Kinetic resolution irreversible reaction

The kinetic resolution using a chiral zirconocene-imido complex 286 took place with high enantioselectivity to result in chiral allenes 287 (up to 98% ee) (Scheme 4.74) [116]. However, a potential drawback of these methods is irreversible consumption of half of the allene even if complete recovery of the desired enantiomer is possible. Dynamic kinetic resolutions avoid this disadvantage in the enantiomer-differentiating reactions. Node et al. transformed a di-(-)-L-menthyl ester of racemic allene-l,3-dicarboxylate [(S)- and (RJ-288] to the corresponding chiral allene dicarbox-ylate (R)-288 by an epimerization-crystallization method with the assistance of a catalytic amount of Et3N (Scheme 4.75) [117]. 

An elegant way to avoid the low yields and the need for recycling half of the material in the case of kinetic resolutions is a dynamic kinetic resolution (DKR). The dynamic stands for the dynamic equilibrium between the two enantiomers that are kinetically resolved (Scheme 6.6A). This fast racemisation ensures that the enzyme is constantly confronted with an (almost) racemic substrate. At the end of the reaction an enantiopure compound is obtained in 100% yield from racemic starting material. Mathematical models describing this type of reaction have been published and applied to improve this important reaction [32, 33]. There are several examples, in which the reaction was performed in water (see below). In most cases the reaction is performed in organic solvents and the hydrolase-catalysed reaction is the irreversible formation of an ester (for example see Figs. 9.3, 9.4, 9.6, 9.12) or amide (for example see Figs. 9.13, 9.14, 9.16). 

The classical chemical kinetics allows resolution of the problem by clas sifying aU of the steps of the stepwise process into two categories fast (i.e., those resulting in partial dynamic equihbria of some of elementary reac tions) and slow (those that are far from their dynamic equilibria). In this case, the overall reaction rate v appears to be a function of parameters kj of the direct reaction only for the slow stages and of parameters Kj for the fast stages. Thus, the slow elementary reactions are considered as kinet icaUy irreversible— that is, only a forward reaction i but not its backward reaction can be considered. 

Another method that has been used to approaeh 100% theoretieal yield in asym-metrie syntheses is dynamic kinetic resolution (DKR), which has been reviewed [130-133] and has been applied to just chemical or a combination of chemical and biochemical reactions. Only those examples in which biochemical transformations are included in the approach are presented here. If the mterconversion between the two enantiomeric substrates is rapid and the product is relatively stable, and, thus, irreversibly formed, then the magnitude of the rate constants, k2 and k, will dictate which product isomer is formed (Figure 3). This interconversion between the isomers is sometimes catalyzed by metal ions, silica, or ion exchange resin, or it could be due to the lability of the stereogenic center. 

This is a kinetic resolution that works by enantioselective acylation of the unwanted enantiomer of the alcohol. The reaction is therefore an ester exchange and vinyl acetate is an efficient acetate transfer agent since the other product is vinyl alcohol better known as the enol of acetaldehyde so the reaction is irreversible. 

Quantitative Analysis of Irreversible Kinetic Resolution. Enantiomeric excess (ee) is the measure of enantiopurity, and the value is most often determined by chiral GC (gas chromatograph equipped with a chiral column) or HPLC (high performance liquid chromatograph equipped with a chiral column) methods. Enantiomeric excess is the ratio of the concentration difference of the enantiomers to the total concentration as shown in equation 1 for the substrate and the product enantiomers. The value is mostly expressed by multiplying with 100 to get the percentage value. In kinetic resolution, ees of the less reactive substrate enantiomer [S ] and eep of the product enantiomer depend on the progress (conversion) of the reaction. 

To make a reaction irreversible, it can be performed in neat acyl donor, for instance, in ethyl acetate, which otherwise is reversible (Fig. 12, entry 9). Acylation with S-ethyl thiooctanoate has allowed successful kinetic resolution of secondary alcohols, because evaporation of the formed thioethanol easily shifts the equilibrium to the product side (entry 3) (18). However, acid anhydrides and especially activated esters, which liberate a low nucleophilic (entry 8) or unstable (entries 1, 5, and 6) alcohol, are usually more appropriate. When acid... 

The kinetic resolution of primary alcohols (RCH2OH) by enzymatic acylation is often demanding because of the remote position of the asymmetric center firom the reaction site. Moreover, special attention is needed to keep the acyl transfer irreversible and to prevent hydrolysis of the acylated product. 

