- Divorce in the two-component BVMO family: The single oxygenase for enantioselective chemo-enzymatic Baeyer-Villiger oxidations
-
Two-component flavoprotein monooxygenases consist of a reductase and an oxygenase enzyme. The proof of functionality of the latter without its counterpart as well as the mechanism of flavin transfer remains unanswered beyond doubt. To tackle this question, we utilized a reductase-free reaction system applying purified 2,5-diketocamphane-monooxygenase I (2,5-DKCMO), a FMN-dependent type II Baeyer-Villiger monooxygenase, and synthetic nicotinamide analogues (NCBs) as dihydropyridine derivatives for FMN reduction. This system demonstrated the stand-alone quality of the oxygenase, as well as the mechanism of FMNH2transport by free diffusion. The efficiency of this reductase-free system strongly relies on the balance of FMN reduction and enzymatic (re)oxidation, since reduced FMN in solution causes undesired side reactions, such as hydrogen peroxide formation. Design of experiments allowed us to (i) investigate the effect of various reaction parameters, underlining the importance to balance the FMN/FMNH2cycle, (ii) optimize the reaction system for the enzymatic Baeyer-Villiger oxidation of rac-bicyclo[3.2.0]hept-2-en-6-one,rac-camphor, andrac-norcamphor. Finally, this study not only demonstrates the reductase-independence of 2,5-DKCMO, but also revisits the terminology of two-component flavoprotein monooxygenases for this specific case.
- R?llig, Robert,Paul, Caroline E.,Claeys-Bruno, Magalie,Duquesne, Katia,Kara, Selin,Alphand, Véronique
-
supporting information
p. 3441 - 3450
(2021/05/03)
-
- Genome mining reveals new bacterial type I Baeyer-Villiger monooxygenases with (bio)synthetic potential
-
Baeyer-Villiger monooxygenases (BVMOs) are oxidorreductases that catalyze the oxidation of ketones in a very selective manner. By genome mining we detected seven putative type I BVMOs in Bradyrhizobium diazoefficiens USDA 110. As we established the phylogenetic relationships among them and with other type I BVMOs, we found out that they belong to different clades of the phylogenetic tree. Thus, we decided to clone and heterologously express five of them. Three of them, each one from a divergent phylogenetic group, were obtained as soluble proteins, allowing us to proceed with their biocatalytic assessment and enzymatic characterization. As to substrate scope and selectivity, we observed a complementary behavior among the three BVMOs. BVMO2 was the more versatile biocatalyst in whole-cell systems while BVMO4 and BVMO5 showed a narrow substrate profile with preference for linear ketones and particular regioselectivity for (±)-cis-bicyclo[3.2.0]hept-2-en-6-one.
- Bianchi, Dario A.,Carabajal, María Ayelén,Ceccoli, Romina D.,Rial, Daniela V.
-
-
- Controlling the Regioselectivity of Baeyer–Villiger Monooxygenases by Mutation of Active-Site Residues
-
Baeyer–Villiger monooxygenase (BVMO)-mediated regiodivergent conversions of asymmetric ketones can lead to the formation of “normal” or “abnormal” lactones. In a previous study, we were able to change the regioselectivity of a BVMO by mutation of the active-site residues to smaller amino acids, which thus created more space. In this study, we demonstrate that this method can also be used for other BVMO/substrate combinations. We investigated the regioselectivity of 2-oxo-Δ3-4,5,5-trimethylcyclopentenylacetyl-CoA monooxygenase from Pseudomonas putida (OTEMO) for cis-bicyclo[3.2.0]hept-2-en-6-one (1) and trans-dihydrocarvone (2), and we were able to switch the regioselectivity of this enzyme for one of the substrate enantiomers. The OTEMO wild-type enzyme converted (?)-1 into an equal (50:50) mixture of the normal and abnormal products. The F255A/F443V variant produced 90 % of the normal product, whereas the W501V variant formed up to 98 % of the abnormal product. OTEMO F255A exclusively produced the normal lactone from (+)-2, whereas the wild-type enzyme was selective for the production of the abnormal product. The positions of these amino acids were equivalent to those mutated in the cyclohexanone monooxygenases from Arthrobacter sp. and Acinetobacter sp. (CHMOArthro and CHMOAcineto) to switch their regioselectivity towards (+)-2, which suggests that there are hot spots in the active site of BVMOs that can be targeted with the aim to change the regioselectivity.
- Balke, Kathleen,B?umgen, Marcus,Bornscheuer, Uwe T.
