Enzymatic Baeyer-Villiger Oxidation Research Articles

Applanhydrides A and B, lanostane triterpenoids with unprecedented seven-membered cyclo-anhydride in ring C from Ganoderma applanatum

Two novel lanostane triterpenoids with an unprecedented seven-membered cyclo-anhydride moiety in ring C, named applanhydrides A ( 1 ) and B ( 2 ), and two new lanostane triterpenoids with a 1,2-diketone moiety in ring C, named applandiketones A ( 3 ) and B ( 4 ), were isolated from the fruiting bodies of Ganoderma applanatum . The structures of the compounds were determined by extensive NMR spectroscopic analyses and theoretical calculations. Compounds 1 and 2 represent the first cases of triterpenoids featuring a seven-membered cyclo-anhydride moiety in ring C. Co-existing of triterpenoids with anhydride and 1,2-diketone moiety in ring C indicated an enzymatic Baeyer-Villiger oxidation process might occur in the ring C, which is not discovered before. Anti-inflammatory assay revealed that compound 4 showed significant inhibitory activity against NO production in LPS-induced RAW 264.7 cells. • Two novel lanostane triterpenoids were isolated from the fruiting bodies of Ganoderma applanatum. • Two new lanostane triterpenoids with 1,2-diketone moiety in ring C were isolated from Ganoderma applanatum. • One of the compounds showed potent inhibitory effects on NO production in LPS-induced RAW264.7 cells.

Development, optimization and scale-up of stereo-selective enzymatic Baeyer–Villiger oxidation of pyrmetazole to esomeprazole active ingredient in an industrial-scale slurry reactor

An industrial-scale stereo-selective enzymatic oxidation process for the conversion of pyrmetazole to esomeprazole was developed and optimized. Slurry-to-slurry stages are highly demanding synthetic operations due to several deteriorating factors: competing equilibria, mass transfer limitations and long-term bio-catalytic activity. Challenging characteristics of this bio-oxidation included foaming, thickening, continuous dynamic changes in viscosity, mass transport, and bio-catalyst inactivation. By screening pH, optimization of reactant loading ratios, and modification of control, crucial production attributes of materials, such as substrate particle size, were controlled and better batch-to-batch stability and scale-up was achieved.

Enzymatic Baeyer-Villiger oxidation of steroids with cyclopentadecanone monooxygenase

Recombinant cyclopentadecanone monooxygenase from Pseudomonas sp. catalyzed the preparative-scale Baeyer–Villiger oxidation of numerous 3 and 17-ketosteroids with a full control of the regiochemistry of the produced lactones. The recovered product yields were up to 42%.

ChemInform Abstract: The Enzymatic Baeyer-Villiger Oxidation: Synthesis of the C11-C16 Subunit of Ionomycin.

Abstract An efficient synthesis of the C 11 –C 16 subunit of ionomycin from cis -3,5-dimethyl cyclohexanone using as the enzymatic Baeyer-Villiger oxidation to establish the correct absolute stereochemistry at C 12 and C 14 is reported.

BVMO-catalysed dynamic kinetic resolution of racemic benzyl ketones in the presence of anion exchange resins

4-Hydroxyacetophenone monooxygenase from Pseudomonas fluorescens ACB was employed in the presence of a weak anion exchange resin to perform dynamic kinetic resolutions of racemic benzyl ketones with high conversions and good optical purities. Different parameters that affect to the efficiency of the enzymatic Baeyer-Villiger oxidation and racemisation were analyzed in order to optimize the activity and selectivity of the biocatalytic system.

Structure Determination of Grandifotane A from Khaya grandifoliola by NMR, X-ray Diffraction, and ECD Calculation

Grandifotane A (1), a limonoid with an unprecedented carbon skeleton, was isolated from the stem bark of Khaya grandifoliola. The structure of 1 with the absolute configuration was determined by spectroscopic data, X-ray crystallography, and ECD calculation. A biogenetic route for grandifotane A (1) involving an enzymatic Baeyer-Villiger oxidation as the key step is proposed.

