Dynamic kinetic resolution chemoenzymatic

Dynamic kinetic resolution is a technique that combines a racemization with a simultaneous resolution to overcome the inherent 50 % yield limit of kinetic resolution allowing a theoretical 100 % yield. Recently, a novel chemoenzymatic system has been developed for the dynamic kinetic resolution of 6,7-dimethoxy-l-methyl-1,2,3,4-tetrahydroisoquino-hne, building on kinetic resolution methodology developed by Breen. The corresponding (/f)-carbamate was isolated in high yield and enantiomeric excess (Figure 4.2). 

The procedure constitutes the first known example of a chemoenzymatic dynamic kinetic resolution of a secondary amine. The operational simplicity of the procedure is exemplified by the mild conditions, air-stable reagents and low catalyst loading. 

Stirling, M., Blacker J. and Page M.I., Chemoenzymatic dynamic kinetic resolution of secondary amines. Tetrahedron Lett., 2007, 48, 1247. 

Chemoenzymatic Dynamic Kinetic Resolution of (S)-lbuprofen 161 Table 4.7 Results for DKR process... 

Cp Ir(NHC) complexes are a very versatile type of catalyst, with a wide range of applications. In a chemoenzymatic application, Cp Ir complexes activated by fluo-rinated and nonfluorinated NHC ligands were shown to be catalysts for racemiza-tion in the one-pot chemoenzymic dynamic kinetic resolution (DKR) of secondary... 

A prominent example of chemoenzymatic catalysis in bio-organic chemistry is the dynamic kinetic resolution (DKR) of secondary alcohols (Scheme 9) [94, 95] and amines [96-99], In this process, a lipase is employed as an enantioselective acylation catalyst, and a metal-based catalyst ensures continuous racemization of the unreactive enantiomer. 

During the past few years great efforts have been made to overcome the 50% threshold of enzyme-catalyzed KRs. Among the methods developed, deracemization processes have attracted considerable attention. Deracemizations are processes during which a racemate is converted into a non-racemic product in 100% theoretical yield without intermediate separation of materials [5]. This chapter aims to provide a summary of chemoenzymatic dynamic kinetic resolutions (DKRs) and chemoenzymatic cyclic deracemizations. 

It should be mentioned that the great majority of dynamic kinetic resolutions reported so far are carried out in organic solvents, whereas all cyclic deracemizations are conducted in aqueous media. Therefore, formally, this latter methodology would not fit the scope of this book, which is focused on the synthetic uses of enzymes in non-aqueous media. However, to fully present and discuss the applications and potentials of chemoenzymatic deracemization processes for the synthesis of enantiopure compounds, chemoenzymatic cyclic de-racemizations will also be briefly treated in this chapter, as well as a small number of other examples of enzymatic DKR performed in water. 

Kamaruddin AH, Uzir MH et al (2009) Chemoenzymatic and microbial dynamic kinetic resolutions. Chirality 21 449 167... 

Odman P, Wessjohann LA et al (2005) Chemoenzymatic dynamic kinetic resolution of acyloins. J Org Chem 70 9551-9555... 

The remarkable activity of copper catalysts in carbonyl hydrogenation and alcohol dehydrogenation prompts their use also for the racemization of chiral secondary alcohols. Actually, since the first report on chemoenzymatic dynamic kinetic resolution [68], racemization of alcohols via the corresponding ketone has attracted considerably attention, owing to its role as backbone in this resolution [69, 70]. 

A method that has been used to approach 100% theoretical yield in asymmetric syntheses is dynamic kinetic resolution, or DKR. Although this method has been practiced based on strictly chemical reactions, only those chemoenzymatic DKR reactions will be discussed here. Most often, the enzyme used by this method is a hydrolase (lipase, esterase, protease), but other enzymes such as hydantoinases, /V-acylamino acid racemases, and dehydrogenases have also been exploited to effectively carry out DKR reactions.196 For additional details the reader is directed to the many review articles written on DKR.197 206... 

Fransson, A. B. L., Boren, L., Pamies, O., and Backvall, J. 2005. Kinetic resolution and chemoenzymatic dynamic kinetic resolution of functionalized y-hydroxy amides. J. Org. Chem., 70(1) 2582-2587. 

Thalen, L.K., Sumic, A., Bogar, K., Norinder, J., Persson, A.K.A., and Baeckvall, J.-E. (2010) Enantioselective synthesis of I —methyl carboxylic acids from readily available starting materials via chemoenzymatic dynamic kinetic resolution. J. Org. Chem., 75 (20), 6842-6847. 

Bogar, K., Vidal, P.H., Leon, A.R.A., and Baeckvall, J.-E. (2007) Chemoenzymatic dynamic kinetic resolution of allylic alcohols a highly enantioselective route to acyloin acetates. Org. Lett., 9 (17), 3401-3404. 

Sato, Y., Kayaki, Y., and Ikariya, T. (2012) Efficient dynamic kinetic resolution of racemic secondary alcohols by a chemoenzymatic system using bifunctional iridium complexes with C-N chelate amido ligands. Chem. Commun. (Cambridge, UK), 48 (30), 3635-3637. 

In polymer chemistry, one of the most challenging tasks is to efficiently synthesize optically active synthetic polymers. The extraordinary enantioselectivity of lipases offers new perspectives towards these materials, and it is therefore not surprising that some research efforts have focused on the use of lipases to synthesize chiral polymers from racemic monomers. Methodologies like kinetic resolution and even chemoenzymatic dynamic kinetic resolution (DKR) have already been exploited on the industrial scale to afford chiral intermediates for the pharmaceutical and agrochemical industry. Recently, these methodologies have been successfully applied in the synthesis of chiral polymers. 

Scheme 19.6 Chemoenzymatic dynamic kinetic resolution process of a secondary alcohol at room temperature.

The versatility of the combination of enzymes with metal catalysts is also well demonstrated by chemoenzymatic dynamic kinetic resolutions (DKRs). Indeed, to overcome the major drawback of kinetic resolution for which the maximum yield is limited to 50%, the combination of a metal-catalysed racemisation of the slow-reacting enantiomer with an enzyme-catalysed... 

Galletti, P., Emer, E.. Gucciardo, G., Quintavalla, A., Pori, M., and Giacomini, D. (2010) Chemoenzymatic synthesis of (2S)-2-arylpropanols through a dynamic kinetic resolution of 2-arylpropanals with alcohol dehydrogenases. Org. Biomol. Chem., 8,4117-4123. 

Pamies, O. and BackvaU, J.-E. (2002). Enzymatic kinetic resolution and chemoenzymatic dynamic kinetic resolution of delta-hydroxy esters. An efficient route to chiral delta-lac-tones. /. Org. Chem., 67,1261-1265. 

Hoben, C. E., Kanupp, L., and BackvaU, J.-E. (2008). Practical chemoenzymatic dynamic kinetic resolution of primary amines via transfer of a readUy removable benzyloxycar-bonyl group. Tetrahedron Lett., 49,977-979. 

Thalen, L. K., Zhao, D. B., Sortais, J. B., Paetzold, J., et al. (2009). A chemoenzymatic approach to enantiomerically pure amines using dynamic kinetic resolution Application to the synthesis of norsertraline. Chem. Eur.., 15,3403-3410. 

---