- The first 200-L scale asymmetric Baeyer-Villiger oxidation using a whole-cell biocatalyst
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Biocatalytic Baeyer-Villiger oxidations using oxygen as an environmentally friendly oxidant in aqueous media have been shown to proceed with excellent stereo- and enantioselectivity for a large number of substrates at laboratory scale. These are good starting boundary conditions for process research and development compared to systems with reactive oxidants and flammable organic solvents. In this paper we discuss some of the considerations required to scale up a whole-cell biocatalytic oxidation from the laboratory to pilot-plant (200 L) scale. Issues for fermentation, bioconversion, and product recovery are discussed, supported by data from pilot-plant and scale-down experimentation. A simple fed-batch approach has been used.
- Baldwin, Christopher V.F.,Wohlgemuth, Roland,Woodley, John M.
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- Microbial Transformations 16. One-step synthesis of a pivotal prostaglandin chiral synthon via a highly enantioselective microbiological Baeyer-Villiger type reaction
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The bioconversion of bicyclohept-2-en-6-one is described.Each one of its enantiomers affords a different lactone via a highly regio and enantiospecific Beayer-Villiger type process.
- Alphand, Veronique,Archelas, Alain,Furstoss, Roland
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- 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
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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
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- Effect of substrate concentration on the enantioselectivity of cyclohexanone monooxygenase from Acinetobacter calcoaceticus and its rationalization
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The ee values of lactone 3, and not of lactone 2, obtained from the enantiodivergent oxidation of racemic bicyclo[3.2.0]hept-2-en-6-one 1, catalyzed by cyclohexanone monooxygenase from Acinetobacter calcoaceticus, were found to be markedly dependent on the degree of conversion and substrate concentration. The results are rationalized on the basis of a model which hypothesizes the binding of a second substrate molecule to an enzyme site distinct from the catalytic site. Copyright (C) 2000 Elsevier Science Ltd.
- Zambianchi,Pasta,Ottolina,Carrea,Colonna,Gaggero,Ward
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- Microbial transformations, 56. Preparative scale asymmetric baeyer-villiger oxidation using a highly productive two-in-one resin-based in situ SFPR concept
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An efficient preparative scale process for achieving asymmetric Baeyer-Villiger oxidation - a reaction still very difficult to perform using conventional chemistry - is described. This process is based on a biocatalytic whole cells strategy - using a recombinant E. coli strain overexpressing cyclohexanone monooxygenase (CHMO) - combined with a two-in-one in situ substrate feeding and product removal concept (SFPR) using an adsorbent resin. The most efficient resin out of fourteen tested was used in three types of bioreactors (conventional, recycle and bubble column) that were compared. The best one proved to be the bubble column reactor, where 25 g (0.23 M) of rac-bicyclo[3.2.0]hept-2-en-6-one could be totally transformed using a one-litre vessel with a volumetric productivity of about 1 g L-1 h-1 (i.e., 7.7 mmol L-1 h-1). This led to the production of the two corresponding regioisomeric lactones, which were both obtained in excellent enantiomeric purity (ee > 98%) and high preparative yield (84%). To our knowledge, these results represent the best example of a (highly productive) preparative scale asymmetric Baeyer-Villiger oxidation.
- Hilker, Iris,Alphand, Véronique,Wohlgemuth, Roland,Furstoss, Roland
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- Regiodivergent Baeyer-Villiger oxidation of fused ketone substrates by recombinant whole-cells expressing two monooxygenases from Brevibacterium
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Microbial Baeyer-Villiger oxidations of fused bicyclic ketones with a cyclobutanone structural motif were investigated using recombinant Escherichia coli cells expressing two monooxygenases from Brevibacterium. In a kinetic resolution process fused ketones were transformed to regioisomeric lactones: 'normal' lactones were generated by migration of the more substituted carbon atom and 'abnormal' lactones resulted from migration of the less substituted carbon atom. The two Baeyer-Villigerases demonstrated a significantly different stereoselectivity for the regiodivergent biotransformation.
