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

Rioz‐Martínez, Ana; Gonzalo, Gonzalo de; Pazmiño, Daniel E. Torres; Fraaije, Marco W.; Gotor, Vicente

doi:10.1002/ejoc.200900084

Cited by 37 publications

(24 citation statements)

References 39 publications

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“…(18), and 4-hydroxyacetophenone monooxygenase (14). An oxidation product of ketone 4 was identified by comparing it with the product of a reaction catalyzed by the M446G mutant of PAMO (24). The absolute configurations of sulfoxides 5a to 8a and esters 11a to 12a were assigned by comparison of the GC or HPLC retention times with the published data (7,27).…”

Section: Vol 77 2011 Mutational Analysis Of Phenylacetone Monooxygementioning

confidence: 99%

Mapping the Substrate Binding Site of Phenylacetone Monooxygenase from Thermobifida fusca by Mutational Analysis

Dudek

Gonzalo

Pazmino

et al. 2011

Appl Environ Microbiol

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Baeyer-Villiger monooxygenases catalyze oxidations that are of interest for biocatalytic applications. Among these enzymes, phenylacetone monooxygenase (PAMO) from Thermobifida fusca is the only protein showing remarkable stability. While related enzymes often present a broad substrate scope, PAMO accepts only a limited number of substrates. Due to the absence of a substrate in the elucidated crystal structure of PAMO, the substrate binding site of this protein has not yet been defined. In this study, a structural model of cyclopentanone monooxygenase, which acts on a broad range of compounds, has been prepared and compared with the structure of PAMO. This revealed 15 amino acid positions in the active site of PAMO that may account for its relatively narrow substrate specificity. We designed and analyzed 30 single and multiple mutants in order to verify the role of these positions. Extensive substrate screening revealed several mutants that displayed increased activity and altered regio-or enantioselectivity in Baeyer-Villiger reactions and sulfoxidations. Further substrate profiling resulted in the identification of mutants with improved catalytic properties toward synthetically attractive compounds. Moreover, the thermostability of the mutants was not compromised in comparison to that of the wild-type enzyme. Our data demonstrate that the positions identified within the active site of PAMO, namely, V54, I67, Q152, and A435, contribute to the substrate specificity of this enzyme. These findings will aid in more dedicated and effective redesign of PAMO and related monooxygenases toward an expanded substrate scope.Enzymes have been gaining increasing attention as efficient and selective catalysts to be used in synthetic chemistry. Baeyer-Villiger monooxygenases (BVMOs) comprise a group of enzymes that are particularly interesting for synthetic applications. These biocatalysts employ molecular oxygen as a mild oxidant to oxidize carbonylic compounds. Apart from catalyzing Baeyer-Villiger reactions, BVMOs are capable of oxidizing a range of heteroatoms (e.g., sulfur, nitrogen, and boron). Furthermore, they often perform these reactions with high chemo-, regio-, and enantioselectivity (5, 15, 30). The use of oxygen, which is a cheap and clean oxidant, and their diversity of catalyzed reactions make BVMOs attractive candidates for biocatalytic processes.The identification of phenylacetone monooxygenase (PAMO) in the moderately thermophilic bacterium Thermobifida fusca has brought about a breakthrough in the research on BVMOs (11). PAMO is a thermostable enzyme that can easily be expressed in Escherichia coli and purified. Besides, its crystal structure has been solved as the first structure of a BVMO (17). While PAMO shows excellent stability, even in the presence of organic solvents (6, 28), its substrate specificity is rather restricted. The enzyme accepts mainly small aromatic ketones and sulfides (7, 26), whereas the oxidations of bulkier ketones occur with lower activity and selectivity (27). However, the unique...

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Section: Vol 77 2011 Mutational Analysis Of Phenylacetone Monooxygementioning

confidence: 99%

Mapping the Substrate Binding Site of Phenylacetone Monooxygenase from Thermobifida fusca by Mutational Analysis

Dudek

Gonzalo

Pazmino

et al. 2011

Appl Environ Microbiol

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“…218 (HAPMO), one of the Baeyer-Villiger monooxygenase (BVMO) enzymes (summarized in Table 3). 219 They achieved an enantioselective synthesis of 3-methyl-3,4-dihydrocoumarin in low yield and low ee from 2-methylindanone using HAPMO (BVMO) enzyme. 220 Gutiérrez et al have obtained 3,4-dihydrocoumarins from 1-indanone derivatives via the Baeyer-Villiger oxidation using whole cells of the wild type bacteria Pseudomonas sp.…”

