Enantioselective Baeyer-Villiger Oxidations Research Articles

Toward an environmentally friendly synthesis of chiral γ-lactones: A biocatalytically oxidative desymmetrization pathway

The direct use of oxygen for the enantioselective Baeyer–Villiger oxidation of cyclobutanone represents a promising, environmentally benign method of generating substituted chiral γ-lactones, a recurrent motif in natural product skeletons. We herein demonstrate a highly efficient process for the desymmetrization of cyclobutanones by a Baeyer–Villiger monooxygenase that originated from Acinetobacter radioresistens (ArBVMO). By coupling a formate dehydrogenase to the monooxygenase, the reaction can readily be performed at high substrate loading (200 mM) in buffer/toluene biphasic systems. Scaling up the reaction led to bioconversion with a space-time yield of up to 115 g L−1 day−1, and perfect enantioselectivity (> 99% ee). The discovery of ArBVMO provides a practical synthetic route to γ-lactones, overcoming the problems of poor accessibility and the high cost of waste disposal incurred by previous methodologies.

Catalytic Desymmetrizing Baeyer-Villiger Oxidation of Quaternary Carbon-Containing Cyclobutane-1,3-diones.

The first highly enantioselective Baeyer-Villiger oxidation of quaternary carbon-containing cyclobutane-1,3-diones using chiral phosphoric acid catalysis and commercially available oxidants was reported. According to the structure of the substrates, two optimized reaction conditions were developed to afford the corresponding chiral tetronic acid products in ≤93% and ≤95% ee values. This reaction offers the first catalytic asymmetric approach to chiral 5,5-disubstituted tetronic acid derivatives. The synthetic potential of this method has been demonstrated by the formal asymmetric synthesis of (-)-vertinolide and the first catalytic asymmetric total synthesis of plakinidone B.

Hybrid catalysis for enantioselective Baeyer–Villiger oxidation and stereoselective epoxidation: a Cp*Ir complex to fuel FMN and FAD reduction for flavoprotein monooxygenase modules

Taking advantage of the standalone capacity of the two-component flavoenzyme oxygenation module, we extended the scope of the pH and oxygen robust iridium complex, Cp*Ir(bpy-OMe)H+ to drive enzymatic reactions from a low-cost hydride source.

Type II flavoprotein monooxygenase PsFMO_A from the bacterium Pimelobacter sp. Bb-B catalyzes enantioselective Baeyer-Villiger oxidations with a relaxed cofactor specificity

Microbial consortia, which degrade branched, long-chain hydrocarbons, can be regarded as a promising source of novel enzymes for the stereo- and regio-selective oxyfunctionalization of hydrocarbons. The hydrocarbon-degrading bacterium Pimelobacter sp. Bb-B was isolated from the consortium associated with the colonial hydrocarbon-excreting microalga Botryococcus braunii. Three new type II flavoprotein monooxygenases (type II FMOs) from this bacterium have been made available in recombinant form through cloning and overexpression in an E. coli host organism. These enzymes (PsFMO_A-C) were characterized in terms of their capability of catalyzing Baeyer-Villiger oxidations with distinct substrates. The highest activity was detected when utilizing camphor and bicyclo[3.2.0]hept-2-en-6-one as substrate in combination with PsFMO_A as the most promising enzyme. Furthermore, synthetic biotransformations with 5 mM of the substrate bicyclo[3.2.0]hept-2-en-6-one, formate and formate dehydrogenase for in situ-cofactor recycling were conducted with this enzyme, leading to a substrate consumption of 85% after 66 h and excellent enantioselectivity of 99% ee for the (1R,5S)-enantiomer. Additionally, an alternative in situ-cofactor recycling based on the use of microalgae for in situ-production of formate from carbon dioxide, water and light together with a formate dehydrogenase was combined successfully with the enzyme PsFMO_A, leading to a substrate consumption of 94% and an enantioselectivity of >99% ee for the so-called “normal lactone”-enantiomer with the absolute configuration 1R,5S.