- Mihovilovic, Marko D.,Kapitán, Peter
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- (+)-(3S,4S)-3-butyl-4-vinylcyclopentene in brown algae of the genus Dictyopteris
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(-)-(3R,4R)-3-Butyl-4-vinylcyclopentene [(-)-1] was synthesized via (+)- (1S,5R)-3-oxabicyclo [3,3,0] oct-6-en-2-one. Synthetic (-)-1 coincided with the peak with later retention time of racemic (+)-1 in a chiral GC (CP- Cyclodex 236M), while the natural 1 in essential oils from the marine brown algae, Dictyopteris prolifera and D. sp. was identical with the earlier retention time peak. Thus, the absolute configuration of the natural product in Dictyopteris oils was determined as (+)-(3S,4S) with ca 100% enantiomeric excess.
- Kajiwara, Tadahiko,Akakabe, Yoshihiko,Matsui, Kenji,Kodama, Kazuya,Koga, Harunobu,Nagakura, Takamitsu
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- Near-IR spectroscopic monitoring of analytes during microbially catalysed Baeyer-Villiger bioconversions
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Sensitive and robust monitoring of product and reactants in a complex bioconversion stream is essential for the development of effective process-control strategies. In this contribution we report the use of near-infrared spectroscopy (at-line and on-line) to monitor a microbially catalysed Baeyer-Villiger bioconversion of a cyclic ketone to an optically pure lactone. The cyclohexanone monooxygenase-catalysed reaction is characterised by substrate (ketone) and product (lactone) inhibition of enzyme activity at relatively low concentrations. Quantitative multivariate calibration of a near-IR spectrophotometer for ketone and lactone resulted in a standard error of prediction at-line of 0.088 and 0.110 g/L and on-line of 0.130 and 0.180 g/L, respectively. The concentrations of substrate and product could be simultaneously monitored by near-IR, which had a response time of 5.0 and 0.75 min at-line and on-line, respectively. This work has indicated that near-IR spectroscopy has the potential to permit the realisation of an improved control strategy for this conversion based on these response times.
- Bird, Paul A.,Sharp, David C. A.,Woodley, John M.
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- Alloxazinium-Resins as Readily Available and Reusable Oxidation Catalysts
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N5-Modified alloxazinium salts including 5-ethyl-1,3-dimethylalloxazinium and 5-ethyl-1,3-dimethyl-8-(trifluoromethyl)- A lloxazinium salts were readily prepared as alloxazinium-resins from the corresponding N5-unmodified ingredients via the aerobic oxidationion exchange protocol, previously introduced by us for the preparation of isoalloxazine analogues, and their catalysis and reusability in H2O2 oxidations were evaluated.
- Arakawa, Yukihiro,Imada, Yasushi,Kawahara, Takayuki,Minagawa, Keiji
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supporting information
p. 1728 - 1730
(2021/07/19)
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- Genome mining reveals new bacterial type I Baeyer-Villiger monooxygenases with (bio)synthetic potential
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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.
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- Greener Preparation of 5-Ethyl-4a-hydroxyisoalloxazine and Its Use for Catalytic Aerobic Oxygenations
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Isoalloxazine ring systems are found in flavin cofactors in nature, and the simulation of their redox catalyses is an important task for developing sustainable catalytic oxidation reactions. Although 5-ethyl-4a-hydroxyisoalloxazines are among the most promising candidates as catalyst for such purposes, the use of them for laboratorial as well as industrial synthetic chemistry has so far been quite limited presumably due to the lack of their preparation methods readily, safely, and inexpensively available. In this communication, we introduce an environmentally benign and practical preparation of 5-ethyl-4a-hydroxy-3,7,8,10-tetramethylisoalloxazine (1EtOH) from 3,7,8,10-tetramethylisoalloxazine (1), in which conventional synthetic requirements, including (i) operations under inert conditions, (ii) risky or expensive chemicals, and (iii) isolation of labile intermediates, have all been dissolved. In addition, we have presented that 1EtOH could be an effective catalyst for Baeyer–Villiger oxidation as well as sulfoxidation with molecular oxygen (O2) as a terminal oxidant under suitable conditions, which is the first report on aerobic oxygenations catalyzed by 5-alkyl-4a-hydroxyisoalloxazines.