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p. 1627 - 1638
(2017/08/26)
-
- Characterization and Crystal Structure of a Robust Cyclohexanone Monooxygenase
-
Cyclohexanone monooxygenase (CHMO) is a promising biocatalyst for industrial reactions owing to its broad substrate spectrum and excellent regio-, chemo-, and enantioselectivity. However, the low stability of many Baeyer–Villiger monooxygenases is an obstacle for their exploitation in industry. Characterization and crystal structure determination of a robust CHMO from Thermocrispum municipale is reported. The enzyme efficiently converts a variety of aliphatic, aromatic, and cyclic ketones, as well as prochiral sulfides. A compact substrate-binding cavity explains its preference for small rather than bulky substrates. Small-scale conversions with either purified enzyme or whole cells demonstrated the remarkable properties of this newly discovered CHMO. The exceptional solvent tolerance and thermostability make the enzyme very attractive for biotechnology.
- Romero, Elvira,Castellanos, J. Rubén Gómez,Mattevi, Andrea,Fraaije, Marco W.
-
supporting information
p. 15852 - 15855
(2016/12/16)
-
- E. coli cells expressing the Baeyer-Villiger monooxygenase 'MO14' (ro03437) from Rhodococcus jostii RHA1 catalyse the gram-scale resolution of a bicyclic ketone in a fermentor
-
The Baeyer-Villiger monooxygenase (BVMO) 'MO14' from Rhodococcus jostii RHA1, is an enantioselective BVMO that catalyses the resolution of the model ketone substrate bicyclo[3.2.0]hept-2-en-6-one to the (1S,5R)-2-oxa lactone and the residual (1S,5R)-substrate enantiomer. This regio-plus enantioselective behaviour is highly unusual for BVMOs, which often perform enantiodivergent biotransformations of this substrate. The scaleability of the transformation was investigated using fermentor-based experiments, in which variables including gene codon optimisation, temperature and substrate concentration were investigated. E. coli cells expressing MO14 catalysed the resolution of bicyclo[3.2.0]hept-2-en-6-one to yield (1S,5R)-2-oxa lactone of >99% ee and (1S,5R)-ketone of 96% ee after 14 h at a temperature of 16 °C and a substrate concentration of 0.5 g L-1 (4.5 mM). MO14 is thus a promising biocatalyst for the production of enantio-enriched ketones and lactones derived from the [3.2.0] platform.
- Summers, Benjamin D.,Omar, Muhiadin,Ronson, Thomas O.,Cartwright, Jared,Lloyd, Michael,Grogan, Gideon
-
p. 1897 - 1903
(2015/02/19)
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- Type II flavin-containing monooxygenases: A new class of biocatalysts that harbors baeyer-villiger monooxygenases with a relaxed coenzyme specificity
-
Within a newly identified set of flavin-containing monooxygenases (FMOs) from Rhodococcus jostii RHA1, we have identified three monooxygenases (FMO-E, FMO-F, and FMO-G) that are effective in catalyzing Baeyer-Villiger oxidations. These type II FMOs display relaxed coenzyme specificity by accepting both NADPH (reduced form of nicotinamide adenine dinucleotide phosphate) and NADH (reduced form of nicotinamide adenine dinucleotide), as a coenzyme, which is a novel and attractive feature among biocatalysts capable of conducting Baeyer-Villiger oxidations. We purified FMO-E and determined that the Michaelis constants for both coenzymes were in the micromolar range, whereas the activity was highest for NADH. By using the stopped-flow technique, formation of a peroxyflavin-enzyme intermediate was observed, which indicated that type II FMOs follow a catalytic mechanism similar to that of other class B flavoprotein monooxygenases. A set of cyclobutanones and cyclohexanones were used to probe the regio- and enantioselectivity of all three recombinant monooxygenases. The biocatalysts readily accepted small cyclic ketones, which enabled the conversion of previously poorly accepted substrates by other monooxygenases (especially norcamphor), and exhibited excellent and unique regio- and enantioselectivities. Sequence analysis revealed that type II FMOs that act as Baeyer-Villiger monooxygenases contain a unique N-terminal domain. Sequence conservation in this protein domain can be used to identify new NADH-dependent Baeyer-Villiger monooxygenases, which would facilitate future biocatalyst discovery efforts. New kid on the block: Members of a newly recognized group of sequence-related flavin-containing monooxygenases can perform Baeyer-Villiger oxidations. Their coenzyme indifference and unique specificity make them attractive biocatalysts.
- Riebel, Anette,Fink, Michael J.,Mihovilovic, Marko D.,Fraaije, Marco W.
