Baeyer biocatalytic

Camell and co-workers have recently applied lipase-catalysed resolution to formally desymmetrize prochiral ketones that would not normally be considered as candidates for enzyme resolution, through enantioselective hydrolysis of the chemically prepared racemic enol acetate. " For example, an NK-2 antagonist was formally desymmetrized by this approach using Pseudomonas fluorescens hpase (PFL) (Scheme 1.40). By recychng the prochiral ketone product, up to 82 % yields of the desired (5)-enol acetate (99 % ee) could be realized. This method offers a mild alternative to methodologies such as base-catalysed asymmetric deprotonation, which requires low temperature, and biocatalytic Baeyer-Villiger oxidation, which is difficult to scale up. 

Schulz, F., Leca, F., Hollmann, F. and Reetz, M.T., Towards practical biocatalytic Baeyer-Villiger reactions applying a thermostable enzyme in the gram-scale s3mthesis of optically-active lactones in a two-liquid-phase system. BeilsteinJ. Org. Chem., 2005,1, 10. 

The biocatalytical formation of y-butyrolactones through Baeyer-Villiger oxidation is catalyzed by a number of different monooxygenases, yielding precursors to various natural products [29, 38]. Best enantioselectivities were obtained for the... 

Dynamic kinetic resolution process was also applied to biocatalytic Baeyer-Villiger oxidations. The recombinant E. coli expressing the cyclohexanone monooxygenase from A. calcoaceticus was used for the oxidation of racemic... 

When comparing chemical and biocatalytic methods, one could say that, especially for asymmetric oxidations, enzymatic methods enter the scene. This is most evident in the area of asymmetric Baeyer-Villiger oxidation, where biocatalysts take the lead and homogeneous chiral catalysts lag far behind in terms of ee values. Significant progress can be expected in the area of biocatalysis due to the advancement in enzyme production technologies and the possibility of tailor-made enzymes. 

Figure 20.6 Large-scale biocatalytic asymmetric Baeyer-Villiger oxidations.

The large-scale resolution of racemic 2-alkanols to enantiomerically pure (R-)-and (S-t-)-alkanols by lipase shows environmental, health and safety advantages of biocatalysis compared with nonenzymatic syntheses. The biocatalytic Baeyer-Villi-ger oxidation of racemic bicyclo[3.2.0]-hept-2-en-6-one to enantiomerically pure 2-oxabicyclo[3.3.0]-oct-6-en-3-one and 3-oxabicyclo[3.3.0]-oct-6-en-2-one by CHMO represents an asymmetric Baeyer-Villiger oxidation. 

The (1S,5R)-2-oxabicydo-octenone (see Fig. 5) is formed with 96% ee from one ketone enantiomer of racemic bicyclo[3.2.0]hept-2-en-6-one, which is synthesized in a cycloaddition reaction from cyclopentadiene and dichloroacetylchloride with subsequent Zn-reduction. The key limitation to the biocatalytic Baeyer-Villiger process is product inhibition [26]. In order to overcome product inhibition problems, in situ product removal was required. 

Comparison of the Classical Procedure with the Biocatalytic Baeyer-Villiger Reaction... 

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. 

Doig, S. D., Pickering, S. C. R., Lye, G. J., Woodley, J. W., The use of microscale processing technologies for quantifr-cation of biocatalytic Baeyer-Villiger oxidation kinetics, Biotechnol. Bioeng., 80(1), 2002,42-49. 

Olsen T, Kerton F, Marriott R et al. (2006) Biocatalytic esterification of lavandulol in supercritical carbon dioxide using acetic acid as the acyl donor. Enzyme Microb Technol 39(4) 621-625 OttoUna G, de Gonzalo G, Carrea G et al. (2005) Enzymatic Baeyer-Villiger oxidation of bicyclic diketones. Adv Synth Catal 347(7-8) 1035-104... 

Scheme 3.2 Elegant combination of an alcohol dehydrogenase (ADH) and a Baeyer-Villiger monooxygenase (BVMO) for a redox-balanced biocatalytic system.

Baldwin, C.V.F. and Woodley, J.M. (2006) On oxygen limitation in a whole cell biocatalytic Baeyer—Villiger oxidation process. Biotechnol. Bioeng., 95, 362-369. 

Among the various methods for performing asymmetric Baeyer-Villiger reactions, biocatalytic processes represent an interesting alternative. In enzymatic transformations good activities and high enantioselectivities have been achieved with a number of substrates. Often, however, generalization problems still have to be dealt with [353]. 

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