Enzymatic Baeyer–Villiger Oxidation of Benzo‐Fused Ketones: Formation of Regiocomplementary Lactones

AbstractBaeyer–Villiger monooxygenases (BVMOs) are enzymes that are known to catalyse the Baeyer–Villiger oxidation of ketones in aqueous media using O2 as oxidant. Herein, we describe the oxidation of a set of diverse benzo‐fused ketones by three different BVMOs in both aqueous and non‐conventional reaction media. Most of the tested ketones, for example, 1‐tetralone and 1‐ and 2‐indanone, were converted by one of the employed biocatalysts. The catalytic efficiency could be improved by performing the oxidation reactions at a relatively high pH and by adding organic cosolvents. One striking observation is that absolute and complementary regioselectivities were obtained when oxidizing a range of 1‐indanones using two different BVMOs. The conversion of 1‐indanone by 4‐hydroxyacetophenone monooxygenase (HAPMO) results in the formation of the expected lactone, 3,4‐dihydrocoumarin. In contrast, by using a phenylacetone monooxygenase mutein (M‐PAMO), conversion of 1‐indanone leads to the formation of only the unexpected lactone, 1‐isochromanone. This illustrates that by the appropriate choice of BVMO as biocatalyst, the effective and regioselective conversion of a wide range of benzo‐fused ketones is feasible. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

Enzymatic Baeyer–Villiger oxidation of steroids with cyclopentadecanone monooxygenase

Recombinant cyclopentadecanone monooxygenase from Pseudomonas sp. catalyzed the preparative-scale Baeyer–Villiger oxidation of numerous 3 and 17-ketosteroids with a full control of the regiochemistry of the produced lactones. The recovered product yields were up to 42%.

Ring Opening and Rearrangement Reactions of Tricyclo[4.2.1.02,5]nonan-9-one

A general concept is introduced to synthesize bicyclo[4.2.0]octanes by a sequence of intramolecular copper(I)-catalyzed [2+2] photocycloaddition and subsequent fragmentation reactions. The concept was tested by subjecting the photochemically accessible tricyclo[4.2.1.02,5]nonan-9-one to four different ring-opening or rearrangement reactions, which allowed for the formation of functionalized bicyclo[4.2.0]octanes by cleavage of the carbonyl bridge. All four methods investigated, Haller-Bauer cleavage, the Schmidt reaction, Baeyer-Villiger oxidation, and rhodium(II)-catalyzed rearrangement were applicable to tricyclo[4.2.1.02,5]nonan-9-one, but they differed with regard to enan­tioselectivity. Enzymatic Baeyer-Villiger oxidation was the most successful of these methods, also more successful than metal-catalyzed Baeyer-Villiger oxidation, providing access to enantiomerically enriched lactones, for example in 72% yield and 95% ee. The second-most successful method was with a commercially available rhodium catalyst, which effected ring enlargement of tricyclo[4.2.1.02,5]nonan-9-one to its homologue in good overall yield and modest enantioselectivity (up to 24% ee).

Enzymatic kinetic resolution of racemic ketones catalyzed by Baeyer–Villiger monooxygenases

A set of racemic cyclic and linear ketones, as well as 2-phenylpropionaldehyde, were tested as substrates in the enzymatic Baeyer–Villiger oxidation catalyzed by two Baeyer–Villiger monooxygenases: phenylacetone monooxygenase (PAMO) and 4-hydroxyacetophenone monooxygenase (HAPMO). Excellent enantioselectivites ( E > 200) can be obtained in the kinetic resolution processes depending on the substrate structure and the reaction conditions. The parameters affecting the biocatalytic properties of these enzymes were also studied, in order to establish a deeper understanding of these novel biocatalysts.

Enzymatic Baeyer–Villiger Oxidation of Bicyclic Diketones

AbstractCyclohexanone monooxygenase from Acinetobacter calcoaceticus was employed for the Baeyer–Villiger oxidation of racemic bicyclic diketones such as the Wieland–Miescher and the Hajos–Parrish diketones and of some of their derivatives. The corresponding lactones were produced in a highly regio‐ and enantioselective manner. The reactions were carried out using a crude enzyme preparation in aqueous buffer, at room temperature, and the recycling of the expensive coenzyme NADPH was conducted with a second ancillary enzymatic system. The enzymatic process was simple and easy to handle, thus providing a very practical tool to access enantiopure lactones.