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p. 1112 - 1117
(2014/05/06)
-
- Jatrophane diterpenes: Preparation of the western fragment of pl-3
-
Jatrophane diterpenes are structurally intriguing natural products with promising biological properties. Herein, the synthesis of the western fragment of the Euphorbiaceae constituent Pl-3 starting from (1R,5S)-bicyclo[3.2.0]hept- 2-en-6-one is described. Key steps in the sequence include a Baeyer-Villiger oxidation, an iodolactonization reaction, and the installation of the northern side chain through the addition of a lithiated vinyl bromide. The overall efficiency of the route is increased by taking advantage of latent symmetry. The synthesis of the western fragment of Pl-3 is developed by taking advantage of the latent symmetry in an intermediate; both enantiomers are thus converted into the desired substrate. Key steps of the synthesis include a Baeyer-Villiger oxidation, an iodolactonization reaction, and the addition of a vinyllithium species to the completed cyclopentane moiety of the natural product.
- Lentsch, Christoph,Fuerst, Rita,Mulzer, Johann,Rinner, Uwe
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p. 919 - 923
(2014/03/21)
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- Discovery of Baeyer-Villiger monooxygenases from photosynthetic eukaryotes
-
Baeyer-Villiger monooxygenases are attractive "green" catalysts able to produce chiral esters or lactones starting from ketones. They can act as natural equivalents of peroxyacids that are the catalysts classically used in the organic synthesis reactions, consisting in the cleavage of CC bonds with the concomitant insertion of an oxygen atom. In this study, two type I BVMOs have been identified for the first time in photosynthetic eukaryotic organisms, the red alga Cyanidioschyzon merolae (Cm) and the moss Physcomitrella patens (Pp). A biocatalytic characterization of these newly discovered enzymes, expressed in recombinant forms, was carried out. Both enzymes could be purified as holo enzymes containing a FAD cofactor. Their thermostability was investigated and revealed that the Cm-BVMO is the most thermostable type I BVMO with an apparent melting temperature of 56 C. Substrate profiling revealed that both eukaryotic BVMOs accept a wide range of ketones which include aromatic, aliphatic, aryl aliphatic and bicyclic ketones. In particular, linear aliphatic ketones (C9 and C12), carrying the keto functionality in different positions, resulted to be the best substrates in steady state kinetic analyses. In order to restore the BVMO-typifying sequence motif in the Pp-BVMO, a mutant was prepared (Y160H). Intriguingly, this mutation resulted in higher activities on most tested substrates. The recombinant enzymes displayed kcat values in the 0.1-0.2 s-1 range, which is relatively low when compared with other known type I BVMOs. This may hint to a role in secondary metabolism in these photosynthetic organisms, though their exact function remains to be established.
- Beneventi, Elisa,Niero, Mattia,Motterle, Riccardo,Fraaije, Marco,Bergantino, Elisabetta
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p. 145 - 154
(2013/12/04)
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- A Flavoprotein Monooxygenase that Catalyses a Baeyer-Villiger Reaction and Thioether Oxidation Using NADH as the Nicotinamide Cofactor
-
A gene from the marine bacterium Stenotrophomonas maltophilia encodes a 38.6 kDa FAD-containing flavoprotein (Uniprot B2FLR2) named S. maltophilia flavin-containing monooxygenase (SMFMO), which catalyses the oxidation of thioethers and also the regioselective Baeyer-Villiger oxidation of the model substrate bicyclo[3.2.0]hept-2-en-6-one. The enzyme was unusual in its ability to employ either NADH or NADPH as nicotinamide cofactor. The KM and kcat values for NADH were 23.7±9.1 μM and 0.029 s-1 and 27.3±5.3 μM and 0.022 s-1 for NADPH. However, kcat/KM value for the ketone substrate in the presence of 100 μM cofactor was 17 times greater for NADH than for NADPH. SMFMO catalysed the quantitative conversion of 5 mM ketone in the presence of substoichiometric concentrations of NADH with the formate dehydrogenase cofactor recycling system, to give the 2-oxa and 3-oxa lactone products of Baeyer-Villiger reaction in a ratio of 5:1, albeit with poor enantioselectivity. The conversion with NADPH was 15%. SMFMO also catalysed the NADH-dependent transformation of prochiral aromatic thioethers, giving in the best case, 80% ee for the transformation of p-chlorophenyl methyl sulfide to its R enantiomer. The structure of SMFMO reveals that the relaxation in cofactor specificity appears to be accomplished by the substitution of an arginine residue, responsible for recognition of the 2′-phosphate on the NADPH ribose in related NADPH-dependent FMOs, with a glutamine residue in SMFMO. SMFMO is thus representative of a separate class of single-component, flavoprotein monooxygenases that catalyse NADH-dependent oxidations from which possible sequences and strategies for developing NADH-dependent biocatalysts for asymmetric oxygenation reactions might be identified.
