Cyclohexanone Baeyer-Villiger reaction

Bolm et al. (130) reported the asymmetric Baeyer-Villiger reaction catalyzed by Cu(II) complexes. Aerobic oxidation of racemic cyclic ketones in the presence of pivalaldehyde effects a kinetic resolution to afford lactones in moderate enan-tioselectivity. Aryloxide oxazolines are the most effective ligands among those examined. Sterically demanding substituents ortho to the phenoxide are necessary for high yields. Several neutral bis(oxazolines) provide poor selectivities and yields in this reaction. Cycloheptanones and cyclohexanones lacking an aryl group on the a carbon do not react under these conditions. 

Stewart, J.D., Cyclohexanone monooxygenase a useful reagent for as3mimetric Baeyer-Villiger reactions. Curr. Org. Chem., 1998, 2, 195-216. 

In fluorinated alcohol solvents, nonstrained ketones such as cyclohexanone (1) undergo oxidation to lactones in the presence of hydrogen peroxide and catalytic amounts of Brpnsted acids (Berkessel and An-dreae 2001 Berkessel et al. 2002). Unlike the classical Baeyer-Villiger reaction, ketone oxidation with H2O2 in e.g. HFIP proceeds via a spiro-bisperoxide 2 intermediate (Scheme 1). In contrast to other solvents, the acid-catalyzed rearrangement of the spiro-bisperoxide 2 to two equivalents of the product lactone 3 proceeds rapidly and cleanly in HFIP. Preliminary calculations indicate active participation of the fluorinated alcohol solvent in the rate-determining step also in this case. 

Reetz MT, Brunner B, Schneider T, Schulz F, Clouthier CM, Kayser MM (2004a) Directed evolution as a method to create enantioselective cyclohexanone monooxygenases for catalysis in Baeyer-Villiger reactions. Angew Chem Int Ed 43 4075 1078... 

The Baeyer-Villiger reaction occurs with retention of stereochemistry at die migrating center. This stereoselectivity has been utilized in a practical method for the preparation of isotopically chiral metiiyl acetic acid (5) ftom [2- H]cyclohexanone (4) prepared by enzyme-catalyzed stereoselective exchange of the pro-R a -proton and enantioconvergent exchange of the a-proton with deuterium (Scheme 2). As a cautionary note, prior epimerization of an acyl group prior to oxidation has been observed. ... 

A single enzyme is sometimes capable of many various oxidations. In the presence of NADH (reduced nicotinamide adenine dinucleotide), cyclohexanone oxygenase from Acinetobacter NCIB9871 converts aldehydes into acids, formates of alcohols, and alcohols ketones into esters (Baeyer-Villiger reaction), phenylboronic acids into phenols sulfides into optically active sulfoxides and selenides into selenoxides [1034], Horse liver alcohol dehydrogenase oxidizes primary alcohols to acids (esters) [1035] and secondary alcohols to ketones [1036]. Horseradish peroxidase accomplishes the dehydrogenative coupling [1037] and oxidation of phenols to quinones [1038]. Mushroom polyphenol oxidase hydroxylates phenols and oxidizes them to quinones [1039]. 

The Baeyer-Villiger reaction is also effected by biochemical oxidation using the enzyme cyclohexanone oxygenase from Acinetobacter strain NCIB 9871. Cyclohexanone is thus converted into e-caprolactone [1043], and phenylacetone (l-phenyl-2-propanone) is transformed into benzyl acetate. The formation of benzyl acetate from phenylacetone involves the same migration as that in oxidation with peroxytrifluoroacetic acid (equation 387) [1034]. More examples of biochemical Baeyer-Villiger reactions occur in diketones and steroids see equation 397). 

Together with enantioselective hydrolysis/acylation reactions, enantioselective ketone reductions dominate biocatalytic reactions in the pharma industry [10], In addition, oxidases [11] have found synthetic applications, such as in enantioselective Baeyer-Villiger reactions [12] catalyzed by, for example, cyclohexanone monooxygenase (EC 1.14.13) or in the TEMPO-mediated oxidation of primary alcohols to aldehydes, catalyzed by laccases [13]. Hence, the class of oxidoreductases is receiving increased attention in the field of biocatalysis. Traditionally they have been perceived as difficult due to cofactor requirements etc, but recent examples with immobilization and cofactor regeneration seem to prove the opposite. 

Baeyer-Villiger reaction. This peracid has been used for the Baeycr-Villiger reaction with cyclopentanones and cyclohexanones. The reaction is carried out with 1.25 molar equiv. of benzeneseleninic acid and 10 molar equiv. of H2O2 in THF or CH2CI2 buffered to pH 7. Yields are comparable to those with other peracids. One example, 1 2, was reported where oxidation was achieved only with this peracid. 

The Baeyer-Villiger reaction can be carried out using isolated enzymes or whole cell systems. Biotransformations of simple cyclic ketones are most effective. For example, 4-methylcyclohexanone is oxidized with high enantioselectivity by using cyclohexanone monooxygenase (6.64). 

Baeyer-Villiger Reaction. Baeyer-Villiger reaction of cyclohexanone takes place readily at 0 °C with (1) (4-6 h) to furnish hexanollde In 80% yield. Peracid (1) did not react with the ketone (12) and 4,4 dimethylcholestan 3 one. Reaction of (12) with peracetic add boron trifluoride etherate furnished the lactone (13) in 36% 3deld. ... 

Scheme 9.176. A representation of the reaction of the ethyl ester of cyclohexanone-2-car-boxylic acid with excess permethanoic acid (peracetic acid, CH3CO3H). The labile epoxide presumed to be produced from the corresponding enol is expected to rearrange to a ketone, which undergoes the Baeyer-Villiger reaction.

Reetz and co-workers have demonstrated that the methods of directed evolution can be applied successfully to the creation of enantioselective cyclohexanone monooxygenases (CHMOs) as catalysts in Baeyer-Villiger reactions of several different substrates, for which the enantioselectivity ranges between 90-99% [100]. Ketone 5 gives a very poor enantioselectivety (9% ee, R-selective) with the wild-type CHMO. The enantioselectivety for 5 was significantly improved by directed evolution, and an S-selective variant gave 79% ee (Scheme 10.1). 

Scheme 10.1 Directed evolution of cyclohexanone monooxygenases (CHMOs) improves enantioselectivety in Baeyer-Villiger reactions.

A reaction analogous to the Baeyer-Villiger reaction occurs in living systems through the action of enzymes in certain bacteria, for exarrqrle, species of Pseudomonas and Acinetobacter. A preparation of the 5 enantiomer of compound Y has been described using a bacterial cyclohexanone monooxygenase enzyme system What is compound X ... 

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