Enzyme and Metal Combinations

Most substrates for enzyme-catalyzed kinetic resolution reactions do not undergo spontaneous racemization under conditions that are suitable for enzyme activity. One solution to this problem has been to design mild transition metal-catalyzed methods for in situ racemization 17. In order to achieve this goal, the racemisation method must be able to function without an adverse effect on the enzyme. Additionally, the enzyme must not inhibit the racemization method. 

The first example of the use of enzyme and metal combinations to provide a dynamic resolution procedure was reported by Allen and Williams in 1996[18. In this case, a palladium (II) catalyst was employed that was able to racemize the allylic acetate substrate, but did not erode the enantioselectivity of the product allylic alcohol (Fig. 9-11). For example, a cyclic acetate was shown to undergo a simple kinetic resolution, affording enantiomerically enriched starting material and product at approximately 50 % conversion. However, performing the reaction in the presence of a palladium (II) catalyst facilitated a dynamic resolution by continuously racemiz-ing the starting material as the reaction progressed. 

Similar methodology was applied to an acyclic allylic acetate by the group of Kim, who used Pd(0) catalysts119. Acyclic allylic acetates are easier substrates for palladium-catalyzed racemization, and these workers were able to effect a dynamic resolution strategy within a more acceptable time scale (Fig. 9-11). The in situ racemization with palladium catalysts is limited in scope, since allylic acetates are required as substrates. In addition, not all allylic acetates are expected to undergo facile racemization 20.  

An alternative enzyme/transition metal combination employs transfer hydrogenation catalysts that are capable of racemizing secondary alcohols. The racemization procedure temporarily converts the alcohol into an achiral ketone, which is reduced back to the racemic alcohol. Coupling this racemization procedure to an enzyme-catalyzed acylation reaction affords a dynamic resolution process (Fig. 9-12). Several enzyme/transition metal combinations have been shown to be effective for these reactions, although ruthenium complexes 1-3 appear to be especially effective for the in situ racemization of the alcohol. The product esters are not prone to racemization under the reaction conditions. Early results employing transfer hydrogenation catalysts to effect the racemization of alcohols required the use of added ketone 21, 22. However, it was subsequently shown that added ketone was not required when appropriate transition metal complexes were used as catalysts. Furthermore, the use of 4-chlorophenyl acetate as the acyl donor afforded improved results. 

Backvall and co-workers have reported successful results for a wide range of substrates, some of which are identified in Table 9-1. The procedure works well for secondary alcohols containing aryl and alkyl groups [231, diols1241 and a-hydroxy esters[25]. Although catalyst 1 requires no additional base, Kim, Park and co-workers used triethylamine to facilitate racemization using catalyst 2, Table 9-2126]. In their case, small quantities of oxygen were added to initiate the racemization procedure. In the case of allylic alcohols, careful choice of racemisation catalyst is required in order to minimize the amount of conversion of the substrate into saturated or 

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