- Jensen, Chantel N.,Cartwright, Jared,Ward, Jonathan,Hart, Sam,Turkenburg, Johan P.,Ali, Sohail T.,Allen, Michael J.,Grogan, Gideon
-
experimental part
p. 872 - 878
(2012/07/27)
-
- Asymmetric baeyer-villiger oxidation of 2,3- and 2,3,4-substituted cyclobutanones catalyzed by chiral phosphoric acids with aqueous H 2O2 as the oxidant
-
Catalytic asymmetric Baeyer-Villiger (B-V) oxidation of 2,3,4-trisubstituted cyclobutanone (4) has been realized by the catalysis of a 1,1′-bi-2-naphthol (BINOL)-derived chiral phosphoric acid (1j), which contains bulky 2,4,6-triisopropyl phenyl groups at the 3,3′-positions of the BINOL backbone, using 30% aqueous H2O2 as the oxidant, affording the corresponding Iγ-lactone (5) in 99% yield with 95% ee. In a divergent kinetic resolution of racemic 2,3-disubstituted bicyclic cyclobutanones (6) through asymmetric B-V oxidation, the chiral phosphoric acid 1p demonstrated excellent catalytic performance, giving a range of regioisomeric chiral lactones in a normal lactone (nl)/abnormal lactone (al) ratio of up to 2.1:1, with up to 99% ee in the al product. It was found that fine tuning of the stereoelectronic properties of the backbone in chiral phosphoric acids is critically important for attaining high levels of enantioselectivity in the catalysis of B-V reactions of different type of cyclobutanones. The present work has provided a convenient approach to the synthesis of a variety of optically active chiral Iγ-lactones. Asymmetric Baeyer-Villiger oxidation of tricyclic cyclobutaone and a variety of racemic bicyclic cyclobutanone derivatives has been realized by the catalysis of 1,1′-bi-2-naphthol (BINOL)-derived chiral phosphoric acid with high yields and excellent enantioselectivities using 30% aqueous H2O2 as the oxidant.
- Xu, Senmiao,Wang, Zheng,Zhang, Xumu,Ding, Kuiling
-
supporting information; experimental part
p. 110 - 116
(2011/03/21)
-
- Asymmetric Baeyer-Villiger oxidation with Co(Salen) and H2O 2 in water: Striking supramolecular micelles effect on catalysis
-
A micellar environment enables catalytic, diastereoselective and enantioselective Baeyer-Villiger oxidation of cyclobutanones (ee up to 90%) with H2O2 as oxidant using Co(Salen) catalyst 1, while the same catalytic system is inactive in organic solvents. The Royal Society of Chemistry 2009.
- Bianchini, Giulio,Cavarzan, Alessandra,Scarso, Alessandro,Strukul, Giorgio
-
experimental part
p. 1517 - 1520
(2010/06/13)
-
- Laboratory evolution of robust and enantioselective Baeyer-Villiger monooxygenases for asymmetric catalysis
-
The Baeyer-Villiger Monooxygenase, Phenylacetone Monooxygenase (PAMO), recently discovered by Fraaije, Janssen, and co-workers, is unusually thermostable, which makes it a promising candidate for catalyzing enantioselective Baeyer-Villiger reactions in organic chemistry. Unfortunately, however, its substrate scope is very limited, reasonable reaction rates being observed essentially only with phenylacetone and similar linear phenyl-substituted analogs. Previous protein engineering attempts to broaden the range of substrate acceptance and to control enantioselectivity have been met with limited success, including rational design and directed evolution based on saturation mutagenesis with formation of focused mutant libraries, which may have to do with complex domain movements. In the present study, a new approach to laboratory evolution is described which has led to mutants showing unusually high activity and enantioselectivity in the oxidative kinetic resolution of a variety of 2-aryl and 2-alkylcyclohexanones which are not accepted by the wild-type (WT) PAMO and of a structurally very different bicyclic ketone. The new strategy exploits bioinformatics data derived from sequence alignment of eight different Baeyer-Villiger Monooxygenases, which in conjunction with the known X-ray structure of PAMO and induced fit docking suggests potential randomization sites, different from all previous approaches to focused library generation. Sites harboring highly conserved proline in a loop of the WT are targeted. The most active and enantioselective mutants retain the high thermostability of the parent WT PAMO. The success of the "proline" hypothesis in the present system calls for further testing in future laboratory evolution studies.
