Lipase-based dynamic kinetic resolution

A completely different enzyme-catalyzed synthesis of cyanohydrins is the lipase-catalyzed dynamic kinetic resolution (see also Chapter 6). The normally undesired, racemic base-catalyzed cyanohydrin formation is used to establish a dynamic equilibrium. This is combined with an irreversible enantioselective kinetic resolution via acylation. For the acylation, lipases are the catalysts of choice. The overall combination of a dynamic carbon-carbon bond forming equilibrium and a kinetic resolution in one pot gives the desired cyanohydrins protected as esters with 100% yield [19-22]. 

Dynamic kinetic resolution (DKR) is a process in which the resolution process is coupled with in situ racemization of unreacted substrate. This has been shown to be a potential and feasible method to produce 100 % theoretical yield. We have developed a chemo-enzymatic DKR to obtain higher desired yield for (5)-ibuprofen. The combined base catalyst with lipase has resulted in high conversion and excellent ee of the product. 

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. 

J. H. Koh, and J. Park, Dynamic kinetic resolution of allylic alcohols mediated by ruthenium- and lipase-based catalysts,... 

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... 

A number of major pharmaceutical companies have used biocatalytic approaches based on esterases and lipases lo prepare target drugs or intermediates [70,122-126]. Most of these approaches involve resolutions that start with a racemic ester or amide, and as such, yields of < 50% can only be realized. Recent examples of resolutions applied to pharmaceutical intermediates such as the paclitaxel (Taxol) side chain and A-(+)-BMY-14802, an antipsychotic agent, have been described by the Bristol-Myers group [70]. The following sections discuss selected examples of the use of esterases and lipases to hydrolyze prochiral or we o-substrates, where theoretical yields of 100% can be realized, followed by a brief discussion of dynamic kinetic resolution where reaction yields of 100% can also be achieved. 

For a long time, kinetic resolution of alcohols via enantioselective oxidation or via acyl transfer employing, for example, lipases along with dynamic kinetic resolution have been the biocatalytic methods of choice for the preparation of chiral alcohols. In recent years, however, impressive progress has been made in the use of alcohol dehydrogenases (ADHs) and ketor-eductases (KREDs) for the asymmetric synthesis of alcohols by stereoselective reduction of the corresponding ketones. Furthermore, recent remarkable multienzymatic systems have been successfully applied to the deracemisation of alcohols via stereoinversion based on an enantioselective oxidation followed by an asymmetric reduction. 

Other applications of NHC-based rhodium catalysts include the cyclization of acetylene carboxylic acids, cyclopropanation of olefins with diazo compounds, or aryl-aryl cross-coupling combined with dynamic kinetic resolution with the help of a lipase or Beckmann rearrangement. Thus, the chemistry of NHC-Rh catalysts is rich and varied, and we expect new catalysts and patterns of reactivity in the years to come. These will provide new tools for synthetic organic chemistry. 

SCHEME 28.6. Lipase-catalyzed synthesis of cyanohydrins acetates, based on a dynamic kinetic resolution. 

Dynamic resolution of various sec-alcohols was achieved by coupling a Candida antarctica lipase-catalyzed acyl transfer to in-situ racemization based on a second-generation transition metal complex (Scheme 3.17) [237]. In accordance with the Kazlauskas rule (Scheme 2.49) (/ )-acetate esters were obtained in excellent optical purity and chemical yields were far beyond the 50% limit set for classical kinetic resolution. This strategy is highly flexible and is also applicable to mixtures of functional scc-alcohols [238-241] and rac- and mcso-diols [242, 243]. In order to access products of opposite configuration, the protease subtilisin, which shows opposite enantiopreference to that of lipases (Fig. 2.12), was employed in a dynamic transition-metal-protease combo-catalysis [244, 245]. 

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