Enzyme Mediated Baeyer-Villiger Oxidations

Abstract

Oxygenation reactions of ketones to esters are referred to as Baeyer-Villiger oxidations and represent a powerful methodology in synthesis to break carbon-carbon bonds in an oxygen insertion process. Since the seminal work by Adolf Baeyer and Victor Villiger in 1899 substantial progress has been made to understand the mechanism, to predict migratory preference, and to apply this conversion in preparative chemistry. Stereoselective Baeyer-Villiger oxidation of cyclic ketones allows rapid access to chiral lactones as valuable intermediates in enantioselective synthesis. Together with organometal catalysts, biocatalysis offers a "green chemistry" methodology for this transformation. Several organisms have been identified to catalyze this reaction in the course of their metabolic pathways and an increasing number of flavin dependent monooxygenases is reported to accept a multitude of non-natural substrates. Such biocatalysts are used in synthetic chemistry either as isolated enzymes in combination with appropriate cofactor recycling systems or as living whole-cells in native or recombinant form. This review gives an overview of the most abundantly utilized enzymes and the corresponding substrate profiles together with applications in natural product and bioactive compound synthesis. The article focuses on recent developments in biocatalytic Baeyer-Villiger oxidation with promising applications in synthetic chemistry. Complementing these aspects, recent advances in characterizing the biochemistry of Baeyer-Villiger monooxygenases and novel approaches to modify and predict the catalytic performance of these enzymes, which have an impact on the potential as stereoselective catalytic entities, are discussed.Dedicated to Prof. Fritz Sauter on the occasion of his 75th birthday.

Effects of water miscible organic solvents on the activity and conformation of the baeyer–villiger monooxygenases from Thermobifida fusca and Acinetobacter calcoaceticus: A comparative study

“…Phenylacetone monoxygenase from Thermobifida fusca (PAMO; Fraaije et al, 2005) and cyclohexanone monoxygenase from Acinetobacter calcoaceticus (CHMO; Donoghue et al, 1976) are two BVMOs that have numerous biocatalytic applications (Alphand et al, 2003;Kamerbeek et al, 2003;Mihovilovic, 2006). The sequence identity between CHMO (543 amino acids) and PAMO (542 amino acids) is 40.3% (Bocola et al, 2005).…”

Induced allostery in the directed evolution of an enantioselective Baeyer–Villiger monooxygenase

“…Interestingly, the absolute configuration of the lactone products are uniformly opposite to what is observed when using CHMO as the catalyst (17)(18)(19)(20)(21). The latter has been reported to deliver an ee-value of only 52% in the desymmetrization of substrate 4c, whereas the evolved PAMO mutant Gln93Asn/Pro94Asp is highly enantioselective in the opposite absolute sense (Scheme 2).…”

“…Baeyer-Villiger monooxygenases are not considered to be allosterically controlled enzymes (5,(17)(18)(19)(20)(21), yet their structures consist of semirigid domains connected via flexible regions or hinges that are typical features present in allosteric systems. It has been stated that the involvement of both flexibility and semirigidity in allosteric enzymes is likely to be a result of evolution, ensuring a balance between sensitivity or specificity and robustness relating to functional importance (1).…”

“…Here, we describe the experimental implementation of induced allostery using a Baeyer-Villiger monooxygenase (BVMO) as the model enzyme (17)(18)(19)(20)(21).…”

“…Reduced FAD reacts with O 2 forming an alkyl-hydroperoxide that, in the deprotonated form, adds nucleophilically to the carbonyl function of the substrate with formation of the short-lived Criegee intermediate in the rate determining step. Subsequent fragmentation/elimination generates an ester (or lactone) and water, like other BVMOs (17)(18)(19)(20)(21). In the case of PAMO, it was suggested on the basis of the X-ray structure that Arg337 participates in the stabilization of the Criegee intermediate (23).…”