- Reetz, Manfred T.,Wu, Sheng
-
supporting information; experimental part
p. 15424 - 15432
(2010/02/16)
-
- Catalytic asymmetric Baeyer-Villiger oxidation in water by using Pt IIcatalysts and hydrogen peroxide: Supramolecular control of enantioselectivity
-
The enantioselective BaeyerVilliger oxidation of cyclic ketones is a challenging reaction, especially when using environmentally friendly oxidants. The reaction was carried out in water by using soft Lewis acid PtII complexes that have chiral diphosphines as well as monophosphines. Addition of a surfactant is crucial, which leads to the formation of micelles that act as nanoreactors in which the substrate and catalyst encounter each other in an ordered medium that in several cases positively influences both the conversion and the selectivity of the reactions. This is due to the combination of the hydrophobic effect (which confines the components of the reaction in the micelles), together with supramolecular interactions between the partners within the ordered palisade provided by the alkyl chains of the surfactant. For the oxidation of wieso-cyclobutanones, addition of surfactant allowed the reaction to proceed in high yields and the enantiometic excess (ee; 56%) was higher than in organic solvents. Subsequent extension to meso-cyclohexanones resulted in a general decrease in yields but an enhancement of enantioselectivity (ee up to 92%) moving from organic to water-surfactant media, regardless of the substrate or the catalyst employed. Different behaviour was observed with chiral cyclobutanones 7 and 10: with 7 the best catalyst was 1g, whereas with the larger substrate, 10, complexes 1a-b performed better in terms of enantioselectivity. Each combination of substrate, catalyst and surfactant is a new system and supramolecular reciprocal interactions together with the hydrophobic character of the counterparts play crucial roles. The asymmetric Baeyer-Villiger oxidation in water catalyzed by 1a-h in the presence of micelles is a viable reaction that often benefits from the hydrophobic effect, leading to substantial increases in enantioselectivity.
- Cavarzan, Alessandra,Bianchini, Giulio,Sgarbossa, Paolo,Lefort, Laurent,Gladiali, Serafino,Scarso, Alessandro,Strukul, Giorgio
-
scheme or table
p. 7930 - 7939
(2010/03/31)
-
- Self-sufficient Baeyer-Villiger monooxygenases: Effective coenzyme regeneration for biooxygenation by fusion engineering
-
(Chemical Presented) Two-in-one biocatalysts were engineered by the covalent fusion of NADPH-dependent Baeyer-Villiger monooxygenases to a phosphite dehydrogenase for coenzyme regeneration (see scheme). Not only the purified fusion proteins, but also whole cells and crude cell extracts containing the enzyme conjugates, could be used to catalyze biotransformations with high efficiency. NADP+=nicotinamide adenine dinucleotide phosphate.
- Torres Pazmino, Daniel E.,Snajdrova, Radka,Baas, Bert-Jan,Ghobrial, Michael,Mihovilovic, Marko D.,Fraaije, Marco W.
-
supporting information; scheme or table
p. 2275 - 2278
(2009/02/08)
-
- A light-driven stereoselective biocatalytic oxidation
-
Let the sunshine in: Light can be used to drive enantioselective Baeyer-Villiger oxidations of cyclic ketones catalyzed by a flavin-dependent enzyme. Photochemical reduction of the flavin using ethylenediaminetetraacetate (EDTA) as the sacrificial electron donor closes the catalytic cycle, thus providing a means to directly regenerate reduced flavin cofactors without the need for costly nicotinamide cofactors as electron donors. (Chemical Equation Presented).
- Hollmann, Frank,Taglieber, Andreas,Schulz, Frank,Reetz, Manfred T.
-
p. 2903 - 2906
(2008/03/13)
-
- Microbiological transformations 57. Facile and efficient resin-based in situ SFPR preparative-scale synthesis of an enantiopure unexpected lactone regioisomer via a baeyer-villiger oxidation process
-
Equation presented. The microbiological Baeyer-Villiger oxidation of (-)-bicyclo[3.2.0]hept-2-en-6-one allowed exclusive formation of the unexpected lactone regioisomer in 84% yield, high chemical purity, and enantiopure form. Substrate (25 g) was transformed in a 1 L bubble column reactor, following a in situ substrate feeding/product removal methodology, which afforded high volumetric productivity (1.2 g L-1 h -1). This illustrates the high sustainable chemistry advantages of such a process, simply conducted in aqueous medium, at room temperature and using atmospheric oxygen.