- Oonishi, Takahiro,Kawahara, Takayuki,Arakawa, Yukihiro,Minagawa, Keiji,Imada, Yasushi
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supporting information
p. 1791 - 1795
(2019/02/07)
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- Enzyme-like regiodivergent behavior of a flavopeptide catalyst in aerobic baeyer-villiger oxidation
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We recently developed a flavopeptide immobilized on polystyrene resin, Fl-Pep-PS, that could realize the first N5-unmodified neutral flavin (Fl)-catalyzed aerobic oxygenation reactions under non-enzymatic conditions. Although a key active species is assumed to be the corresponding 4a-hydroperoxyflavin (Fl4aOOH) from the unprecedented activity and unique chemoselectivity, further circumstantial support would be helpful to be sure since spectroscopic evidence is difficult to obtain due to the compound's insolubility. In this article, we report that the aerobic Baeyer-Villiger oxidation of a fused cyclobutanone, (±)-cis-bicyclo[3.2.0]hept-2-en-6-one (1), can be promoted with Fl-Pep-PS in a FMO-like chemoselectivity and regiodivergent manner via Fl-related catalytic intermediates, which delivers strong evidence of the involvement of Fl4aOOH as an active species in Fl-Pep-PScatalyzed aerobic oxygenation reactions.
- Yamanomoto, Ken,Kita, Hazuki,Arakawa, Yukihiro,Minagawaa, Keiji,Imada, Yasushi
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p. 866 - 869
(2019/01/21)
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- Controlling the Regioselectivity of Baeyer–Villiger Monooxygenases by Mutation of Active-Site Residues
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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)
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- Polycyclic ketone monooxygenase from the thermophilic fungus Thermothelomyces thermophila: A structurally distinct biocatalyst for bulky substrates
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Regio- and stereoselective Baeyer-Villiger oxidations are difficult to achieve by classical chemical means, particularly when large, functionalized molecules are to be converted. Biocatalysis using flavin-containing Baeyer-Villiger monooxygenases (BVMOs) is a wellestablished tool to address these challenges, but known BVMOs have shortcomings in either stability or substrate selectivity. We characterized a novel BVMO from the thermophilic fungus Thermothelomyces thermophila, determined its three-dimensional structure, and demonstrated its use as a promising biocatalyst. This fungal enzyme displays excellent enantioselectivity, acts on various ketones, and is particularly active on polycyclic molecules. Most notably we observed that the enzyme can perform oxidations on both the A and D ring when converting steroids. These functional properties can be linked to unique structural features, which identify enzymes acting on bulky substrates as a distinct subgroup of the BVMO class.
- Fürst, Maximilian J.L.J.,Savino, Simone,Dudek, Hanna M.,Castellanos, J. Rúben Gómez,De Souza, Cora Gutiérrez,Rovida, Stefano,Fraaije, Marco W.,Mattevi, Andrea
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supporting information
p. 627 - 630
(2017/05/15)
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- Biotransformation of dehydro-epi-androsterone by Aspergillus parasiticus: Metabolic evidences of BVMO activity
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The research on the synthesis of steroids and its derivatives is of high interest due to their clinical applications. A particular focus is given to molecules bearing a D-ring lactone like testolactone because of its bioactivity. The Aspergillus genus has been used to perform steroid biotransformations since it offers a toolbox of redox enzymes. In this work, the use of growing cells of Aspergillus parasiticus to study the bioconversion of dehydro-epi-androsterone (DHEA) is described, emphasizing the metabolic steps leading to D-ring lactonization products. It was observed that A. parasiticus is not only capable of transforming bicyclo[3.2.0]hept-2-en-6-one, the standard Baeyer-Villiger monooxygenase (BVMO) substrate, but also yielded testololactone and the homo-lactone 3β-hydroxy-17a-oxa-d-homoandrost-5-en-17-one from DHEA. Moreover, the biocatalyst degraded the lateral chain of cortisone by an oxidative route suggesting the action of a BVMO, thus providing enough metabolic evidences denoting the presence of BVMO activity in A. parasiticus. Furthermore, since excellent biotransformation rates were observed, A. parasiticus is a promising candidate for the production of bioactive lactone-based compounds of steroidal origin in larger scales.
