Resolution, classical kinetic

The classical kinetic resolution of racemic substrate precursors allows only access to a theoretical 50% yield of the chiral ladone product, while the antipodal starting material remains unchanged in enantiomerically pure form. The regioseledivity for the enzymatic oxidation correlates to the chemical readion with preferred and exclusive migration of the more nucleophilic center (usually the higher substituted a-carbon). The majority of cydoketone converting BVMOs (in particular CHMOAdneto)... 

The identification of a novel BVMO from Mycobacterium tuberculosis (BVMOMtbs) complements this toolbox, as this particular biocatalyst performs a classical kinetic resolution instead of a regiodivergent oxidation vith complete consumption of substrate [140]. Notably, this enzyme accepts only one ketone enantiomer and converts it selectively to the abnormal lactone while the antipodal substrate remains unchanged (Scheme 9.24) [141]. 

Figure 4.6 Classical kinetic resolution with subsequent reracemization of unconverted enantiomer Synthesis of pantoic acid from pantolactone applying a stirred-tank reactor, extraction module and racemization step...

Figure 4.7 Classical kinetic resolution synthesis of L-methionine from IV-acetyl-methionine applying an ultrafiltration-membrane reactor and crystallization step as well as racemization step...

In contrast to the asymmetrization of meso-epoxides, the kinetic resolution of racemic epoxides by whole fungal and bacterial cells has proven to be highly selective (see above). These biocatalysts supply both the unreacted epoxide enantiomer and the corresponding vidnal diol in high enantiomeric excess. This so-called classic kinetic resolution pattern of the biohydrolysis is often regarded as a major drawback since the theoretical chemical yield can never exceed 50% based on the racemic starting material. As a consequence, methods... 

These main groups can be subdivided as shown below. This diagram shows not only the structure of the field asymmetric synthesis but how they are arranged in this book. Resolution, for instance divides into Classical , Kinetic and what we call Fancy Kinetic which means dynamic kinetic... 

Other symbols used in the realm of kinetic resolution include C, the level of conversion where 0 < C < 1. In a classical kinetic resolution where one enantiomer reacts faster than the other and the other is left behind then the following equation is true.4 This equation is important as relates three crucial factors—conversion, ee and selectivity.5... 

Classical kinetic resolution of racemates is frequently employed for the preparation of enantiopure compounds. In order to circumvent the limitation... 

Classical kinetic resolution (KR), in which one of the enantiomers of the ketone is converted into a different optically pure lactone, and the other ketone enantiomer recovered. 

The first artificial catalysts for the BV oxidation of racemic cyclic ketones via classical kinetic resolutions were independently and almost simultaneously reported by Bolm et and Strukul and coworkers. b These studies produced chiral lactones in moderate ee using chiral Cu conplex 99 (Scheme 2.25 and diphosphane/Pt complex 111 (Scheme 2.26 as catalyst. 

Thus, kinetic resolutions are distinct from enantioselective reactions that occur with prochiral substrates and create new chiral elements. Kinetic resolutions do not usually generate additional stereochemishy (an exception is shown in Figure 14.8D). Rather, they distinguish one enantiomer from another by enantioselectively creating new functionality. Kinetic resolutions are also distinct from classical resolutions. Classical resolutions are conducted with stoichiometric amounts of chiral resolving agents, but kinetic resolutions are... 

Comparison of a classical kinetic resolution with a dynamic kinetic resolution. In the dynamic kinetic resolution. I is an achiral intermediate or transition state. 

As long as the a-substituent consists of an alkyl- or aryl-group, dynamic resolution is readily achieved, leading to chemical yields far beyond the 50% which would be the maximum for a classic kinetic resolution. However, in-sim racemization is not possible due to electronic reasons for a-hydroxy- [914], a-alkylthio- [899], ot-azido- [915], or a-acetylamino derivatives [916], which are subject to kinetic resolution. The same holds for substrates which are fully substituted at the a-posi-tion, due to the impossibility of form the corresponding enolate. 

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]. 

Most recently, the combination of several (bio)catalytic steps onto each other in a cascade reaction [20] has resulted in the development of so-called deracemization techniques, which lead to the transformation of a racemate into a single stereoisomer as the sole product. In an economic sense, these methods are far superior to classic kinetic resolution, which provides two enantiomers each in 50% yield [21]. 

It is a combination of these twin goals that has led to the evolution of classical kinetic resolution into DKR. In such a process, one can in principle obtain a quantitative yield of one of the enantiomers. Effectively, DKR combines the resolution step of kinetic resolution with an in situ equilibration or racemisation of the chirally labile substrate. In DKR, the enantiomers of a... 

Scheme 11 Various resolutions of racemic 5-methylcyclohexenone. (a) Classic kinetic resolution.

General representation of classical kinetic resolutions (a), dynamic kinetic resolutions (b), and desym-metrization processes (c). 

The chemoenzymatic DKR protocol combines the enzyme-catalyzed resolution of a racemic substrate with the in situ racemization of the less reactive enantiomer, thus, producing optically active products in up to quantitative yield. This is a significant improvement with respect to the maximum yield of 50% obtained in classic kinetic resolution (KR). However, certain requirements have to be fulfilled to achieve an efficient DKR 1) The substrate must racemize at least as fast as the subsequent enzymatic reaction (2) no product racemization has to occur under the reaction conditions and (3) the enzymatic reaction must be both irreversible and highly stereoselective. Given that the racemization rate is higher than the resolution rate, the aizyme... 

Scheme 6 Classic kinetic resolution where R and S denote the substrate enantiomers and P and Q represent their products, respectively.

Dynamic resolutions are kinetic resolutions modified with an additional feature, i.e., a racemization step (Scheme 9). This can afford 100% yield of the fastest reacting enantiomer if rac — and product racemization does not occur. Furthermore, in contrast to a classic resolution process, the enantiomeric excess of the product in a dynamic resolution process becomes independent of the conversion. 

---