- Hilker, Iris,Gutierrez, Maria C.,Alphand, Veronique,Wohlgemuth, Roland,Furstoss, Roland
-
p. 1955 - 1958
(2007/10/03)
-
- A short stereoselective synthesis of (+)- and (-)-2-oxabicyclo[3.3.0]oct-6-en-3-one by intramolecular carbon-hydrogen insertion catalyzed by chiral dirhodium(II) carboxamidates
-
The synthesis of (1S,5R)-(-)-2-oxabicyclo[3.3.0]oct-6-en-3-one, a useful synthetic precursor en route to various prostaglandins, from divinylcarbinol via catalytic metathesis and C-H insertion of 3-cyclopentenyl diazoacetate is described. Enantioselectivities of 90±1% have been achieved in the insertion process.
- Doyle, Michael P.,Catino, Arthur J.
-
p. 925 - 928
(2007/10/03)
-
- Identification of novel mammalian squalene synthase inhibitors using a three-dimensional pharmacophore
-
Squalene synthase (E.C. 2.5.1.21) catalyses the reductive dimerisation of farnesyl diphosphate in a [1-4] head to head fashion to form squalene, and is the first committed step in cholesterol biosynthesis. Specific inhibitors of squalene synthase would inhibit cholesterol formation and allow production of other important compounds derived from the cholesterol biosynthetic pathway, namely the ubiquinones (co-enzyme Q10), dolichol, and would also allow the isoprenylation process of ras by farnesyl-protein transferase. The construction of a hypothetical squalene synthase three-dimensional pharmacophore is presented. It serves as a template for the identification of several new potential classes of inhibitors. The synthesis, anti-microbial and mammalian pig liver squalene synthase activities of analogues based on the bicyclo[3.2.0]heptane and bicyclo[3.3.0]octane ring systems are reported. Analogues of the latter system are pro-drug type inhibitors and exhibit promising biological activity.
- Fairlamb, Ian J.S.,Dickinson, Julia M.,O'Connor, Rachael,Higson, Seamus,Grieveson, Lynsey,Marin, Veronica
-
p. 2641 - 2656
(2007/10/03)
-
- Preparation of TADOOH, a hydroperoxide from TADDOL, and use in highly enantioface- and enantiomer-differentiating oxidations
-
Replacement of one OH group in TADDOL ( = a,a,a′,a′-tetraaryl-1,3-dioxolane-4.5-dimethanol) by an OOH group gives a stable, crystalline chiral hydroperoxy alcohol TADOOH ( = [(4R,5R)-5-[(hydroperoxydiphenyl)methyl]-2,2-dimethyl-1,3-dioxolan-4-yl] diphenylmethanol) 3, the crystal structure of which resembles those of numerous other TADDOL derivatives (Fig. 2). The new hydroperoxide was tested as chiral oxidant in three types of reactions: the epoxidation of enones with base catalysis (Scheme 2), the sulfoxidation of methyl phenyl sulfide (Scheme 3), and the Baeyer-Villiger oxidation of bicyclic and tricyclic cyclobutanones, rac-10a-d with kinetic resolution (Scheme 4, Fig. 3, and Table). Products of up to 99% enantiomer purity were isolated (the highest values yet observed for oxidations with a chiral hydroperoxide!). Mechanistic models are proposed for the stereochemical courses of the three types of reactions (Schemes 5 and 6, and Fig. 4). Results of AM1 calculations of the relative transition-state energies for the anionic rearrangements of the exo Criegee adducts of TADOOH to the enantiomeric bicyclo[3.2.0]heptan-6-ones are in qualitative agreement with the observed relative rates (Table and Fig. 5).
- Aoki, Masao,Seebach, Dieter
-
p. 187 - 207
(2007/10/03)
-
- Chiral aluminum complexes as catalysts in asymmetric Baeyer-Villiger reactions of cyclobutanones
-
BINOL-aluminum complexes were successfully employed as mediators and catalysts in asymmetric Baeyer-Villiger rearrangements of cyclobutanones. Good enantioselectivies were achieved with only 15 mol% of the chosen chiral Lewis acid. The enantiomeric excesses obtained have never been reached before in such metal-catalyzed Baeyer-Villiger reactions.