- Mascotti, M. Laura,Palazzolo, Martín A.,Bisogno, Fabricio R.,Kurina-Sanz, Marcela
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- Characterization and Crystal Structure of a Robust Cyclohexanone Monooxygenase
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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.
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supporting information
p. 15852 - 15855
(2016/12/16)
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- Functional divergence between closely related Baeyer-Villiger monooxygenases from Aspergillus flavus
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Baeyer-Villiger monooxygenases (BVMOs) catalyse the chemo-, regio- and enantioselective oxidation of ketones to esters and lactones. To date, most of the cloned BVMOs available are derived from bacteria, although Baeyer-Villiger oxidations using fungi have frequently been demonstrated. Here we report the cloning and characterization of four BVMOs from the fungus Aspergillus flavus NRRL3357. Phylogenetic analysis shows these four BVMOs to cluster in a distinct group apart from other well-characterized BVMOs including cyclohexanone, phenylacetone and 4-hydroxyacetophenone monooxygenase. Building on the Grogan classification/clustering of BVMOs, we have designated this new group of BVMOs, Group VI. Group VI BVMOs show an early divergence from the cyclopentanone monooxygenase (CPMO) type BVMOs (Group I). Substrate profiling using cyclic, bicyclic, aliphatic and aryl ketones show a clear divergence in function and specificity not only between this new group of BVMOs and the CPMO-type BVMOs, but also between the four A. flavus BVMO paralogues despite their high sequence similarity. This study not only contributes to the growing number of available BVMOs, but also addresses the current classification of Type I BVMOs, and the usefulness of phylogenetic clustering and prediction of function and selectivity when genome-mining is used to search for new biocatalysts.
- Ferroni,Smit,Opperman
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- Type II flavin-containing monooxygenases: A new class of biocatalysts that harbors baeyer-villiger monooxygenases with a relaxed coenzyme specificity
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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)
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- Discovery of Baeyer-Villiger monooxygenases from photosynthetic eukaryotes
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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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- Baeyer-villiger oxidation and oxidative cascade reactions with aqueous hydrogen peroxide catalyzed by lipophilic Li[B(C6F5) 4] and Ca[B(C6F5)4]2
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Efficient and selective: Two lipophilic catalysts were used for Baeyer-Villiger (BV) oxidations to give lactones in high yields (see scheme). Cascade reactions involving this BV oxidation were used to selectively obtain either unsaturated carboxylic acids or hydroxylactones in high yields from β-silyl cyclohexanones. Copyright
- Uyanik, Muhammet,Nakashima, Daisuke,Ishihara, Kazuaki
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supporting information
p. 9093 - 9096
(2012/11/07)
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- Sarkomycin a methyl esters and functionalized cyclopentane blocks for brefeldin a
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Sarkomycin A methyl esters and functionalized cyclopentane blocks for brefeldin A were synthesized starting from diastereoisomeric (1R,2S)-and (1S,2R)-2-hydroxymethyl-N-[(1R)-1-phenylethyl]cyclopent-3-ene-1-carboxamides. Pleiades Publishing, Ltd., 2012.
- Gimazetdinov,Ishmurzina,Miftakhov
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body text
p. 8 - 17
(2012/05/20)
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- A Flavoprotein Monooxygenase that Catalyses a Baeyer-Villiger Reaction and Thioether Oxidation Using NADH as the Nicotinamide Cofactor
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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
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experimental part
p. 872 - 878
(2012/07/27)
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- 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
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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
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supporting information; experimental part
p. 110 - 116
(2011/03/21)
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- Asymmetric Baeyer-Villiger oxidation with Co(Salen) and H2O 2 in water: Striking supramolecular micelles effect on catalysis
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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
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experimental part
p. 1517 - 1520
(2010/06/13)
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- Catalytic asymmetric Baeyer-Villiger oxidation in water by using Pt IIcatalysts and hydrogen peroxide: Supramolecular control of enantioselectivity
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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
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scheme or table
p. 7930 - 7939
(2010/03/31)
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- Laboratory evolution of robust and enantioselective Baeyer-Villiger monooxygenases for asymmetric catalysis
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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
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supporting information; experimental part
p. 15424 - 15432
(2010/02/16)
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- Simple synthetic protocol for the preparation of enantiomeric 3-oxabicyclo[3.3.0]oct-6-en-2-ones
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Diastereomeric amides produced via the decomposition of easily available (±)-7,7-dichlorobicyclo[3.2.0]hept-2-en-6-one by treatment with (+)- or (-)-α-methylbenzylamines were transformed into bicyclic lactam-aminals, which can easily be separated using the column chromatography on SiO2. The latter products lead to enantiomeric 3-oxabicyclo[3.3.0]oct-6-en-2-ones after the removal of the chiral auxiliary. Crown Copyright
- Gimazetdinov, Airat M.,Vostrikov, Nikolay S.,Miftakhov, Mansur S.
