Transaminases, dynamic kinetic resolution

Scheme 4.12 co-Transaminase-catalyzed amination of a carbaldehyde in a dynamic kinetic resolution with subsequent lactamization cascade to provide (R)-4-phenyipyrroiidin-2-one. 

Koszelewski, D., Clay, D., Faber, K., and Kroutil, W. (2009) Synthesis of 4-phenylpyrrolidin-2-one via dynamic kinetic resolution catalyzed by OJ-transaminases. 

Like amine oxidases, one can also combine amino add dehydrogenases with in situ chemical reduction, a transaminase, or an amino add dehydrogenase to effect dynamic kinetic resolutions of amino adds. Details of these more complex processes are desaibed in the appropriate later chapters. 

Another example, from the Pfizer portfolio, of successful incorporation of biocatalysis to make functional group interconversions (FGIs) more efficient in API synthesis is in a program for a smoothened (SMO) receptor inhibitor [17], Introduction of a transaminase-catalyzed stereoselective reductive amination of a 4-piperidone 4 with concurrent dynamic kinetic resolution (DKR) gave amine 5 (Scheme 7.2), resulting in the highly efficient incorporation of two chiral centers in a single step. 

Transaminases can either be uhlized in kinetic resolution or as)unmetric synthesis (Scheme 29.3). Asymmetric synthesis, starting with a prochiral ketone substrate, can theoretically lead to 100% conversion and is usually the preferred route to chiral products (Scheme 29.3a). Furthermore high enantiomeric purity is not dependent on conversion rates, whereas a kinetic resolution (Scheme 29.3b) needs 50% conversion for a high enantiomeric excess (ee). But kinetic resolution is thermodynamically favored, if pyruvate is the amino acceptor, compared to as5munetric synthesis where the equilibrium lies on the substrate side [5,34]. To achieve 100% conversion, dynamic kinetic resolution serves as an alternahve with spontaneous deracemization or the initiation of a suitable racemate for enantiomerically pure substrates (Scheme 29.3c). Deracemization in a one-pot two-step reaction with an (S)-and (R)-selective transaminase, respectively, is a method of choice, but unfortunately two enantiocomplemen-tary enzymes are needed (Scheme 29.3d) [35]. Therefore deracemization with a dehydrogenase in the kinetic resolution step and a transaminase in the following step... 

General synthesis strategies for transaminase-catalyzed reactions. (a) Asymmetric synthesis with transaminase, (b) Kinetic resolution with transaminase, (c) Dynamic kinetic resolution with transaminase, (d) One-pot two-step deracemization with transaminase. 

Another approach has recently been described by Cuetos et al. for the dynamic kinetic resolution of a-substituted p-amino esters [77]. Several ra-transaminases and acyclic alkyl-p-keto esters were tested, leading to high conversion rates and high ee and de values. With this result in mind it seems feasible that novel transaminases will be designed to create enantiomeric pure molecules under mild and economically feasible conditions. 

Dynamic kinetic resolution (DKR) is a method that allows for conversion of the racemic mixture into the desired enantiomer with up to 100% of the theoretical yield. " DKR is a powerful approach to asymmetric synthesis and can be achieved by the application of transition-metal catalysts, Lewis acids, organocatalysts, or enzymes (e.g., hydrolases, dehydrogenases, haloalcohol dehalogenases, and transaminases). 

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