- One-Pot Enzymatic Synthesis of Cyclic Vicinal Diols from Aliphatic Dialdehydes via Intramolecular C?C Bond Formation and Carbonyl Reduction Using Pyruvate Decarboxylases and Alcohol Dehydrogenases
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An enzymatic cascade reaction was developed for one-pot enantioselective conversion of aliphatic dialdehydes to chiral vicinal diols using pyruvate decarboxylases (PDCs) and alcohol dehydrogenases (ADHs). The PDCs showed promiscuity in catalysing the cyclization of aliphatic dialdehydes through intramolecular stereoselective carbon-carbon bond formation. Consequently, 1,2-cyclopentanediols in three different stereoisomeric forms and 1,2-cyclohexanediols in two different stereoisomeric forms could be prepared with high conversion and stereoisomeric ratio from the respective initial substrates, glutaraldehyde and adipaldehyde. These cascade reactions represent a promising approach to the biocatalytic synthesis of important chiral vicinal diols. (Figure presented.).
- Zhang, Yan,Yao, Peiyuan,Cui, Yunfeng,Wu, Qiaqing,Zhu, Dunming
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supporting information
p. 4191 - 4196
(2018/09/25)
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- Structural and Computational Insight into the Catalytic Mechanism of Limonene Epoxide Hydrolase Mutants in Stereoselective Transformations
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Directed evolution of limonene epoxide hydrolase (LEH), which catalyzes the hydrolytic desymmetrization reactions of cyclopentene oxide and cyclohexene oxide, results in (R,R)- and (S,S)-selective mutants. Their crystal structures combined with extensive theoretical computations shed light on the mechanistic intricacies of this widely used enzyme. From the computed activation energies of various pathways, we discover the underlying stereochemistry for favorable reactions. Surprisingly, some of the most enantioselective mutants that rapidly convert cyclohexene oxide do not catalyze the analogous transformation of the structurally similar cyclopentene oxide, as shown by additional X-ray structures of the variants harboring this slightly smaller substrate. We explain this puzzling observation on the basis of computational calculations which reveal a disrupted alignment between nucleophilic water and cyclopentene oxide due to the pronounced flexibility of the binding pocket. In contrast, in the stereoselective reactions of cyclohexene oxide, reactive conformations are easily reached. The unique combination of structural and computational data allows insight into mechanistic details of this epoxide hydrolase and provides guidance for future protein engineering in reactions of structurally different substrates.
- Sun, Zhoutong,Wu, Lian,Bocola, Marco,Chan, H. C. Stephen,Lonsdale, Richard,Kong, Xu-Dong,Yuan, Shuguang,Zhou, Jiahai,Reetz, Manfred T.
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supporting information
p. 310 - 318
(2018/01/17)
-
- Hydrogen Bonding-Assisted Enhancement of the Reaction Rate and Selectivity in the Kinetic Resolution of d,l-1,2-Diols with Chiral Nucleophilic Catalysts
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An extremely efficient acylative kinetic resolution of d,l-1,2-diols in the presence of only 0.5 mol% of binaphthyl-based chiral N,N-4-dimethylaminopyridine was developed (selectivity factor of up to 180). Several key experiments revealed that hydrogen bonding between the tert-alcohol unit(s) of the catalyst and the 1,2-diol unit of the substrate is critical for accelerating the rate of monoacylation and achieving high enantioselectivity. This catalytic system can be applied to a wide range of substrates involving racemic acyclic and cyclic 1,2-diols with high selectivity factors. The kinetic resolution of d,l-hydrobenzoin and trans-1,2-cyclohexanediol on a multigram scale (10 g) also proceeded with high selectivity and under moderate reaction conditions: (i) very low catalyst loading (0.1 mol%); (ii) an easily achievable low reaction temperature (0 °C); (iii) high substrate concentration (1.0 M); and (iv) short reaction time (30 min). (Figure presented.).