Enzymatic Baeyer–Villiger Oxidation of Benzaldehydes

AbstractThe selectivity of the chemical Baeyer–Villiger oxidation of benzaldehydes depends on steric and electronic factors, the type of oxidizing agent and the reaction conditions. Here we report on the enzymatic Baeyer–Villiger oxidation of fluorobenzaldehydes as catalyzed by the flavoprotein 4‐hydroxyacetophenone monooxygenase (HAPMO). HAPMO was most active with 4‐amino‐ and 4‐hydroxybenzaldehydes. With these compounds significant substrate inhibition occurred. Monofluoro‐ and difluorobenzaldehydes were readily oxidized by HAPMO without substrate inhibition. 19F NMR analysis revealed that 4‐fluoro‐, 2,6‐difluoro‐, 3,4‐difluoro‐, 2‐fluoro‐4‐hydroxy‐ and 3‐fluoro‐4‐hydroxybenzaldehyde were quantitatively converted by HAPMO to the corresponding fluorophenyl formates. These products spontaneously hydrolyzed to fluorophenols. The HAPMO‐mediated conversion of 2‐fluoro‐, 3‐fluoro‐, 2,3‐difluoro‐ and 2,4‐difluorobenzaldehyde yielded, besides fluorophenols, also minor amounts of fluorobenzoic acids. The high preference of HAPMO for the production of fluorophenols is in disagreement with the rule derived from chemical studies that electron‐poor benzaldehydes form mainly benzoic acids. This suggests that interactions of the benzaldehyde substrates with amino acids and/or the flavin cofactor in the enzyme active site influence the selection of the migratory group in favor of the phenyl ring.

Lathyranoic Acid A: First Secolathyrane Diterpenoid in Nature fromEuphorbia lathyris

[structures: see text] Lathyranoic acid A (1), the first secolathyrane diterpenoid with an unprecedented skeleton, and a new diterpenoid Euphorbia factor L11 (2) were isolated from the seeds of Euphorbia lathyris. Their structures were elucidated by spectroscopic analysis and chemical methods. A biogenetic route involving an enzymatic Baeyer-Villiger oxidation as the key step was postulated for the transformation of 2 to 1 and mimicked by an unusual chemical Baeyer-Villiger oxidation.

Enzymatic Baeyer–Villiger Oxidation as the Key Step in Decano‐4‐lactone and Decano‐5‐lactone Degradation by Sporobolomyces odorus

The biosyntheses of aroma active gamma- and delta-lactones have been previously characterized in yeasts and plants by incubation of labeled fatty acid derivatives. The lactones were considered as end products. Liquid cultures of the lactone-producing yeast Sporobolomyces odorus were used to investigate catabolic pathways of the lactones by incubation of ethyl (+/-)-5-hydroxy(1-(13)C1)decanoate ((13C)-1b) and methyl (+/-)-4-hydroxy(1-(13)C1)decanoate ((13C)-7a). Aliquots of the culture broth were analyzed with GC/MS after CH2N2 derivatization. S. odorus degraded (13C)-1b to 5-oxo(1-(13)C1)decanoic acid ((13C)-2c) and, subsequently, to pentyl (1-(13)C1)pentanedioate ((13C)-3c) and 3-[(1-(13)C1)carboxypropyl] hexanoate ((13C)-4c) by a Baeyer-Villiger-type oxidation (BVO). In addition, the oxidation of (13C)-7a to 4-oxo(1-(13)C1)decanoic acid ((13C)-8c) and a BVO of (13C)-8c to hexyl (1-(13)C1)butanedioate ((13C)-9c) is reported. So far, BVO has been observed in bacteria and some fungi; the data presented indicate a BVO catalyzed by the yeast S. odorus in the course of endogenous lactone metabolism.

An efficient enzymatic Baeyer-Villiger oxidation by engineered Escherichia coli cells under non-growing conditions.

Economical methods of supplying NADPH must be developed before biotransformations involving this cofactor can be considered for large-scale applications. We have studied the enzymatic Baeyer-Villiger oxidation of cyclohexanone as a model for this class of reactions and developed a simple approach that uses whole, non-growing Escherichia coli cells to provide high productivity (0.79 g epsilon-caprolactone/L/h = 18 micromol epsilon-caprolactone/min/g dcw) and an 88% yield. Glucose supplied the reducing equivalents for this process, and no exogenous cofactor was required. The volumetric productivity of non-growing cells was an order of magnitude greater than that achieved with growing cells of the same strain. Cells of an engineered E. coli strain that overexpresses Acinetobacter sp. cyclohexanone monooxygenase were grown under inducing conditions in rich medium until the entry to stationary phase; the subsequent cyclohexanone oxidation was carried out in minimal salts medium lacking a nitrogen source. After the biotransformation was complete, the lactone product was adsorbed to a solid support and recovered by washing with an organic solvent.