Phosphothreonine (pThr)-Based Multifunctional Peptide Catalysis for Asymmetric Baeyer-Villiger Oxidations of Cyclobutanones.

Biologically inspired phosphothreonine (pThr)-embedded peptides that function as chiral Brønsted acid catalysts for enantioselective Baeyer-Villiger oxidations (BV) of cyclobutanones with aqueous H2O2 are reported herein. Complementary to traditional BINOL-derived chiral phosphoric acids (CPAs), the functional diversity of the peptidic scaffold provides the opportunity for multiple points of contact with substrates via hydrogen bonding, and the ease of peptide synthesis facilitates rapid diversification of the catalyst structure, such that numerous unique peptide-based CPA catalysts have been prepared. Utilizing a hypothesis-driven design, we identified a pThr-based catalyst that contains an N-acylated diaminopropionic acid (Dap) residue, which achieves high enantioselectivity with catalyst loadings as low as 0.5 mol%. The power of peptide-based multi-site binding is further exemplified through reversal in the absolute stereochemical outcome upon repositioning of the substrate-directing group (ortho- to meta). Modifications to the i+3 residue (LDap to LPhe) lead to an observed enantiodivergence without inversion of any stereogenic center on the peptide catalyst, due to noncovalent interactions. Structure-selectivity and 1H-1H-ROESY studies revealed that the proposed hydrogen bonding interactions are essential for high levels of enantioinduction. The ability for the phosphopeptides to operate as multifunctional oxidation catalysts expands the scope of pThr catalysts and provides a framework for the future selective diversification of more complex substrates, including natural products.

Regio- and enantioselective Baeyer-Villiger oxidation: kinetic resolution of racemic 2-substituted cyclopentanones.

A kinetic resolution of racemic 2-substituted cyclopentanones via highly regio- and enantioselective Baeyer-Villiger oxidation has been successfully developed. The reaction could afford the normal 6-substituted δ-lactones in up to 98% ee and >19/1 regioselectivity. Meanwhile, the unreacted ketones were recovered in excellent ee values (up to 98%). It represents the best results of the kinetic resolution of racemic 2-substituted cyclopentanones via nonenzymic asymmetric BV oxidation.

Correction to Enantioselective Baeyer–Villiger Oxidation: Desymmetrization of Meso Cyclic Ketones and Kinetic Resolution of Racemic 2-Arylcyclohexanones

Correction to Enantioselective Baeyer–Villiger Oxidation: Desymmetrization of Meso Cyclic Ketones and Kinetic Resolution of Racemic 2-Arylcyclohexanones

Expanding the biocatalytic toolbox of flavoprotein monooxygenases from Rhodococcus jostii RHA1

With the aim to enlarge the set of available flavoprotein monooxygenases, we have cloned 8 unexplored genes from Rhodococcus jostii RHA1 that were predicted to encode class B flavoprotein monooxygenases. Each monooxygenase can be expressed as soluble protein and has been tested for conversion of sulfides and ketones. Not only enantioselective sulfoxidations, but also enantioselective Baeyer–Villiger oxidations could be performed with this set of monooxygenases. Interestingly, in contrast to known class B flavoprotein monooxygenases, all studied biocatalysts showed no nicotinamide coenzyme preference. This feature coincides with the fact that the respective sequences appear to form a discrete group of sequence related proteins, distinct from the known class B flavoprotein monooxygenases subclasses: the so-called flavin-containing monooxygenases (FMOs), N-hydroxylating monooxygenases (NMOs) and Type I Baeyer–Villiger monooxygenases (BVMOs). Taken together, these data reveal the existence of a new subclass of class B flavoprotein monooxygenases, which we coined as Type II FMOs, that can perform Baeyer–Villiger oxidations and accept both NADPH and NADH as coenzyme. The uncovered biocatalytic properties of the studied Type II FMOs make this newly recognized subclass of monooxygenases of potential interest for biocatalytic applications.

