Baeyer–Villiger Monooxygenases in Organic Synthesis

Abstract

The sections in this article are Introduction General Aspects of the Baeyer–Villiger Oxidation Mechanistic Aspects Chemical Versus Enzymatic Baeyer–Villiger Oxidation Biochemistry of Baeyer–Villiger Monooxygenases Catalytic Mechanism Structural Features Application of Baeyer–Villiger Monooxygenases in Organic Chemistry Isolated Enzymes Versus Whole Cells Baeyer–Villiger Monooxygenases Relevant for Synthetic Applications Representative Synthetic Applications Kinetic Resolutions of Racemic Ketones Desymmetrization of Prochiral Ketones Regiodivergent Transformations Large‐Scale Application Heteroatom Oxidation Protein Engineering Conclusions and Perspectives Acknowledgments

Biocatalytic Asymmetric Oxidations in Stereoselective Synthesis

“…They catalyze the biological counterpart of the chemical Baeyer-Villiger oxidation (BVO), e.g., the conversion of ketones into the corresponding esters or lactones using molecular oxygen from air as the oxidant. 41 Additionally, they can oxidize aldehydes and heteroatoms like sulfur, nitrogen, boron, or phosphorous. In the first step of the catalytic mechanism, the reduced flavin 28 is formed, which subsequently reacts with molecular oxygen to give a flavin-C4a-peroxoanion 29 (Scheme 36.12).…”

“…Thanks to the advances in molecular biology and especially in genome sequencing, many more BVMOs with complementary substrate specificity and stereoselectivity could be recently identified. 41 Thus, enzymes converting very diverse substrates ranging from monocyclic ketones (C 4 -C 15 ) over aryl-aliphatic and acyclic ketones in polycyclic ones (e.g., steroids) are nowadays available in recombinant form expanding the BVMO toolbox for synthetic applications. Unfortunately, only a few of these enzymes are so far commercially available.…”

“…For a more comprehensive compilation of enzyme-mediated BVOs, the reader is referred to several excellent reviews. 41,43,44 Desymmetrizations of various prochiral, p-substituted cyclobutanones and cylohexanones giving the corresponding lactones in high yields and excellent optical purities have been reported using different microbial BVMOs. 43 Formed chiral g-butyrolactones thereby represent important building blocks for the total syntheses of various bioactive compounds and natural products like the lignans (þ)-enterolactone, (þ)-hinokinin, (À)-steganacine, and (À)-transburseran or the g-aminobutyric acid (GABA) inhibitor (R)-baclofen.…”

“…Nevertheless, most of the preparative applications of BVMOs have been reported for this type of reaction. 41,43 As an example, BVMO MO2 from Pseudomonas putida was applied in the stereoselective BVO of 2-(2 0 -acetoxyethyl) cyclohexanone 35 to synthesize the corresponding (R)-lactone 36 (Scheme 36.14). The product was further converted into (R)-(þ)-lipoic acid 37, a bioactive compound for the treatment of hepatitis, pancreatitis, and induced carcinomas.…”

Engineering of a Baeyer–Villiger monooxygenase reveals key residues for the asymmetric oxidation of omeprazole sulfide

“…The catalytic asymmetric sulfoxidation of prochiral thioethers constitutes an important reaction in organic chemistry, 1,2 as mediated by chiral synthetic transition metal complexes, [3][4][5] organic catalysts, [6][7][8] or Baeyer-Villiger monooxygenases (BVMOs). [9][10][11][12] BVMOs provide a green and useful approach to synthesize sulfoxides, and have been well investigated in the stereoselective catalytic oxyfunctionalization of sulfides.…”