- Fujii, Kazuki,Mitsudo, Koichi,Mandai, Hiroki,Suga, Seiji
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supporting information
p. 2778 - 2788
(2017/08/23)
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- Chiral-Substituted Poly-N-vinylpyrrolidinones and Bimetallic Nanoclusters in Catalytic Asymmetric Oxidation Reactions
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A new class of poly-N-vinylpyrrolidinones containing an asymmetric center at C5 of the pyrrolidinone ring were synthesized from l-amino acids. The polymers, particularly 17, were used to stabilize nanoclusters such as Pd/Au for the catalytic asymmetric oxidations of 1,3- and 1,2-cycloalkanediols and alkenes, and Cu/Au was used for C-H oxidation of cycloalkanes. It was found that the bulkier the C5 substituent in the pyrrolidinone ring, the greater the optical yields produced. Both oxidative kinetic resolution of (±)-1,3- and 1,2-trans-cycloalkanediols and desymmetrization of meso cis-diols took place with 0.15 mol % Pd/Au (3:1)-17 under oxygen atmosphere in water to give excellent chemical and optical yields of (S)-hydroxy ketones. Various alkenes were oxidized with 0.5 mol % Pd/Au (3:1)-17 under 30 psi of oxygen in water to give the dihydroxylated products in >93% ee. Oxidation of (R)-limonene at 25 °C occurred at the C-1,2-cyclic alkene function yielding (1S,2R,4R)-dihydroxylimonene 49 in 92% yield. Importantly, cycloalkanes were oxidized with 1 mol % Cu/Au (3:1)-17 and 30% H2O2 in acetonitrile to afford chiral ketones in very good to excellent chemical and optical yields. Alkene function was not oxidized under the reaction conditions. Mechanisms were proposed for the oxidation reactions, and observed stereo- and regio-chemistry were summarized.
- Hao, Bo,Gunaratna, Medha J.,Zhang, Man,Weerasekara, Sahani,Seiwald, Sarah N.,Nguyen, Vu T.,Meier, Alex,Hua, Duy H.
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supporting information
p. 16839 - 16848
(2017/01/10)
-
- Comparing Different Strategies in Directed Evolution of Enzyme Stereoselectivity: Single- versus Double-Code Saturation Mutagenesis
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Saturation mutagenesis at sites lining the binding pockets of enzymes constitutes a viable protein engineering technique for enhancing or inverting stereoselectivity. Statistical analysis shows that oversampling in the screening step (the bottleneck) increases astronomically as the number of residues in the randomization site increases, which is the reason why reduced amino acid alphabets have been employed, in addition to splitting large sites into smaller ones. Limonene epoxide hydrolase (LEH) has previously served as the experimental platform in these methodological efforts, enabling comparisons between single-code saturation mutagenesis (SCSM) and triple-code saturation mutagenesis (TCSM); these employ either only one or three amino acids, respectively, as building blocks. In this study the comparative platform is extended by exploring the efficacy of double-code saturation mutagenesis (DCSM), in which the reduced amino acid alphabet consists of two members, chosen according to the principles of rational design on the basis of structural information. The hydrolytic desymmetrization of cyclohexene oxide is used as the model reaction, with formation of either (R,R)- or (S,S)-cyclohexane-1,2-diol. DCSM proves to be clearly superior to the likewise tested SCSM, affording both R,R- and S,S-selective mutants. These variants are also good catalysts in reactions of further substrates. Docking computations reveal the basis of enantioselectivity.
- Sun, Zhoutong,Lonsdale, Richard,Li, Guangyue,Reetz, Manfred T.
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p. 1865 - 1872
(2016/11/06)
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- Structure-Guided Triple-Code Saturation Mutagenesis: Efficient Tuning of the Stereoselectivity of an Epoxide Hydrolase
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The directed evolution of enzymes promises to eliminate the long-standing limitations of biocatalysis in organic chemistry and biotechnology - the often-observed limited substrate scope, insufficient activity, and poor regioselectivity or stereoselectivity. Saturation mutagenesis at sites lining the binding pocket with formation of focused libraries has emerged as the technique of choice, but choosing the optimal size of the randomization site and reduced amino acid alphabet for minimizing the labor-determining screening effort remains a challenge. Here, we introduce structure-guided triple-code saturation mutagenesis (TCSM) by encoding three rationally chosen amino acids as building blocks in the randomization of large multiresidue sites. In contrast to conventional NNK codon degeneracy encoding all 20 canonical amino acids and requiring the screening of more than 1015 transformants for 95% library coverage, TCSM requires only small libraries not exceeding 200-800 transformants in one library. The triple code utilizes structural (X-ray) and consensus-derived sequence data, and is therefore designed to match the steric and electrostatic characteristics of the particular enzyme. Using this approach, limonene epoxide hydrolase has been successfully engineered as stereoselective catalysts in the hydrolytic desymmetrization of meso-type epoxides with formation of either (R,R)- or (S,S)-configurated diols on an optional basis and kinetic resolution of chiral substrates. Crystal structures and docking computations support the source of notably enhanced and inverted enantioselectivity.