- Bolm, Carsten,Beckmann, Oliver,Palazzi, Chiara
-
p. 1593 - 1597
(2007/10/03)
-
- Biological Baeyer-Villiger Oxidation of Some Monocyclic and Bicyclic Ketones using Monooxygenases from Acinetobacter calcoaceticus NCIMB 9871 and Pseudomonas putida NCIMB 10007
-
A. calcoaceticus NCIMB 9871 and Ps. putida NCIMB 10007 have been utilized as biocatalysts in Baeyer-Villiger oxidations.The former microorganism oxidized the racemic ketone 6 non-selectively but transformed the dihalogeno ketone (+/-)-8 into optically active lactone 10 and recovered ketone.Ps. putida NCIBM 10007 oxidized the two enantiomers of the ketone 6 at different rates while both enantiomers of ketone (+/-)-1 were converted into lactones, one enantiomer giving 3-oxabicyclooctenone preferentially, while the other enantiomer gave 2-oxabicyclooctenone.Ps. putida NCIMB 10007 contains two quite different types of monooxygenase enzyme, one using NADH as cofactor (labelled MO1) the other employing NADPH as cofactor (labelled MO2).Monooxygenase MO1 proved to be a selective efficient biocatalyst for the oxidation of bicyclic ketones such as 1 and 6 while monooxygenase MO2 is a useful catalyst for the oxidation of cyclopentanones 15 - 17.Cofactor recycling was effected using dehydrogenase enzymes in preparative-scale experiments.
- Gadnon, Rene,Grogan, Gideon,Levitt, Melissa S.,Roberts, Stanley M.,Wan, Peter W. H.,Willetts, Andrew J.
-
p. 2537 - 2544
(2007/10/02)
-
- Radical-Type Cyclization of Dienes, VI. - Substrate-Controlled Asymmetric Synthesis of (3aS,6aR)-(+)-3,3a,6,6a-Tetrahydro-2H-cyclopentafuran-2-one
-
(R)-(-)-Carvone (1) was converted via straightforward reactions into 10-hydroxycarvone (4) which was cyclized to 5 via the mercury-mediated free-radical method.Periodate cleavage of 5 yields the bicyclic dione.Regio- and stereoselective reduction of 6 with lithium tri(tert-butyloxy)hydridoaluminate results in 7 (80percent yield). 7 was directly converted into γ-lactone 8 via Baeyer-Villiger oxidation.Saponification of 8 to 9, mesylation of 9 to 10 followed by elimination of methanesulfonic acid yield enantiomerically pure (3aS,6aR)-(+)-3,3a,6,6a-tetrahydro-2H-cyclopentafuran-2-one (11).The synthesis can be carried out with readily available, and economical, (S)-(+)-carvone to yield ent-11.Key Words: Cyclopentafuran-2-one, (2aS,6aR)-(+)-3,3a,6,6a-tetrahydro-2H- / Radicals / Cyclization / Carvone
- Weinges, Klaus,Schwarz, Georg
-
p. 811 - 814
(2007/10/02)
-
- Some Baeyer-Villiger Oxidations using a Monooxygenase Enzyme from Pseudomonas putida NCIMB 10007
-
A monooxygenase from Pseudomonas putida NCIMB 10007 is shown to catalyse stereoselective Baeyer-Villiger-type oxidations on the bicyclic ketones 2, 7, 8 and 9.
- Grogan, Gideon,Roberts, Stanley M.,Willetts, Andrew J.
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p. 699 - 701
(2007/10/02)
-
- Synthesis of both the enantiomers of methyl epijasmonate
-
Both the pure enantiomers of methyl epijasmonate 1 with potato-tuber inducing activity were synthesized stereoselectively starting from 2-oxabicyclo[3.3.0]-oct-6-en-3-one 6 in 20% yield through 11 steps.
- Kitahara, Takeshi,Nishi, Tsunehiro,Mori, Kenji
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p. 6999 - 7006
(2007/10/02)
-
- Microbial Oxidation of 7endo-Methylbicyclohept-2-en-6-one, 7,7-Dimethylbicyclohept-2-en-6-one and 2exo-Bromo-3endo-hydroxy-7,7-dimethylbicycloheptan-6-one using Acinetobacter NCIMB 9871
-
A bio-Bayer-Villiger reaction using Acinetobacter NCIMB 9871 and the bicycloheptanone 2 provided the corresponding substituted oxabicyclooctanones 6 and 7.Similarly the ketones 3 and 9 furnished the lactones 8 and 10 respectively: the lactones 6, 7 and 10 were obtained in states of high optical purity.
- Carnell, Andrew J.,Roberts, Stanley M.,Sik, Vladimir,Willetts, Andrew J.
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p. 2385 - 2390
(2007/10/02)
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- Vitamin B12, a Catalyst in the Synthesis of Prostaglandins
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A prostaglandin F2α precursor containing all structural features from C6 to C20 with 8R,9S, 11R and 12R chirality is obtained by the one step formation of two C-C bonds in the B12-catalyzed radical cyclization-addition sequence starting from a chiral cyclopentene bromoacetal and 1-octyne-3-one.The B12-catalyzed radical cyclization-elimination sequence of a chiral cyclopentene precursor leads to (-)-(3aR,6aS)-3,3a,6,6a-tetrahydro-2H-cyclopentafuran-2-one.Its (+)-(3aS,6aR)-enantiomer is obtained via B12-catalyzed, enantioselective isomerization of cyclopentene oxide to (R)-2-cyclopentene-1-ol followed by the B12-catalyzed cyclization-elimination sequence of its bromoacetal.
