Racemization metal-catalyzed

In 1997, Sturmer highlighted the importance of the combination of enzymes and transition metals in one pot [36]. Since then, this concept has aroused much interest within the scientific community. In all the DKRs presented in this section, the enzyme catalyzes a transesterification process. Thus, enzyme- and metal-catalyzed DKRs are categorized according to the nature of the substrates as being allylic substrates, secondary alcohols, or primary amines. In the first case, 

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Catalytic transformation based on combined enzyme and metal catalysis is described as a new class of methodology for the synthesis of enantiopure compounds. This approach is particularly useful for dynamic kinetic resolution in which enzymatic resolution is coupled with metal-catalyzed racemization for the conversion of a racemic substrate to a single enantiomeric product. 

Dynamic kinetic resolution (DKR) is an attractive protocol for the production of enantiopure compounds from racemic mixtures [45]. The concept of DKR is illustrated in Scheme 5.13. In many cases, DKRs are accomplished by the combination of enzymatic resolution and transition-metal-catalyzed racemization based on hydrogen transfer. Thus, the use of Cp Ir complexes as catalysts for racemization in DKR can be anticipated. 

DKR of secondary alcohol is achieved by coupling enzyme-catalyzed resolution with metal-catalyzed racemization. For efficient DKR, these catalyhc reactions must be compatible with each other. In the case of DKR of secondary alcohol with the lipase-ruthenium combinahon, the use of a proper acyl donor (required for enzymatic reaction) is parhcularly crucial because metal catalyst can react with the acyl donor or its deacylated form. Popular vinyl acetate is incompatible with all the ruthenium complexes, while isopropenyl acetate can be used with most monomeric ruthenium complexes. p-Chlorophenyl acetate (PCPA) is the best acyl donor for use with dimeric ruthenium complex 1. On the other hand, reaction temperature is another crucial factor. Many enzymes lose their activities at elevated temperatures. Thus, the racemizahon catalyst should show good catalytic efficiency at room temperature to be combined with these enzymes. One representative example is subtilisin. This enzyme rapidly loses catalytic activities at elevated temperatures and gradually even at ambient temperature. It therefore is compatible with the racemization catalysts 6-9, showing good activities at ambient temperature. In case the racemization catalyst requires an elevated temperature, CALB is the best counterpart. 

Dynamic kinetic resolutions of secondary alcohols and amines have been achieved by the combination of biocatalysts with metal catalysts.12 For example, a metal catalyst was used to racemize the substrate, phenylethanol, and a lipase was used for the enantioselective esterification as shown in Figure 12. The yield was improved from 50% in kinetic resolution without racemization of the substrate to 100% with metal catalyzed racemization. 

Subsequently the groups of Williams [7] and Backvall [8] showed, in 1996 and 1997, respectively, that lipase-catalyzed transesterification of alcohols could be combined with transition metal-catalyzed racemization to produce an efficient dynamic kinetic resolution of chiral secondary alcohols (Fig. 9.2). 

Fig. 9.14 Side reactions in metal-catalyzed racemization of amines.

The reaction time in the second example (Scheme 4) is rather long as well the rate-determining step is again the metal-catalyzed racemization. After 6 days the conversion is 76 % with 3 mol % [Rh(COD)Cl]2 and the enantiomeric excess reaches 80 %. 

This concept was also recently extended by Reetz et al. to the resolution of phenylethylamine [12]. In this case, an immobilised lipase and ethyl acetate as acyl donor are used the non-acylated (S)-enantiomer of the amine is racemized in situ by palladium on charcoal. After 8 days -the metal catalyzed racemization is again likely to he the rate-determining step - (/ )-A-acetyl-phenylethylamine is isolated in 64 % yield and 99 % enantiomeric excess. 

Figure 9-12. Transition metal-catalyzed racemization of alcohols coupled with enantioselective enzyme-catalyzed acetylation.

In contrast to the facile in-situ racemization of sec-alcohols via Ru-catalysts (Schemes 3.14 and 3.17), which allows dynamic resolution, the isomerization of ot-chiral amines requires more drastic conditions. Hydrogen transfer catalyzed by Pd [283, 284], Ru [285, 286] Ni, or Co [287] is slow and requires elevated temperatures close to 100°C, which still requires the spatial separation of (metal-catalyzed) racemization from the lipase aminolysis [288]. 

After screening a range of metal complexes based on iridium, aluminum, rhodium, or ruthenium toward their suitability to racemize (S)-l-phenylethanol, Williams and Harris et al. [12] demonstrated a proofof concept for the combination of such a metal-catalyzed racemization of 1-phenylethanol with an in situ enzymatic acylation of preferentially one enantiomer, although some Hmitations appeared such as limited conversion and the need for a range of additives. A representative example for this type of DKR is shown in Scheme 19.4 with the successful synthesis of the ester (R)-IO with enantioselectivity of 98% ee at 60% conversion. 

For a long time, metal-catalyzed racemization in such chemoenzymatic DKRs has been preferentially carried out with ruthenium and palladium and related heavy metal catalysts. An interesting alternative for this process was reported by the Berkessel group [24], who developed an efficient DKR based on an aluminum catalyst for racemization. Compared to heavy metals, aluminum represents an economically attractive and readily available metal, and thus an interesting metal component for a racemization catalyst (Scheme 19.8). The aluminum complexes that turned out to be most successful in these studies were prepared starting from... 

The classical enzymatic kinetic resolution of a racemic substrate provides two enantiomers as the product and unreacted substrate. In this case, the theoretical maximum yield for one enantiomer is 50%. To improve the yield, tite opposite enantiomer is racemized and then recycled for the second enzymatic kinetic resolution. The racemi-zation-recycling process should be repeated at least three times to achieve more than a 90% yield. In the metalloenzymatic DKR, the enzymatic kinetic resolution occurs simultaneously with the metal-catalyzed racemization, so all tiie substrates can be converted to the products to provide a near 100% yield in a single operation. Each DKR process, however, gives only single enantiomeric products. Accordingly, two stereocomplementary enzymes are needed for the synthesis of a pair of enantiomeric products via DKR. 

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. 

SCHEME 57.21. Metal-catalyzed racemization of benzylic amines and possible side-products. 

Metal-catalyzed racemization of amines generally takes place via reversible dehydrogenation-hydrogenation steps through imine intermediates (Scheme 57.21). During this process, and facilitated by the elevated temperatures required for racemization, the imine intermediate can undergo side reactions (condensation with an amine molecule, hydrolysis, etc.), which could lower the yield of the amide and make it difficult to isolate. 

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