Enantioselective Baeyer–Villiger Oxidation: Desymmetrization of Meso Cyclic Ketones and Kinetic Resolution of Racemic 2-Arylcyclohexanones

Catalytic enantioselective Baeyer-Villiger (BV) oxidations of racemic and meso cyclic ketones were achieved in the presence of chiral N,N'-dioxide-Sc(III) complex catalysts. The BV oxidations of prochiral cyclohexanones and cyclobutanones afforded series of optically active ε- and γ-lactones, respectively, in up to 99% yield and 95% ee. Meanwhile, the kinetic resolution of racemic 2-arylcyclohexanones was also realized via an abnormal BV oxidation. Enantioenriched 3-aryloxepan-2-ones, whose formation is counter to the migratory aptitude, were obtained preferentially. Both the lactones and the unreacted ketones were obtained with high ee values.

ChemInform Abstract: Recent Developments in the Application of Baeyer—Villiger Monooxygenases as Biocatalysts

AbstractReview: ca. 200 refs.

Recent Developments in the Application of Baeyer–Villiger Monooxygenases as Biocatalysts

Baeyer-Villiger monooxygenases (BVMOs) represent a specific class of monooxygenases that are capable of catalyzing a variety of oxidation reactions, including Baeyer-Villiger oxidations. The recently elucidated BVMO crystal structures have provided a more detailed insight into the complex mechanism of these flavin-containing enzymes. Biocatalytic studies on a number of newly discovered BVMOs have shown that they are very potent oxidative biocatalysts. In addition to catalyzing the regio- and enantioselective Baeyer-Villiger oxidations of a wide range of carbonylic compounds, epoxidations, and enantioselective sulfoxidations have also been shown to be part of their catalytic repertoire. This review provides an overview on the recent developments in BVMO-mediated biocatalytic processes, identification of the catalytic role of these enzymes in metabolic routes and prodrug activation, as well as the efforts in developing effective biocatalytic methodologies to apply BVMOs for the synthesis of high added value compounds.

Catalytic Asymmetric Baeyer–Villiger Oxidation in Water by Using PtII Catalysts and Hydrogen Peroxide: Supramolecular Control of Enantioselectivity

The enantioselective Baeyer-Villiger 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 Pt(II) 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 meso-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 1 g, whereas with the larger substrate, 10, complexes 1 a-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 1 a-h in the presence of micelles is a viable reaction that often benefits from the hydrophobic effect, leading to substantial increases in enantioselectivity.

Asymmetric Baeyer–Villiger oxidation with Co(Salen) and H2O2 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.

ChemInform Abstract: Enantioselective Baeyer—Villiger Oxidation Catalyzed by Palladium(II) Complexes with Chiral P,N‐Ligands.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Enantioselective Baeyer–Villiger Oxidation Catalyzed by Palladium(II) Complexes with Chiral P,N-Ligands

Asymmetric Baeyer-Villiger reaction of symmetrical cyclobutanones 1a-j with urea-hydrogen peroxide (UHP) can be catalyzed by a complex of Pd(II) and the new terpene-derived P, N-ligand 7. The resulting lactones 2a-j were obtained in high yields and with good enantioselectivity (< or =81% ee).

Chiral Brønsted Acid Catalyzed Asymmetric Baeyer–Villiger Reaction of 3‐Substituted Cyclobutanones by Using Aqueous H2O2

A catalytic amount of a chiral Brønsted acid with aqueous H2O2 as the oxidant is sufficient for the enantioselective Baeyer–Villiger oxidation of 3-substituted cyclobutanones to give the corresponding γ-lactones in excellent yields and up to 93 % ee. The method employs benign aqueous H2O2 instead of stoichiometric amounts of a dangerous peracid.