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p. 1094 - 1099
(2008/09/20)
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- Self-sufficient Baeyer-Villiger monooxygenases: Effective coenzyme regeneration for biooxygenation by fusion engineering
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(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.
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supporting information; scheme or table
p. 2275 - 2278
(2009/02/08)
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- A light-driven stereoselective biocatalytic oxidation
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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.
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p. 2903 - 2906
(2008/03/13)
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- Resolution of fused bicyclic ketones by a recombinant biocatalyst expressing the Baeyer-Villiger monooxygenase gene Rv3049c from Mycobacterium tuberculosis H37Rv
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Recombinant Escherichia coli B834 (DE3) pDB5 expressing the Rv3049c gene encoding a Baeyer-Villiger monooxygenase from Mycobacterium tuberculosis H37Rv was used for regioselective oxidations of fused bicyclic ketones. This whole-cell system represents the first recombinant Baeyer-Villiger oxidation biocatalyst that effectively resolves the racemic starting materials in this series. Within biotransformations using this organism one substrate enantiomer remains in high optical purity, while the second enantiomer is oxidized to one type of regioisomeric lactone preferably.
- Snajdrova, Radka,Grogan, Gideon,Mihovilovic, Marko D.
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p. 4813 - 4817
(2007/10/03)
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- Family clustering of Baeyer-Villiger monooxygenases based on protein sequence and stereopreference
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(Chemical Equation Presented) The identification of enzyme pairs with overlapping substrate specificity and enantiocomplementary transformations is a key challenge in biocatalysis. Enantio and regiodivergent Baeyer-Villiger oxidations were successfully carried out by using a small library of recombinant Escherichia coli strains expressing monooxygenases of various microbial origin (see picture). The clustering of enzymes based on stereopreference is in good agreement with phylogenetic similarity.
- Mihovilovic, Marko D.,Rudroff, Florian,Groetzl, Birgit,Kapitan, Peter,Snajdrova, Radka,Rydz, Joanna,Mach, Robert
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p. 3609 - 3613
(2007/10/03)
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- A one-pot remote allylic hydroxylation and Baeyer-Villiger oxidation of a bicyclo[3.2.0]hept-2-en-6-one by Cunninghamella echinulata NRRL 3655.
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7-exo-Methyl-7-endo-phenylbicyclo[3.2.0]hept-2-en-6-one 3 undergoes Baeyer-Villiger and allylic oxidation, to yield novel hydroxylactone 8 in good yield by Cunninghamella echinulata NRRL 3655, representing a one step biocatalytic access to a cyclopentanoid scaffold with three chiral centers. Interesting, allylic oxidation occurs with transposition of the double bond.
- Fairlamb, Ian J S,Grant, Stephanie,Grogan, Gideon,Maddrell, David A,Nichols, Josephine C
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p. 1831 - 1833
(2007/10/03)
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- Chiral aluminum complexes as catalysts in asymmetric Baeyer-Villiger reactions of cyclobutanones
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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
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p. 1593 - 1597
(2007/10/03)
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- An integrated chemoenzymatic synthesis of enantiopure (-)-(1R,5S)-cyclosarkomycin: A sarkomycin precursor
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A five-step chemoenzymatic synthesis of (-)-(1R,5S)-cyclosarkomycin 2 has been achieved starting from commercial racemic bicycloheptenone 3. The strategy developed involved - as key steps - an enantioselective microbiologically catalyzed Baeyer-Villiger oxidation followed by a chemical regioselective epoxide ring opening.