- Sun, Zhoutong,Lonsdale, Richard,Wu, Lian,Li, Guangyue,Li, Aitao,Wang, Jianbo,Zhou, Jiahai,Reetz, Manfred T.
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p. 1590 - 1597
(2016/03/15)
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- Mixing and matching chiral cobalt- and manganese-based calix-salen catalysts for the asymmetric hydrolytic ring opening of epoxides
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Homochiral oligomeric salen macrocycles possessing aromatic spacers have been prepared as new calix-salen derivatives. The corresponding cobalt and manganese complexes were synthesized and characterized, and their catalytic activities have been studied in the challenging hydrolysis of meso epoxides. While manganese calix-salen complexes were not active in the studied reactions, the dual heterobimetallic system, using an equimolar combination of cobalt and manganese calix-salen derivatives proved to be more enantioselective than the sole cobalt system. Furthermore, as heterogeneous complexes, the catalytic mixture could be easily recovered by simple filtration and successfully reengaged in subsequent catalytic runs. Interestingly, no need for cobalt reactivation was noticed to maintain maximum efficiency of this dual system. The matched Co/Mn dual catalyst was also used to promote the dynamic hydrolytic kinetic resolution of epibromohydrin.
- Dandachi, Hiba,Zaborova, Elena,Kolodziej, Emilie,David, Olivier R.P.,Hannedouche, Jér?me,Mellah, Mohamed,Jaber, Nada,Schulz, Emmanuelle
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p. 246 - 253
(2017/03/01)
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- Microstructure Analysis of Poly(cyclopentene carbonate)s at the Diad Level
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The spectroscopic assignment of poly(cyclopentene carbonate)s at the diad level was performed by using two kinds of model compounds: isotactic and syndiotactic dimers of cyclopentene carbonate unit. By comparing the signals in the carbonyl region, we concluded that the signals at 153.85 and 153.78 ppm in the 13C NMR spectrum of poly(cyclopentene carbonate) were attributed to m-diad and r-diad, respectively. The signals at 82.61 and 82.53 ppm in the 13C NMR spectrum were assigned to m-diad and r-diad peak of methine resonance, respectively. It was found that the carbonate carbon signals were sensitive toward the stereocenters on adjacent epoxide ring-opening units. The syndiotactic and isotactic diads matched well with the microstructures of the stereoregular poly(cyclopentene carbonate)s that were prepared by using chiral dinuclear Co(III) complex catalysts.
- Liu, Ye,Li, Rong-Rong,Lu, Xiao-Bing
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p. 6941 - 6947
(2015/10/28)
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- Enantioselective Cascade Biocatalysis via Epoxide Hydrolysis and Alcohol Oxidation: One-Pot Synthesis of (R)-α-Hydroxy Ketones from Meso- or Racemic Epoxides
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A new type of cascade biocatalysis was developed for one-pot enantioselective conversion of a meso- or racemic epoxide to an α-hydroxy ketone in high ee via an epoxide hydrolase-catalyzed hydrolysis of the epoxide, an alcohol dehydrogenase-catalyzed oxidation of the diol intermediate, and an enzyme-catalyzed cofactor regeneration. In vitro cascade biotransformation of meso-epoxides (cyclopentene oxide 1a, cyclohexene oxide 1b, and cycloheptene oxide 1c) was achieved with cell-free extracts containing recombinant SpEH (epoxide hydrolase from Sphingomonas sp. HXN-200), BDHA (butanediol dehydrogenase from Bacillus subtilis BGSC1A1), and LDH (lactate dehydrogenase form Bacillus subtilis) or NOX (NADH oxidase from Lactobacillus brevis DSM 20054), respectively, giving the corresponding (R)-α-hydroxycyclopentanone 3a, (R)-α-hydroxycyclohexanone 3b, and (R)-α-hydroxycycloheptanone 3c in 98-99% ee and 70-50% conversion with TTN of NAD+-recycling of 5500-26000. Cascade catalysis with mixed cells of Escherichia coli (SpEH) and