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Enantioselective reduction of a series of substituted aryl trichloromethyl ketones with the CBS-catecholborane reagent afforded homochiral aryl trichloromethyl carbinols which have been elaborated to give homochiral α-arylglycines in high e.e.
- Mellin-Morliere, Christelle,Aitken, David J.,Bull, Steven D.,Davies, Stephen G.,Husson, Henri-Philippe
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p. 149 - 155
(2007/10/03)
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- Fast ester cleavage of sterically hindered α- and β-aminoesters under non-aqueous conditions. Application to the kinetic resolution of aziridine esters
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Various protected α- and β-aminoesters undergo fast ester cleavage by treatment with t-BuOK in THF. The accelerating effect of a neighboring chelating group was used for the efficient kinetic resolution of non-racemic aziridine esters. (C) 2000 elsevier Science Ltd.
- Alezra, Valérie,Bouchet, Céline,Micouin, Laurent,Bonin, Martine,Husson, Henri-Philippe
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p. 655 - 658
(2007/10/03)
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- Asymmetric synthesis of α-Amino acid derivatives via an electrophilic amination of chiral amide cuprates with Li t-Butyl-N-tosyloxycarbamate
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The utility of lithium t-butyl-N-tosyloxycarbamate (LiBTOC) as a (+)NHBOC synthon in highly diastereoselective reactions with chiral cis-aminoindanol derived amide cuprates is described. The diastereoselectivities of these reactions ranged from 96% to greater than 99%. The subsequent transformation of these adducts to α-amino acids is also described.
- Zheng, Nan,Armstrong III, Joseph D.,McWilliams, J. Christopher,Volante
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p. 2817 - 2820
(2007/10/03)
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- α-Amino acids and N-protected α-amino aldehydes by stereoselective additions of a chiral vinyllithium reagent to sulfonylimines
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The chiral vinyllithium reagent (S)-1b, readily generated from dibromoalkene (S)-1a by bromine/lithium exchange, adds stereoselectively to mesitylsulfonylimines 2a-f so that the diastereomers 3 are obtained in ≥98% d.e. after column chromatography. The bromoalkenes 3a-d are submitted to ozonolysis in methanol to give α-mesitylsulfonylamino esters (S)-8a-d which can be hydrolyzed to deliver N-protected α- amino acids in >95% e.e. On the other hand, α-mesitylsulfonylamino aldehydes 12a-d are available when bromoalkenes 3a, d-f are first debrominated (→ 11a-d) and subsequently ozonized. In order to avoid reacemization, the aldehydes 12a-d are not purified but submitted to a Mukaiyama-type aldol addition whereby hydroxyesters 15a-d are formed as single diastereomers in a chelate-controlled reaction. The relative configuration of the esters 15a-d is proven by conversion into the oxazolidinones 16a-d whose optical purity is determined to exceed 92% e.e. by 1H-NMR measurements in the presence of chiral shift reagents. The sulfonylimine 21a and a series of para-substituted derivatives 21b-h are also allowed to react with the vinyllithium reagent 1b to give mixtures of diastereomers 22/23. The logarithms of the diastereomeric ratios 22:23 correlate with Hammett's σ-values. VCH Verlagsgesellschaft mbH, 1997.
- Braun, Manfred,Opdenbusch, Kersten
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p. 141 - 154
(2007/10/03)
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- Reversal of the stereochemical course of the addition of phenylmagnesium bromide to N-benzylimines derived from R-glyceraldehyde depending on the O-protecting group and its application to the synthesis of both enantiomers of phenylglycine
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The N-Benzyl imines derived from 2,3-di-O-benzyl-D-glyceraldehyde and 2,3-di-O-isopropylidene-D-glyceraldehyde reacted with phenylmagnesium bromide to afford fully protected aminodiols with total diastereoselectivity. The stereochemical course of the addition reaction depends on the nature of the O-protecting group. These compounds can be easily transformed to enantiomerically pure (R) and (S)α-phenylglycine.
- Badorrey, Ramon,Cativiela, Carlos,Diaz-De-Villegas, Maria D.,Galvez, Jose A.
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p. 1411 - 1416
(2007/10/03)
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- Asymmetric synthesis of α-amino acids via diastereoselective addition of (R)-pantolactone to their ketenes
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The diastereoselective addition of (R)-pantolactone to various amino ketenes derived from phthalylamino acids is reported. The configuration of the newly-generated asymmetric center is dependent on alkyl or aryl C(x substitution. This method constitutes a novel and convenient way of amino acid deracemization.
- Calmes, Monique,Daunis, Jacques,Mai, Nathalie
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p. 1641 - 1648
(2007/10/03)
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- Schiff bases of amino acid esters as new substrates for the enantioselective enzymatic hydrolysis and accompanied asymmetric transformations in aqueous organic solvents
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The enzyme (lipases and chymotrypsin)-catalyzed hydrolysis of Schiff bases derived from racemic amino acid esters and aromatic aldehydes has been investigated. The reactions were successfully carried out in different aqueous organic solvents at ambient temperature, but the aqueous acetonitrile (5.4% water content by volume) was the solvent of choice. The L-amino acid (ee 98%) precipitated out from the solution as the reaction progressed, and the liberated aldehyde and unhydrolyzed D-ester (ee 40-98%) remained in the solution. The range of substrates included amino acids having different types of side chains. The addition of an organic base (DABCO) into the solution resulted in the racemization of the remaining D-ester and the additional hydrolysis of the substrate, thus leading to the effective asymmetric transformation of the initial ester. Upto 87.5% of the initial racemate was converted into the L-enantiomer.
- Parmar, Virinder S.,Singh, Amarjit,Bisht, Kirpal S.,Kumar, Naresh,Belokon,Kochetkov,Ikonnikov,Orlova,Tararov,Saveleva
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p. 1223 - 1226
(2007/10/03)
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- New hydantoinases from thermophilic microorganisms - Synthesis of enantiomerically pure D-amino acids
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A series of 14 D-α-amino acids were prepared in high chemical and optical yields from the corresponding racemic hydantoins by employing two novel hydantoinases from thermophilic microorganisms.
- Keil,Schneider,Rasor
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p. 1257 - 1260
(2007/10/02)
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