- Busato, Stephan,Tinembart, Olivier,Zhang, Zhong-da,Scheffold, Rolf
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p. 3155 - 3166
(2007/10/02)
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- Total synthesis of a potent thromboxane A2 antagonist
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The synthesis of the powerful thromboxane A2 antagonist 3 (EC50 3 nM) is reported.
- Corey,Su, Wei-Guo
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p. 3833 - 3836
(2007/10/02)
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- A Facile Chemoenzymatic Route to Optically Pure Building Blocks for Cyclopentanoid Natural Products
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Compound (1R,4S)-(4a), a central chiral building block for cyclopentanoid natural products, was prepared in high yield and optically pure by enantioselective hydrolysis of (5a) in the presence of several lipases, and was further transformed into (R)-(1a), (1R,5S)- and (1S,5R)-(2), (7), and (8), important synthons for this class of compounds.
- Laumen, Kurt,Schneider, Manfred P.
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p. 1298 - 1299
(2007/10/02)
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- OPTICAL RESOLUTION OF KEY COMPOUNDS OF PROSTAGLANDIN SYNTHESIS AND RELATED COMPOUNDS
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Hundred per cent optically pure bicyclic lactones and bicyclic ketones were easily obtained by complexation method with optically active 1,6-bis(2-chlorophenyl)-1,6-diphenylhexa-2,4-diyne-1,6-diol.
- Toda, Fumio,Tanaka, Koichi
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p. 885 - 888
(2007/10/02)
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- ENZYMATIC HYDROLYSIS OF PROCHIRAL CIS-1,4-DIACYL-2-CYCLOPENTADIENOLS: PREPARATION OF (1S,4R)- AND (1R,4S)-4-HYDROXY-2-CYCLOPENTENYLDERIVATIVES, VERSATILE BUILDING BLOCKS FOR CYCLOPENTANOID NATURAL PRODUCTS.
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The enzymatic hydrolysis of prochiral diesters 1 was studied in presence of seven enzymatic systems, resulting in the enantioselective preparation of both enantiomeric series of chiral building blocks 2-4 and ent-2-4 on a preparative scale.
- Laumen, Kurt,Schneider, Manfred
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p. 5875 - 5878
(2007/10/02)
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- STEREOCHEMICAL STUDIES - LVII. SYNTHESIS OF OPTICALLY ACTIVE COMPOUNDS BY THE NOVEL USE OF MESO-COMPOUNDS -1. EFFICIENT SYNTHESIS OF TWO STRUCTURAL TYPES OF OPTICALLY PURE PROSTAGLANDIN INTERMEDIATES.
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With an aim to overcome several inefficient aspects of ordinary methods of preparing optically active compounds, we have developed a new method which recommends utilization of symmetrically functionalized meso-compounds in place of racemic compounds.As shown in Scheme 1, when the meso-compound (I) is monofunctionalized by an optically active functional group (A) and each of the formed diastereomers (II and III) is subjected to further chemical elaborations including protective group transposition, it is theoretically possible to convert the total amount of the starting material (I) into the requisite optically pure product (VI or VII) by selecting synthetic schemes.By employing this novel concept, two structural types of the prostaglandin intermediates ((-)- and (+)-2a,b) have been prepared from the meso-diols (1a,b) by way of the two diastereomeric monoesters (13a,b and 14a,b) which are produced by the reactions 1a,b with N-mesyl- and N-phthaloyl-(S)-phenylalanyl chloride (3a,b).
- Nara, M,Terashima, S.,Yamada, S.
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p. 3161 - 3170
(2007/10/02)
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- Asymmetric synthesis of optically active prostaglandins
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An asymmetric synthesis of optically active prostaglandin F2α from cyclopentadiene including intermediates in this synthesis.
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- Certain hexahydro-2-loweralkoxy-5-oxycyclopenta [b] furans containing an olefinic substituent in the 4-position
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Process for synthesizing a prostaglandin from a hexahydro-4-(lower alkoxy)-2H-oxireno[3,4]cyclopenta[1,2-b]furan, utilizing as an intermediate in the process a hexahydro-5-hydroxy-2-lower alkoxy-2H-cyclopenta[b]furan-4-carboxaldehyde, and the novel cyclopenta(b)furan intermediates of the process.
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