E. coli (BDHA-NOX) converted 100-300 mM meso-epoxides 1a-1c to (R)-α-hydroxy ketones 3a-3c in 98-99% ee and 85-57% conversion. Cells of E. coli (SpEH-BDHA-NOX) coexpressing all three enzymes were also proven as good catalysts for the cascade conversion of 100-200 mM meso-epoxides 1a-1c, giving (R)-α-hydroxy ketones 3a-3c in 98-99% ee and 79-52% conversion. The cascade biocatalysis for one-pot synthesis of α-hydroxy ketone in high ee was also successfully demonstrated with a racemic epoxide (1,2,3,4-tetrahydronaphthalene-1,2-oxide 1d) as the substrate. By using two whole-cells based approaches, (R)-α-hydroxytetralone 3d was obtained in 99% ee and 49-40% conversion from 20 to 5 mM racemic epoxide 1d. Preparative cascade biotransformation of cyclohexene oxide 1b gave (R)-α-hydroxycyclohexanone 3b in 98% ee with 70% isolated yield. The developed new type of cascade biocatalysis is enantioselective, green, and often high yielding. The concept might be generally applicable to produce other useful enantiopure α-hydroxy ketones from the corresponding meso- or racemic epoxides by cascade catalysis using appropriate enzymes. (Chemical Equation Presented).
- Zhang, Jiandong,Wu, Shuke,Wu, Jinchuan,Li, Zhi
-
-
- Reshaping an Enzyme Binding Pocket for Enhanced and Inverted Stereoselectivity: Use of Smallest Amino Acid Alphabets in Directed Evolution
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Directed evolution based on saturation mutagenesis at sites lining the binding pocket is a commonly practiced strategy for enhancing or inverting the stereoselectivity of enzymes for use in organic chemistry or biotechnology. However, as the number of residues in a randomization site increases to five or more, the screening effort for 95% library coverage increases astronomically until it is no longer feasible. We propose the use of a single amino acid for saturation mutagenesis at superlarge randomization sites comprising 10 or more residues. When used to reshape the binding pocket of limonene epoxide hydrolase, this strategy, which drastically reduces the search space and thus the screening effort, resulted in R,R- and S,S-selective mutants for the hydrolytic desymmetrization of cyclohexene oxide and other epoxides. X-ray crystal structures and docking studies of the mutants unveiled the source of stereoselectivity and shed light on the mechanistic intricacies of this enzyme.
- Sun, Zhoutong,Lonsdale, Richard,Kong, Xu-Dong,Xu, Jian-He,Zhou, Jiahai,Reetz, Manfred T.
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supporting information
p. 12410 - 12415
(2015/10/12)
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- Alcohol cross-coupling for the kinetic resolution of diols via oxidative esterification
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We present an organocatalytic C-O-bond cross-coupling strategy to kinetically resolve racemic diols with aromatic and aliphatic alcohols, yielding enantioenriched esters. This one-pot protocol utilizes an oligopeptide multicatalyst, m-CPBA as the oxidant, and N,N-diisopropylcarbodiimide as the activating agent. Racemic acyclic diols as well as trans-cycloalkane-1,2-diols were kinetically resolved, achieving high selectivities and good yields for the products and recovered diols.
- Hofmann, Christine,Schümann, Jan M.,Schreiner, Peter R.
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p. 1972 - 1978
(2015/02/19)
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- En route to multicatalysis: Kinetic resolution of trans-cycloalkane-1,2- diols via oxidative esterification
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We demonstrate the application of a multicatalyst to the oxidation of a broad variety of aldehydes and subsequent enantioselective esterification of the incipient acids with (±)-trans-cycloalkane-1,2-diols. This reaction operates well with a multicatalyst bearing two independent catalytic moieties that provide monoprotected 1,2-diols in one pot.
- Hofmann, Christine,Schuler, Soeren M. M.,Wende, Raffael C.,Schreiner, Peter R.