19 F NMR study on the biological Baeyer-Villiger oxidation of acetophenones

The biological Baeyer-Villiger oxidation of acetophenones was studied by 19F nuclear magnetic resonance (NMR). The 19F NMR method was used to characterise the time-dependent conversion of various fluorinated acetophenones in either whole cells of Pseudomonas fluorescens ACB or in incubations with purified 4'-hydroxyacetophenone monooxygenase (HAPMO). Whole cells of P. fluorescens ACB converted 4'-fluoroacetophenone to 4-fluorophenol and 4'-fluoro-2'-hydroxyacetophenone to 4-fluorocatechol without the accumulation of 4'-fluorophenyl acetates. In contrast to 4-fluorophenol, 4-fluorocatechol was further degraded as evidenced by the formation of stoichiometric amounts of fluoride anion. Purified HAPMO catalysed the strictly NADPH-dependent conversion of fluorinated acetophenones to fluorophenyl acetates. Incubations with HAPMO at pH 6 and 8 showed that the enzymatic Baeyer-Villiger oxidation occurred faster at pH 8 but that the phenyl acetates produced were better stabilised at pH 6. Quantum mechanical characteristics explained why 4'-fluoro-2'-hydroxyphenyl acetate was more sensitive to base-catalysed hydrolysis than 4'-fluorophenyl acetate. All together, 19F NMR proved to be a valid method to evaluate the biological conversion of ring-substituted acetophenones to the corresponding phenyl acetates, which can serve as valuable synthons for further production of industrially relevant chemicals.

19F NMR study on the biological Baeyer-Villiger oxidation of acetophenones.

The biological Baeyer-Villiger oxidation of acetophenones was studied by (19)F nuclear magnetic resonance (NMR). The (19)F NMR method was used to characterise the time-dependent conversion of various fluorinated acetophenones in either whole cells of Pseudomonas fluorescens ACB or in incubations with purified 4'-hydroxyacetophenone monooxygenase (HAPMO). Whole cells of P. fluorescens ACB converted 4'-fluoroacetophenone to 4-fluorophenol and 4'-fluoro-2'-hydroxyacetophenone to 4-fluorocatechol without the accumulation of 4'-fluorophenyl acetates. In contrast to 4-fluorophenol, 4-fluorocatechol was further degraded as evidenced by the formation of stoichiometric amounts of fluoride anion. Purified HAPMO catalysed the strictly NADPH-dependent conversion of fluorinated acetophenones to fluorophenyl acetates. Incubations with HAPMO at pH 6 and 8 showed that the enzymatic Baeyer-Villiger oxidation occurred faster at pH 8 but that the phenyl acetates produced were better stabilised at pH 6. Quantum mechanical characteristics explained why 4'-fluoro-2'-hydroxyphenyl acetate was more sensitive to base-catalysed hydrolysis than 4'-fluorophenyl acetate. All together, (19)F NMR proved to be a valid method to evaluate the biological conversion of ring-substituted acetophenones to the corresponding phenyl acetates, which can serve as valuable synthons for further production of industrially relevant chemicals.

ChemInform Abstract: Enzymatic Baeyer-Villiger Oxidation with Cyclohexanone Monooxygenase: A New System of Cofactor Regeneration

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The enzymatic baeyer-villiger oxidation: A study of 4-substituted cyclohexanones

A study of the enzymatic Baeyer-Villiger oxidation of a number of 4-substituted cyclohexanones utilizing the enzyme cyclohexanone oxygenase (E.C.1.14.13.-), isolated from the bacteria Acinetobacter NCIB 9871, is described.

Microbiological transformations. 25. Enantioselective baeyer-villiger oxidation as a tool for the synthesis of enantiopure bicyclic furofuran and pyrofuran chirons.

Several bicyclic [n.2.0] ketones were submitted to enzymatic Baeyer-Villiger oxidation and provided the corresponding regioisomeric lactones showing high enantiopurities. These products could be used as interesting chirons for the synthesis of various natural compounds. The absolute configurations of the obtained lactones were assigned using circular dichroism measurements.