Some Applications of Kinetic Resolution

In the practical applications of kinetic resolution, any combination of the different types of enantiomerically pure reactants reported in Figs. 2-4 can provide a multiple stereodifferen-tiating reaction. Some possibilities are collected in Fig. 7. 

Despite its widespread application [31,32], the kinetic resolution has two major drawbacks (i) the maximum theoretical yield is 50% owing to the consumption of only one enantiomer, (ii) the separation of the product and the remaining starting material may be laborious. The separation is usually carried out by chromatography, which is inefficient on a large scale, and several alternative methods have been developed (Figure 6.2). For example, when a cyclic anhydride is the acyl donor in an esterification reaction, the water-soluble monoester monoacid is separable by extraction with an aqueous alkaline solution [33,34]. Also, fiuorous phase separation techniques have been combined with enzymatic kinetic resolutions [35]. To overcome the 50% yield limitation, one of the enantiomers may, in some cases, be racemized and resubmitted to the resolution procedure. 

Conventional gas chromatography (GC) based on the use of chiral stationary phases can handle only a few dozen ee determinations per day. In some instances GC can be modified so that, in optimal situations, about 700 exact ee and E determinations are possible per day [29]. Such meclium-throughputmay suffice in certain applications. The example concerns the lipase-catalyzed kinetic resolution of the chiral alcohol (R)- and (S)-18 with formation of the acylated forms (R)- and (S )-19. Thousands of mutants of the lipase from Pseudomonas aeruginosa were created by error-prone PCR for use as catalysts in the model reaction and were then screened for enantioselectivity [29]. 

Because of the specificity and the enantioselectivity of some enzyme-catalyzed reactions, the application of enzymes is increasingly important in asymmetric induction and kinetic resolution in organic synthesis. A large number of publications were recently reviewed, focusing on utilization of enzymes and microorganisms to stereospecific hydrolysis and other reactions to produce pure stereoisomers (2,3). However, the use of an enzyme as a catalyst has usually been limited to small-scale experiments in the laboratory. 

The coarse-grained approach utilizes a simplified system representation with fewer degrees of freedom, resulting in faster simulations but with reduced spatial and/or temporal resolution [97-99]. Different coarse-graining (CG) schemes have been devised to preserve the most relevant properties of the molecular system. Such methods can be applied to describe time scales that are far beyond the scope of allatom M D or KMC simulations, and thus extend the scope of molecular simulation to the nanoscale. Some examples of successful application of CG methods are the simulation of the different phases of the lipid-water system, interactions of peptides and proteins with biological membranes, and the electrodeposition of copper to form nanowires, nanofilms and nanoclusters in kinetic-limited regimes [182]. 

Needless to say, enzymatic reactions are also perfectly suited to perform highly efficient kinetic resolutions, but their range of applicability is limited to some classes of compounds and reactions. 

Several excellent books and reviews are available on the use of enzymes in stereoselective synthesis and resolutions. Therefore, Table 4 only summarizes the enzymes used in chiral separations [68, 69], while Table 5 provides some selected examples of enzyme applications for the kinetic resolution of drug enantiomers [70-83]. 

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