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supporting information
p. 1221 - 1223
(2014/01/17)
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- Enantioselective biooxidation of racemic trans-cyclic vicinal diols: One-pot synthesis of both enantiopure (S,S)-cyclic vicinal diols and (R)-α-hydroxy ketones
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Highly regio- and enantioselective alcohol dehydrogenases BDHA (2,3-butanediol dehydrogenase from Bacillus subtilis BGSC1A1), CDDHPm (cyclic diol dehydrogenase from Pseudomonas medocina TA5), and CDDHRh (cyclic diol dehydrogenase from Rhodococcus sp. Moj-3449) were discovered for the oxidation of racemic trans-cyclic vicinal diols. Recombinant Escherichia coli expressing BDHA was engineered as an efficient whole-cell biocatalyst for the oxidation of (±)-1,2-cyclopentanediol, 1,2-cyclohexanediol, 1,2-cycloheptane-diol, and 1,2-cyclooctanediol, respectively, to give the corresponding (R)-α-hydroxy ketones in >99% ee and (S,S)-cyclic diols in >99% ee at 50% conversion in one pot. Escherichia coli (BDHA-LDH) co-expressing lactate dehydrogenase (LDH) for intracellular regeneration of NAD+ catalyzed the regio- and enantioselective oxidation of (±)-1,2-dihydroxy-1,2,3,4- tetrahydronaphthalene to produce the corresponding (R)-α-hydroxy ketone in >99% ee and (S,S)-cyclic diol in 96% ee at 49% conversion. Preparative biotransformations were also demonstrated. Thus, a novel and useful method for the one-pot synthesis of both vicinal diols and α-hydroxy ketones in high ee was developed via high Copyright
- Zhang, Jiandong,Xu, Tingting,Li, Zhi
-
supporting information
p. 3147 - 3153
(2013/12/04)
-
- Enhanced rate and selectivity by carboxylate salt as a basic cocatalyst in chiral N-heterocyclic carbene-catalyzed asymmetric acylation of secondary alcohols
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The rate and enantioselectivity of chiral NHC-catalyzed asymmetric acylation of alcohols with an adjacent H-bond donor functionality are remarkably enhanced in the presence of a carboxylate cocatalyst. The degree of the enhancement is correlated with the basicity of the carboxylate. With a cocatalyst and a newly developed electron-deficient chiral NHC, kinetic resolution and desymmetrization of cyclic diols and amino alcohols were achieved with extremely high selectivity (up to s = 218 and 99% ee, respectively) at a low catalyst loading (0.5 mol %). This asymmetric acylation is characterized by a unique preference for alcohols over amines, which are not converted into amides under the reaction conditions.
- Kuwano, Satoru,Harada, Shingo,Kang, Bubwoong,Oriez, Raphael,Yamaoka, Yousuke,Takasu, Kiyosei,Yamada, Ken-Ichi
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p. 11485 - 11488
(2013/09/02)
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- Enantioselective hydrolysis of racemic and meso -epoxides with recombinant escherichia coli expressing epoxide hydrolase from Sphingomonas sp. HXN-200: Preparation of epoxides and vicinal diols in high ee and high concentration
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A unique epoxide hydrolase (SpEH) from Sphingomonas sp. HXN-200 was identified and cloned based on genome sequencing and expressed in Escherichia coli. The engineered E. coli (SpEH) showed the same selectivity and substrate specificity as the wild type strain and 172 times higher activity than Sphingomonas sp. HXN-200 for the hydrolysis of styrene oxide 1. Hydrolysis of racemic styrene oxide 1, substituted styrene oxides 3, 5-7, and N-phenoxycarbonyl-3,4-epoxypiperidine 8 (200-100 mM) with resting cells of E. coli (SpEH) gave (S)-epoxides 1, 3, 5-7 and (-)-8 in 98.0-99.5% enantiomeric excess (ee) and 37.6-46.5% yield. Hydrolysis of cyclopentene oxide 9, cyclohexene oxide 10, and N-benzyloxycarbonyl-3,4-epoxypyrrolidine 11 (100 mM) afforded the corresponding (R, R)-vicinal trans-diols 12-14 in 86-93% ee and 90-99% yield. The ee of (1R, 2R)-cyclohexane-1,2-diol 13 was improved to 99% by simple crystallization. These biotransformations showed high specific activity (0.28-4.3 U/mg cdw), product concentration, product/cells ratio, and cell-based productivity. Hydrolysis at even higher substrate concentration was also achieved: (S)-1 was obtained in 430 mM (51 g/Lorg) and 43% yield; (1R, 2R)-13 was obtained in 500 mM (58 g/L) and >99% yield. Gram-scale preparation of epoxides (S)-1, (S)-3, (S)-6 and diols (1R, 2R)-12, (1R, 2R)-13, (3R, 4R)-14 were also demonstrated. E. coli (SpEH) cells showed the highest enantioselectivity to produce (S)-1 (E of 39) among all known EHs in the form of whole cells or free enzymes and the highest enantioselectivities to produce (S)-3, 5, 6, 7, (-)-8, and (R, R)-14 (E of 36, 35, 28, 57, 22, and 28) among all known EHs. The easily available and highly active E. coli (SpEH) cells are the best biocatalysts known thus far for the practical preparation of these useful and valuable enantiopure epoxides and vicinal diols via hydrolysis.
