Applications of Dynamic Kinetic Resolution

5 DYNAMIC KINETIC RESOLUTION OF ALCOHOLS, AMINES, AND AMINO ACIDS 

The coupling of enzyme-catalyzed resolution with metal-catalyzed racemization constitutes a powerful DKR methodology for the synthesis of enantioenriched alcohols, amines, and amino acids. In many cases, the metalloenzymatic DKRs provide high yields and excellent enantiopurities, both approaching 100%, and thus provide useful alternatives to the chemical catalytic asymmetric reactions employing transition metals (complexes) or organocatalysts. The wider applications of a metalloenzymatic DKR method, however, are often limited by the low activity, narrow substrate specificity, or modest enantioselectivity of the enzyme employed. The low activities of metal-based catalysts, particularly in the racemization of amines and amino acids, also limit the wider applications of DKR. It is expected that fm-ther efforts to overcome these limitations with the developments of new enzyme-metal combinations will make the metalloenzymatic DKR more attractive as a tool for asymmetric synthesis in the future. 

Diastereomeric excess Dynamic kinetic resolution Enantiomeric excess Kinetic resolution 

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Application of dynamic kinetic resolution has also been reported in a whole-cell enzymatic Baeyer-Villiger process. While this was initially done using slightly basic conditions, Furstoss and Alphand have more recently reported the use of a weakly basic anion exchange resin to promote racemization of the slow oxidizing enantiomer 99 to the fast enantiomer 100.53 Baeyer-Villiger oxidation using recombinant E. coli to overexpress the CHMO from A. calcoaceticus provided excellent yield and % ee of lactone 101. 

Chapter 3 describes the application of lipases, proteases and sulfatases for the kinetic resolution of a range of interesting molecules. A selection of dynamic kinetic resolution (DKR) procedures is disclosed in Chapter 4. DKRs are attracting a significant amount of... 

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. 

A tandem 1,4-addition-Meerwein-Ponndorf-Verley (MPV) reduction allows the reduction of a, /i-unsaturated ketones with excellent ee and in good yield using a camphor-based thiol as reductant.274 The 1,4-addition is reversible and the high ee stems from the subsequent 1,7-hydride shift the overall process is thus one of dynamic kinetic resolution. A crossover experiment demonstrated that the shift is intramolecular. Subsequent reductive desulfurization yielded fiilly saturated compounds in an impressive overall asymmetric reductive technique with apparently wide general applicability. 

Dijksman, A. Elzinga, M., J. Li, Yu-Xin, Arends, I., Sheldon, R., A. Efficient ruthenium-catalyzed racemization of secondary alcohols application to dynamic kinetic resolution. Tetrahedron Asymmetry 2002, 13, 879-884. 

Song and coworkers have developed a series of cinchona-derived dimeric squaramides and have studied their application in dynamic kinetic resolution reaction... 

Shakeri, M., Engstrom, K., Sandstrom, A. G., and BackvaU, J.-E. (2010). Highly enantiose-lective resolution of beta-amino esters by Candida antarctica lipase A immobilized in mesoceUular foam Application to dynamic kinetic resolution. ChemCatChem, 2, 534-538. 

Shaken M, Engstrom K, Sandstrom AG, Backvall J-E. Highly enantioselective resolution of -amino esters by Candida ant-arctica lipase A immobilized in mesoceUular foam application to dynamic kinetic resolution. ChemCatChem 2010 2 534-538. 

Blacker AJ, Stirling MJ, Page MI. Catalytic racemisation of chiral amines and application in dynamic kinetic resolution. Org. Process Res. Dev. 2007 11 642 48. 

For most chemical transformations, especially for industrial applications, the yield of 50% cannot be accepted. Since each enantiomer constitutes only 50% of the racemic mixture, the best way to increase the yield of the desired enantiomer is racemization of the unwanted one (Scheme 5.7). This reaction mustproceed simultaneously with the enzymatic kinetic resolution. In order to indicate the dynamic character of such processes, the term dynamic kinetic resolution has been introduced. 

Another approach to the synthesis of chiral non-racemic hydroxyalkyl sulfones used enzyme-catalysed kinetic resolution of racemic substrates. In the first attempt. Porcine pancreas lipase was applied to acylate racemic (3, y and 8-hydroxyalkyl sulfones using trichloroethyl butyrate. Although both enantiomers of the products could be obtained, their enantiomeric excesses were only low to moderate. Recently, we have found that a stereoselective acetylation of racemic p-hydroxyalkyl sulfones can be successfully carried out using several lipases, among which CAL-B and lipase PS (AMANO) proved most efficient. Moreover, application of a dynamic kinetic resolution procedure, in which lipase-promoted kinetic resolution was combined with a concomitant ruthenium-catalysed racem-ization of the substrates, gave the corresponding p-acetoxyalkyl sulfones 8 in yields... 

Dynamic kinetic resolution enables the limit of 50 % theoretical yield of kinetic resolution to be overcome. The application of lipase-catalyzed enzymatic resolution with in situ thiyl radical-mediated racemization enables the dynamic kinetic resolution of non-benzylic amines to be obtained. This protocol leads to (/f)-amides with high enantioselectivities. It can be applied either to the conversion of racemic mixtures or to the inversion of (5)-enantiomers. 