- Andrau, Laura,Lebreton, Jacques,Viazzo, Pascale,Alphand, Veronique,Furstoss, Roland
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p. 825 - 826
(2007/10/03)
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- A short chemoenzymatic synthesis of (+)-Multifidene and (+)-Viridiene
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(+)-Multifidene 1 and (+)-Viridiene 2, the major constituents of some brown algae pheromones, were synthesized in five steps from racemic bicycloheptenone 3 via a novel microbiological Baeyer-Villiger oxidation performed using the fungi Cunninghamella echinulata.
- Lebreton, Jacques,Alphand, Veronique,Furstoss, Roland
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p. 1011 - 1014
(2007/10/03)
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- Stereochemical congruence of Baeyer-Villigerases
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The enantiomeric bicyclic ketones 1, 3 and the tricyclic ketone 5 undergo stereochemically congruent Baeyer-Villiger oxidations with CHMO from Acinetobacter sp., CPMO from Pseudomonas sp. as well as 2,5-DKCMO, 3,6-DKCMO and MO2 from P. putida; in every case the tricyclic ketone 5 is transformed with > 96% ee. N-terminal sequences for the FAD/NADPH linked enzymes from Acinetobacter sp., Pseudomonas sp. and a novel CHMO from R. coprophilus have high homology with each other but no homology with the FMN/NADH linked enzymes; 2,5-DKCMO and 3,6-DKCMO.
- Kelly, David R.,Knowles, Christopher J.,Mahdi, Jassem G.,Wright, Michael A.,Taylor, Ian N.,Roberts, Stanley M.,Wan, Peter W. H.,Grogan, Gideon,Pedragosa-Moreau, Sandrine,Willetts, Andrew J.
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p. 2333 - 2334
(2007/10/03)
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- Biological Baeyer-Villiger Oxidation of Some Monocyclic and Bicyclic Ketones using Monooxygenases from Acinetobacter calcoaceticus NCIMB 9871 and Pseudomonas putida NCIMB 10007
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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.
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p. 2537 - 2544
(2007/10/02)
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- 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
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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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- Intramolecular Cyclopentene Annulation. 3. Synthesis and Carbon-13 Nuclear Magnetic Resonance Spectroscopy of Bicyclic Cyclopentene Lactones as Potential Perhydroazulene and/or Monoterpene Synthons
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The internal cyclopropanation of several diversely substituted dienic diazo esters is described.Thermolysis of the resulting vinylcyclopropanes yielded cyclopentene-annulated lactones in good yields.Depending on the choice of the dienyl unit, either guaiane or pseudoguaiane substitution patterns of the cyclopentene portion were obtained.Stereochemical assignments based on 13C NMR data are provided for all of these lactones.Subsequent transformations of the bicyclic lactones to differentially functionalized cyclopentenes are described.The potential of these synthons in the synthesis of perhydroazulene sesquiterpenes and several monoterpene cyclopentanoid natural products is addressed.
- Hudlicky, Tomas,Reddy, D. Bhaskar,Govindan, S. V.,Kulp, Thomas,Still, Bobbi,Sheth, Jagdish P.
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p. 3422 - 3428
(2007/10/02)
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- Synthesis of (+/-)-Desmarestene and (+/-)-Viridiene, the Two Sperm Releasing and Attracting Pheromones from the Brown Algae Desmarestia aculeata and Desmarestia viridis
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Desmarestene 1 6-(1Z,3-butadienyl)-1,4-cycloheptadiene) and viridiene 3 cis-3-(1Z,3-butadienyl)-4-vinylcyclopentene) are chemical messengers for male gametes of the brown algae Desmarestia aculeata and Desmarestia viridis.Total syntheses of 1, 3 and their stereoisomers 1a, 3a-c are reported.Gas-chromatographic comparison of synthetic 1 and 3 with the corresponding natural products has established their structural identity.
- Boland, Wilhelm,Jakoby, Karin,Jaenicke, Lothar
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p. 2355 - 2362
(2007/10/02)
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