Light‐Driven Biocatalytic Oxidation and Reduction Reactions: Scope and Limitations

The quest for practical regeneration concepts for nicotinamide-dependent oxidoreductases continues. Recently we proposed the use of visible light to promote the direct reductive regeneration of a flavin-dependent monooxygenase. With this enzyme (PAMO-P3) light-driven enantioselective Baeyer-Villiger oxidations were performed. In spite of the significant reduction in the complexity achieved, catalytic performance of the novel approach did not meet the requirements for an efficient biocatalytic oxygenation system. Driven by this ultimate goal, we further investigated the limiting factors of our particular system. We discovered that oxidative uncoupling of the flavin-regeneration reaction from enzymatic O2-activation accounts for the futile consumption of approximately 95% of the reducing equivalents provided by the sacrificial electron donor, EDTA. Furthermore, it was found that the apparent turnover frequency (TOF) for PAMO-P3 in the present setup is approximately two orders of magnitude lower than in conventional setups that use NADPH as reductant. This finding was traced to sluggish electron transfer kinetics that arose from an impeded interaction between PAMO-P3-bound FAD and the reducing catalyst. The limiting factors and potential approaches for their circumvention are discussed. Furthermore, we broadened the light-driven regeneration approach to the class of flavin-dependent reductases. By using the Old Yellow Enzyme homologue YqjM as a model system, a significantly higher catalytic turnover for the enzyme catalyst was achieved, which we assign to a higher accessibility of the prosthetic group as well as to the absence of oxidative uncoupling.

Asymmetric Baeyer–Villiger Biooxidation of α‐Substituted Cyanocyclohexanones: Influence of the Substituent Length on Regio‐ and Enantioselectivity

AbstractCells of Escherichia coli expressing cyclohexanone monooxygenase catalyzed a highly enantioselective Baeyer–Villiger oxidation of α‐substituted cyanocyclohexanones, leading to the corresponding enantiopure caprolactones (ees &gt;97 %). Classical kinetic resolution and regiodivergent parallel kinetic resolution patterns were observed, depending on the length of the linear chain at the alpha position. Regioselectivity was compared with that of chemical BV oxidations. Cells revealed an outstanding stability since 50 % of the specific BV activity was retained after 42 days of storage, which facilitates their use in biotransformations.

Enantioselective Baeyer–Villiger Oxidation of Bicyclo[3.2.0]hept-2-en-6-One with Fungi: Optimization of Biotransformation and Use of TiO2 as Support of Cell Growth

Fungi from Amazonian forest soil (Ecuador) and an Italian factory were screened for Baeyer-Villiger (BV) oxidation of bicyclo [3.2.0]hept-2-en-6-one to 2-oxabicyclo[3.3.0]oct-6-en-3-one (Corey's lactone). Isolates of Fusarium sp. and F. solani produced the (+)-(1R,5S)-lactone while isolates of Aspergillus terricola and A. amazonicus afforded the (-)-(1S,5R)-lactone. Highest conversions (85% yield and 70% enantiomeric excess) were obtained with A. amazonicus grown in presence of 2.7 mM titanium dioxide.

Towards practical biocatalytic Baeyer-Villiger reactions: applying a thermostable enzyme in the gram-scale synthesis of optically-active lactones in a two-liquid-phase system.

Baeyer-Villiger monooxygenases (BVMOs) are extremely promising catalysts useful for enantioselective oxidation reactions of ketones, but organic chemists have not used them widely due to several reasons. These include instability of the enzymes in the case of in vitro and even in vivo systems, reactant/product inhibition, problems with upscaling and the necessity of using specialized equipment. The present study shows that the thermally stable phenylacetone monooxygenase (PAMO) and recently engineered mutants can be used as a practical catalysts for enantioselective Baeyer-Villiger oxidations of several ketones on a preparative scale under in vitro conditions. For this purpose several parameters such as buffer composition, the nature of the solvent system and the co-factor regeneration system were optimized. Overall a fairly versatile and efficient catalytic system for enantioselective laboratory scale BV-oxidations of ketones was developed, which can easily be applied even by those organic chemists who are not well versed in the use of enzymes.