- Wu, Shuke,Li, Aitao,Chin, Yit Siang,Li, Zhi
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p. 752 - 759
(2013/06/05)
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- Enantiomerically enriched trans-diols from alkenes in one pot: A multicatalyst approach
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Multicatalysts consisting of non-natural oligopeptides with distinctly different catalytic moieties create molecular complexity in a multistep one-pot sequence starting from simple alkenes yielding highly enantiomerically enriched trans-diols. The Royal Society of Chemistry 2012.
- Hrdina, Radim,Mueller, Christian E.,Wende, Raffael C.,Wanka, Lukas,Schreiner, Peter R.
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supporting information; experimental part
p. 2498 - 2500
(2012/04/10)
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- Manipulating the stereoselectivity of limonene epoxide hydrolase by directed evolution based on iterative saturation mutagenesis
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Limonene epoxide hydrolase from Rhodococcus erythropolis DCL 14 (LEH) is known to be an exceptional epoxide hydrolase (EH) because it has an unusual secondary structure and catalyzes the hydrolysis of epoxides by a rare one-step mechanism in contrast to the usual two-step sequence. From a synthetic organic viewpoint it is unfortunate that LEH shows acceptable stereoselectivity essentially only in the hydrolysis of the natural substrate limonene epoxide, which means that this EH cannot be exploited as a catalyst in asymmetric transformations of other substrates. In the present study, directed evolution using iterative saturation mutagenesis (ISM) has been tested as a means to engineer LEH mutants showing broad substrate scope with high stereoselectivity. By grouping individual residues aligning the binding pocket correctly into randomization sites and performing saturation mutagenesis iteratively using a reduced amino acid alphabet, mutants were obtained which catalyze the desymmetrization of cyclopentene-oxide with stereoselective formation of either the (R,R)- or the (S,S)-diol on an optional basis. The mutants prove to be excellent catalysts for the desymmetrization of other meso-epoxides and for the hydrolytic kinetic resolution of racemic substrates, without performing new mutagenesis experiments. Since less than 5000 tranformants had to be screened for achieving these results, this study contributes to the generalization of ISM as a fast and reliable method for protein engineering. In order to explain some of the stereoselective consequences of the observed mutations, a simple model based on molecular dynamics simulations has been proposed.
- Zheng, Huabao,Reetz, Manfred T.
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supporting information; experimental part
p. 15744 - 15751
(2011/02/21)
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- Enantioselective kinetic resolution of trans-cycloalkane-1,2-diols
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Finally! The title resolution is achieved with a nonnatural, partially rigid, lipophilic tetrapeptide at low catalyst loadings without additional base or cosolvents. The transition-state model (ball-and-stick model in the scheme; C gray, N blue, O red) emphasizes the interplay between hydrogen-bonding and hydrophobic interactions. (Chemical Equation Presented)
- Mueller, Christian E.,Wanka, Lukas,Jewell, Kevin,Schreiner, Peter R.
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supporting information; experimental part
p. 6180 - 6183
(2009/04/06)
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- Kinetic resolution of d,l-1,2-diols catalyzed by amine-phosphinite bifunctional organocatalysis derived from quinidine
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Racemic C2-symmetric 1,2-diols were kinetically resolved by the acylation reaction catalyzed by the phosphinite derivative of quinidine to afford the corresponding monoacylated product with good to high enantioselectivities.