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... 

The application of the Hoffmann test """ " confirms configurational stability of these lithium compounds on the microscopic scale at low temperature, indicating that rather thermodynamic than dynamic kinetic resolution is operating at the reaction conditions " . 

The enzyme-catalyzed regio- and enantioselective reduction of a- and/or y-alkyl-substituted p,5-diketo ester derivatives would enable the simultaneous introduction of up to four stereogenic centers into the molecule by two consecutive reduction steps through dynamic kinetic resolution with a theoretical maximum yield of 100%. Although the dynamic kinetic resolution of a-substituted P-keto esters by chemical [14] or biocatalytic [15] reduction has proven broad applicability in stereoselective synthesis, the corresponding dynamic kinetic resolution of 2-substituted 1,3-diketones is rarely found in the literature [16]. 

As well as biocatalysis in neat organic solvents and biphasic systems (fundamentals and synthetic applications), the present volume covers new and promising aspects of non-aqueous enzymology that have emerged in recent years, including biocatalysis with undissolved solid substrates or vaporized compounds, the use of ionic liquids as solvents, and the preparative-scale exploitation of oxynitrilases and dynamic kinetic resolutions . For the sake of completeness and comparison,... 

While enzymes and chiral chemical catalysts compete for best performance in a variety of situations, they have also been used jointly to afford a desired reaction result (Choi, 1999). By far the most frequent application of this concept, termed an enzyme-metal combi reaction (EMCR) , is the dynamic kinetic resolution (DFR) of a racemic mixture with a lipase and an organometallic complex to afford in-situ racemization. 

V Ratovelomanana-Vidal, J.-P. Genet, Synthetic Applications of the Ruthenium-Catalyzed Hydrogenation via Dynamic Kinetic Resolution, Can. J. Chem. 2000, 78, 846-851. 

Instead of starting with racemic starting material it is also possible to use symmetric substrates [25]. The hydrolase selectively catalyses the hydrolysis of just one of the two esters, amides or nitriles, generating an enantiopure product in 100% yield (Scheme 6.7). No recycling is necessary, nor need catalysts be combined, as in the dynamic kinetic resolutions, and no follow-up steps are required, as in the kinetic resolutions plus inversion sequences. Consequently this approach is popular in organic synthesis. Moreover, symmetric diols, diamines and (activated) diacids can be converted selectively into chiral mono-esters and mono-amides if the reaction is performed in dry organic solvents. This application of the reversed hydrolysis reaction expands the scope of this approach even further [22, 24, 27]. 

Recently it was reported that an a-amino-e-caprolactam racemase from Achro-mobacter obae can racemise a-amino acid amides efficiently. In combination with a D-amino acid amidase from Ochrobactrum anthropi L-alanine amide could be converted into D-alanine. This tour de force demonstrates the power of the racemase [84]. If racemic amide is used as a starting material the application of this racemase in combination with a d- or L-amidase allows the preparation of 100% d- or L-amino acid, a dynamic kinetic resolution instead of DSM s kinetic resolution (Scheme 6.24). 

The enzymes of the nucleic acid metabolism are used for several industrial processes. Related to the nucleobase metabolism is the breakdown of hydantoins. The application of these enzymes on a large scale has recently been reviewed [85]. The first step in the breakdown of hydantoins is the hydrolysis of the imide bond. Most of the hydantoinases that catalyse this step are D-selective and they accept many non-natural substrates [78, 86]. The removal of the carbamoyl group can also be catalysed by an enzyme a carbamoylase. The D-selective carbamoylases show wide substrate specificity [85] and their stereoselectivity helps improving the overall enantioselectivity of the process [34, 78, 85]. Genetic modifications have made them industrially applicable [87]. Fortunately hydantoins racemise readily at pH >8 and additionally several racemases are known that can catalyze this process [85, 88]. This means that the hydrolysis of hydantoins is always a dynamic kinetic resolution with yields of up to 100% (Scheme 6.25). Since most hydantoinases are D-selective the industrial application has so far concentrated on D-amino acids. Since 1995 Kaneka Corporation has produced 2000 tons/year of D-p-hydroxyphenylglycine with a D-hydantoinase, a d-carbamoylase [87] and a base-catalysed racemisation [85, 89]. 

The reduction of yff-ketoesters to aldols is one of the most important applications of Ru(II)-BlNAP catalysts [7]. As a special bonus, the chirally labile C2 stereogenic center can be exploited in a dynamic kinetic resolution such that racemic reactants yield only one of the four conceivable stereoisomers in high diastereomeric and enantiomeric excess. This strategy has been extended to the reduction of -ketophosphonates 10. The 3-hydroxyphosphonic acids 7 which are accessible by this route constitute promising starting materials for the synthesis of peptide analog and antibiotics [8]. 

Synthetically, in racemization has been shown to play an important role in biologi-cal 22 chemical dynamic kinetic resolution of carbonyl compounds . Generally, if the required in siturac mization is faster than the kinetic resolution (deriva-tization step), this process can allow the conversion of a racemic substrate into a single enantiomeric product in quantitative yield This strategy has found industrial application in the synthesis of Levobupivacaine , Bupivacaine and Roxiban . ... 

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