Dynamic enantiomeric purities, product

Organosulfur chemistry is presently a particularly dynamic subject area. The stereochemical aspects of this field are surveyed by M. Mikojajczyk and J. Drabowicz. in the fifth chapter, entitled Qural Organosulfur Compounds. The synthesis, resolution, and application of a wide range of chiral sulfur compounds are described as are the determination of absolute configuration and of enantiomeric purity of these substances. A discussion of the dynamic stereochemistry of chiral sulfur compounds including racemization processes follows. Finally, nucleophilic substitution on and reaction of such compounds with electrophiles, their use in asymmetric synthesis, and asymmetric induction in the transfer of chirality from sulfur to other centers is discussed in a chapter that should be of interest to chemists in several disciplines, in particular synthetic and natural product chemistry. 

A huge improvement on the KR is determined by an enhanced reaction setup where the racemization of the substrate is carried out in situ in parallel to its resolution. This means that, while the preferred enantiomer is transformed by the enzyme, the other one does not accumulate but is continuously converted into its antipode, thus fueling the reaction until aU the substrate is consumed. In this case, a quantitative conversion can be reached moreover, the enantiomeric purity of the product is often higher as compared to the simple KR, because the enzyme is continuously exposed to comparable concentrations of both of the two stereoisomers, which is a requirement for the maximum efficiency in their discrimination [2,3]. This improved setup is called dynamic kinetic resolution DKR), and it has become very attractive in recent years [4-9]. 

Enzymes - and thus hydrolases - can realize all kinds of selectivities such as chemo-, regio-, diastereomer and diastereotopic selectivity, as well as enantiomer and enantiotopic selectivity [83]. Accordingly, lipases were apphed in all possible kinds of stereoselective biotransformations [29, 30, 79, 81, 83] such as KR [79, 84], deracemization, and dynamic kinetic resolution (DKR) [85]. In this review, we wish to concentrate on methods enabling the continuous-mode hydrolase-mediated production of compounds in high enantiomeric purity. 

The product of a NHase/amidase cascade reaction is an acid, which is the same as the single enzymatic reaction performed by a nitrilase. However, the NHases usually have different substrate specificities than nitrilases, making them more suitable for the production of certain compounds. Although most organisms have both NHase and amidase activity (see earlier text), it is sometimes preferable, in a synthetic application, to combine enzymes from different organisms. The reasons for this are the enantioselectivity of the amidase or specific activity or substrate specificity of either of the enzymes. In this way, products with different enantiomeric purity can be obtained. Recently, a coupling of a NHase with two different amidases with opposite enantiopreference together with an -amino-a-caprolactam racemase that allows the formation of small aliphatic almost enantiopure (R)- or (S)-amino acids via dynamic kinetic resolution processes has been described [52]. 

A dynamic kinetic resolution extends the high yield advantage of desymmeUiza-tions to racemic substrates. A dynamic kinetic resolution is a kinetic resolution combined with rapid in situ racemization of the substrate. The requirements for a dynamic kinetic resolution are (1) the substrate must racemize at least as fast as the subsequent enzymatic reaction, (2) the product must not racemize, and (3) as in any asymmetric synthesis, the enzymic reaction must be highly stereoselective. The equations relating product enantiomeric purity and enantioselectivity are the same as those for desymmetrizations. 

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... 

In contrast to a conventional kinetic resolution of a racemate, asymmetrization of prochiral and meso compounds can give 100% theoretical yield. Still, the ratio of biocatalyzed asymmetrizations vs. kinetic resolutions has been reported to be only 1 4 [112]. Similar to a dynamic kinetic resolution, the enantiomeric purity of the product of an asymmetrization reaction remains constant and is independent of the extent of conversion. The enantiomeric excess of the product (e.e.p) is given by... 

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