The ideal acyl donor would be inexpensive, acylate quickly and irreversibly in the presence of hydrolase, be completely unreactive in the absence of hydrolase and, for kinetic resolutions, yield a product that is easily separated from the starting material. No acyl donor fulfills all of these criteria. The irreversibility is important for enantioselective reactions because reversibility lowers the enantiomeric purity of the product [24]. 

To design an efficient DKR, certain requirements have to be fulfilled. First, the kinetic resolution has to be irreversible to ensure the high enantioselectivity. Moreover, the enantiomeric ratio (E = kjj/kj) must be at least >20, and to prevent depletion of Sjj, the racemiza-tion (k v) should be at least equal to or greater than the reaction rate of the fast enantiomer (kj ) (Figure 1.42). And finally, under the reaction conditions, any spontaneous reaction involving the substrate enantiomers as well as racemization of the product should be absent. DKR is an example of a Curtin-Hammett system in which the composition of products is controlled by the free energies of the transition states and not by the composition of the starting materials. 

The base-catalyzed reaction of HCN on carbonyl substrates leading to a racemic product is normally considered an undesired background reaction in the HNL-catalyzed synthesis of cyanohydrins because it yields racemic products. However, this dynamic equilibrium can be also displaced to the desired enantiomer by using a second, irreversible, and enantioselective reaction in situ. This one-pot, two-step process is then called dynamic kinetic resolution. 

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... 

When, as it is assumed here, the B —> C reaction is the rate-determining step, the dimensionless rate parameter, 2, is the same as in the ECE case. As 2 increases, the wave loses its reversibility while the electron stoichiometry passes from 1 to 2, as in the ECE case. Unlike the latter, there is no trace crossing upon scan reversible. This is related to the fact that now only the reduction of A contributes to the current. C has indeed disappeared by means of its reaction with B before being able to reach back to the electrode surface. The characteristic equations, their dimensionless expression, and their resolution are detailed in Section 6.2.1. The dimensionless peak current, tjj, thus varies with the kinetic parameter, 2, from 0.446, the value characterizing the reversible uptake of one electron, to 2 x 0.496 = 0.992, the value characterizing the irreversible exchange of two electrons (Figure 2.11a). 

Dynamic combinatorial nitroaldol libraries were also used to illustrate iDCR [5,6], In this case, one of the library components was selected for its possibility to undergo an irreversible tandem cyctizafion reaction following equilibrium formation. This provided an internal kinetic selection pressure on the library, subsequently forcing the library to complete amplification of this novel reaction product. Furthermore, interesting crystalline properties were observed for one of the diastereoisomers of this isoindolinone-type product, providing a route to demonstrate consecutive resolution processes resolving coupled DCLs in a one-pot experiment. 

The above examples demonstrate the DSR concept as a useful approach to generate and interrogate simultaneously complex systems for different applications. A range of reversible reactions, in particular carbon-carbon bond-formation transformations, was used to demonstrate dynamic system formation in both organic and aqueous solutions. By applying selection pressures, the optimal constituents were subsequently selected and amplified from the dynamic system by irreversible processes under kinetic control. The DSR technique can be used not only for identification purposes, but also for evaluation of the specificities of selection pressures in one-pot processes. The nature of the selection pressure applied leads to two fundamentally different classes external selection pressures, exemplified by enzyme-catalyzed resolution, and internal selection pressures, exemplified by transformation- and/or crystallization-induced resolution. Future endeavors in this area include, for example, the exploration of more complex dynamic systems, multiple resolution schemes, and variable systemic control. 

The overall gas-liquid effectiveness factor is thus proportional to the inverse of the mass transfer Sherwood number, and we have a nice theoretical resolution for the analysis of gas-liquid reaction for the irreversible first-order kinetics considered. 

Recently, a cascade process for the simultaneous preparation of two enantiopure secondary alcohols by the same ADH was investigated [12]. In this work, a kinetic oxidative resolution of different secondary alcohols was coupled with the irreversible asymmetric reduction of selected prochiral activated ketones, that is, a-chloro ketones (Scheme 11.5a). The proposed strategy, named PIKAT (parallel intercoimected kinetic asymmetric transformations), represents an example of redox neutral (or self-sufficient) cascade, with no additional reducing or oxidizing reagents being required. Moreover, the reaction was catalyzed by a single enzyme in the presence of catalytic amounts of the cofactor. As the outcome of the cascade process is a mixture of two different enantioenriched products, substrates were properly selected on the basis of different physical properties. 

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