3.4 Baeyer–Villiger Oxidation

Abstract

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). ...