- Mizuta, Shinya,Ohtsubo, Yutaka,Tsuzuki, Takeo,Fujimoto, Tetsuya,Yamamoto, Iwao
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p. 8227 - 8229
(2007/10/03)
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- Convenient route to both enantiomerically pure forms of trans-4,5-dihydroxy-2-cyclopenten-1-one: Efficient synthesis of the neocarzinostatin chromophore core
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An enantioselective synthesis of an epoxybicyclo[7.3.0]dodecenediyne core system of the neocarzinostatin chromophore has been achieved via intramolecular acetylide addition and palladium-mediated coupling of iodocyclopentene 5 with alkyne 6. The key cyclopentene moiety, trans-4,5-dihydroxy-2-cyclopenten-1-one 7, was conveniently prepared in both enantiomerically pure forms via enzymatic desymmetrization of meso-3,4,5-trans,trans-trihydroxycyclopentene derivatives.
- Toyama,Iguchi,Sakazaki,Oishi,Hirama
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p. 997 - 1008
(2007/10/03)
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- Chiral synthesis via organoboranes. 45. Asymmetric hydroboration of 1-cyclopentenol derivatives using diisopinocampheylborane. Synthesis of optically active cyclopentane-1,2-diol derivatives of high optical purity
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The asymmetric hydroboration of 1-cyclopentenol derivatives, such as ethers, acetate, silyl ether and borinate, was investigated using diisopinocampheylborane, dIpc2BH. The product trialkylboranes were treated with excess of acetalde
- Brown, Herbert C.,Murali, Dhanabalan,Singaram, Bakthan
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p. 116 - 121
(2007/10/03)
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- Kinetic resolution of vic-diols by Bacillus stearothermophilus diacetyl reductase
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The kinetic resolution of several racemic syn- and anti-1,2-diols by enzymatic oxidation with Bacillus stearothermophilus diacetyl reductase is described. The enantiomerically pure (R,R)- and (R,S)-diols are recovered in almost quantitative yield.
- Bortolini, Olga,Casanova, Elena,Fantin, Giancarlo,Medici, Alessandro,Poli, Silvia,Hanau, Stefania
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p. 647 - 651
(2007/10/03)
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- Enantioselective hydrolysis of aryl, alicyclic and aliphatic epoxides by Rhodotorula glutinis
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Enantioselective epoxide hydrolysis by yeasts has been demonstrated for the hydrolysis of several aryl, alicyclic and aliphatic epoxides by a strain of Rhodotorula glutinis. High enantioselectivity was obtained in the hydrolysis of methyl substituted aryl and aliphatic epoxides whereas selectivity towards terminal epoxides in all cases was lower. Homochiral vicinal diols were formed from several methyl substituted epoxides and also from meso epoxides. Kinetic resolution of trans-1-phenyl-1,2-epoxypropane was studied in more detail.
- Weijers, Carel A. G. M.
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p. 639 - 647
(2007/10/03)
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- Experimental and theoretical approach to hydrogen-bonded diastereomeric interactions in a model complex
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Binding affinities of (R,R)-1,2-cyclohexanediamine (R) to (R,R)-1,2-cyclopentanediol (R5) and (S,S)-1,2-cyclopentanediol (S5) and to the corresponding cyclohexanediols (R6 and S6) have been measured in benzene and in CCl4 at 298 K by microcalorimetry, and unexpected differences between the diastereomeric complexes are observed. Long time scale (0.1 μs) molecular-dynamics simulations of the two smaller diastereomeric complexes, R/R5 and R/S5, in a simplified solvent model are reported. A direct free energy calculation gives results in good agreement with the experimental values measured in benzene for the first pair, but nearly identical results for the second pair, which is at variance with experiment. A systematic analysis of the dependence of simulation results on model parameters is performed, and no possibility is found to improve the enantioselectivity by parameter tuning. Other possible causes for discrepancies are specific solute-solvent or solvent-solvent interactions, electronic charge redistribution effects, or formation of clusters of more than two molecules. Owing to the long time scales reached, a well-converged picture of the dynamics is obtained, and the species present at equilibrium can be studied in detail. The average lifetime of the complex is found to be about 200 ps, whereas that of a hydrogen bond is only about 5 ps. Besides the unbound state, the dominant species observed in the simulations for both diastereomeric pairs are singly hydrogen-bonded complexes, with a clear preference for a O to N over the N to O hydrogen bond. Many other hydrogen-bonding patterns (bridged, double) are also observed in minor amounts.