Section: Scheme 76cmentioning

confidence: 99%

Syntheses and Biological Activities of Chroman-2-ones. A Review

Kamat

Tilve

Kamat

et al. 2015

Organic Preparations and Procedures International

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“…Benzo-fused ketones have also been oxidized by purified HAPMO, phenylacetone monooxygenase (PAMO) from Thermobifida fusca, and its Met446Gly mutant (M446G PAMO) (Scheme 4). [27] In order to increase the biocatalytic activity of these enzymes, a small amount of organic cosolvent (5% v/v) is required. The presence of organic cosolvents in Baeyer-Villiger monooxygenase catalyzed oxidations can affect the biocatalysts properties by modifying its structure.…”

Section: 421mentioning

confidence: 99%

“…6-Chloro-3,4-dihydro-1H-2-benzopyran-1-one (6); Typical Procedure: [27] To a soln of 5-chloro-2,3-dihydro-1H-inden-1-one ( (8) is formed after 2 days with 90% yield by oxidation of androstenedione (7) (Scheme 5). The fungus Penicillium citreoviride oxidizes various steroids such as progesterone, dehydroepiandrosterone, and androstenedione (7) which lead to the same final product 8 with good yields (60-70%) after 5 days.…”

Section: 421mentioning

confidence: 99%

3.4 Baeyer–Villiger Oxidation

de Gonzalo Calvo,

van Berkel,

Fraaije

2015

Biocatalysis in Organic Synthesis 3

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The Baeyer-Villiger oxidation, a reaction described more than 110 years ago by Alfred Baeyer and Victor Villiger, [1] is among the most well-known and commonly applied reactions in organic synthesis. [2][3][4] The reaction entails the oxidation of a carbonyl compound employing an organic peracid, finally yielding an ester or lactone. Its versatility is due to the following factors: (i) different types of carbonyl compounds, such as aldehydes and linear or cyclic ketones, can be oxidized; (ii) other functional groups are well tolerated in the substrate structure; (iii) the regiochemistry is usually predictable, with the migratory aptitude being tertiary alkyl > cyclohexyl > secondary alkyl > benzyl > phenyl > primary alkyl > methyl; (iv) the migrating group retains its configuration.The mechanism of this reaction has been widely studied. [5] In the first step of the process, the peracid performs a nucleophilic attack on the carbonyl group of the ketone, leading to a tetrahedral Criegee intermediate. After oxygen insertion and the migration of the more highly substituted group, the final product is formed. The migration of the substituent and the release of the leaving group occur in a concerted way and are usually the ratelimiting step of the reaction.The classical Baeyer-Villiger procedure using organic peracids suffers from several disadvantages. First of all, organic peracids are expensive and/or hazardous, which limits their commercial application. Peracids are powerful oxidative agents, necessitating laborious protection and deprotection steps in synthesis to prevent side reactions. Due to these issues, different methodologies for carrying out the Baeyer-Villiger oxidation have been developed using mild oxidants, such as molecular oxygen or hydrogen peroxide, in the presence of organometallic catalysts or organocatalytic compounds. [6][7][8] The recent development of biocatalysis as an alternative, useful tool in organic synthesis has allowed the application of different types of enzymes, lipases and monooxygenases, in order to perform selective Baeyer-Villiger oxidations while using mild and environmentally friendly conditions. 3.4.1 Reactions Catalyzed Indirectly by HydrolasesLipases are the most widely employed biocatalysts in organic synthesis because of their high stability, catalytic efficiency, commercial availability, and broad substrate specificity. [9] Apart from their use in hydrolytic procedures, lipases have been used in other "nonconventional" reactions, such as C-C bond formation, carbon-heteroatom bond formation, and oxidative processes. [10] Lipases have also been employed in Baeyer-Villiger oxidations, as they catalyze the perhydrolysis of carboxylic acids and esters, generating the corresponding peracids, which subsequently oxidize the target substrate. Thus, the oxidation of cyclic ketones, e.g. 1, is catalyzed by the Candida antarctica lipase B (CALB) in toluene in the presence of stoichiometric amounts of myristic acid (tetradecanoic acid) and an excess of hydrogen peroxide (Scheme 1). ...

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

Cited by 37 publications

References 39 publications

Mapping the Substrate Binding Site of Phenylacetone Monooxygenase from Thermobifida fusca by Mutational Analysis

Mapping the Substrate Binding Site of Phenylacetone Monooxygenase from Thermobifida fusca by Mutational Analysis

Syntheses and Biological Activities of Chroman-2-ones. A Review

3.4 Baeyer–Villiger Oxidation

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