- Hünenberger, Philippe H.,Granwehr, Josef K.,Aebischer, Jean-Nicolas,Ghoneim, Nagwa,Haselbach, Edwin,Van Gunsteren, Wilfred F.
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p. 7533 - 7544
(2007/10/03)
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- Enzymatic hydrolysis and esterification. Routes to optically pure cyclopentanols
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Using an esterhydrolase from Pseudomonas sp. (SAM II), a series of optically pure cyclopentanols 1-4 was prepared by enzymatic hydrolysis of their corresponding acetates.Using the same enzyme, these cyclopentanols were esterified by enol esters as acyl do
- Seemayer, R.,Schneider, M. P.
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p. 171 - 174
(2007/10/02)
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- Asymmetric conjugate addition of organometallic reagents to chiral α,β-unsaturated esters
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Asymmetric conjugate addition to α,β-unsaturated ester was studied using four kinds of cyclic diols (1c-4c) as chiral auxiliaries. Among the tested substrates, (R,R)-cyclohexane-1,2-diol derivatives (6a-c) and (1R,2S)-2-hydroxymethylcyclopentanol derivative (7a) showed high and reverse diastereoselectivity in conjugate addition by organocuprates (R2CuLi) and/or Grignard reagents in the presence of copper iodide (RMgBr + CuI), respectively.
- Fang,Ogawa,Suemune,Sakai
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p. 389 - 398
(2007/10/02)
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- Product Enantioselectivity of the Microsomal and Cytosolic Epoxide Hydrolase catalysed Hydrolysis of meso Epoxides
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1,2-Epoxycycloalkanes from C5 to C8 and cis-stilbene oxide are respectively hydrolysed to the corresponding (-)-(R,R)-trans-diols and to (+)-(R,R)-1,2-diphenylethane-1,2-diol by both the microsomal and the cytosolic epoxide hydrolase of rabbit liver, the former enzyme being more active and giving higher enantiomeric excesses.
- Bellucci, Giuseppe,Capitani, Isabella,Chiappe, Cinzia,Marioni, Franco
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p. 1170 - 1171
(2007/10/02)
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- APPLICATION OF MICROORGANISMS AND ENZYMES TO THE SYNTHESIS OF CHIRAL CYCLOPENTANE AND BICYCLOOCTANE DERIVATIVES
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Optically active cyclopentane and bicyclooctane derivatives were synthesized by utilizing biochemical methods.Pseudomonas fluorescens lipase was found to be an effective enzyme for the enantioselective hydrolysis of monoacetoxy- and diacetoxycyclopentanes such as (+/-)-4a, (+/-)-5a, (+/-)-6a, and 7a.However,hydrolysis of bicyclooctane trans-acetate ((+/-)-8a) using this enzyme resulted low enantioselectivity.Optically pure (+)-8b for the synthesis of carbacyclin was obtained from (+/-)-8a by using porcine pancreatic lipase.Reduction of 3-acetyl-7-oxobicyclo-oct-2-ene with baker's yeast afforded a useful intermediate((+)-11b) for the synthesis of hirsutic acid.Keywords - enzymatic hydrolysis; enantioselective hydrolysis; bicyclo-octane; baker's yeast; carbacyclin; hirsutic acid
- Xie, Zhuo-Feng,Suemune, Hiroshi,Nakamura, Izumi,Sakai, Kiyoshi
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p. 4454 - 4459
(2007/10/02)
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- Enzymatic Hydrolysis of (+/-)-trans-1,2-Diacetoxycycloalkanes. A Facile Route to Optically-active Cycloalkane-1,2-diols
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The racemic title compounds were resolved conveniently into the enantiomers with high optical purities by enzymatic hydrolysis in the presence of porcine liver esterase.
- Crout, David H. G.,Gaudet, Veronique S. B.,Laumen, Kurt,Schneider, Manfred P.
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p. 808 - 810
(2007/10/02)
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