Dynamic enantiomer-selective reaction

Enzymatic resolution of racemic secondary alcohols by enantiomer-selective acylation gives optically pure compounds with up to 50% yield [332], When this method is coupled with the principle of dynamic kinetic resolution (see Section 1.4.1.5), the theoretical yield increases to 100%. Thus a reaction system consisting of an achiral transition-metal catalyst for racemization, a suitable enzyme, acetophenone, and an acetyl donor allows the transformation of racemic 1-phenylethanol to the R acetates with an excellent ee (Scheme 1.93) [333]. The presence of one equiv. of acetophenone is necessary to promote the alcohol racemization catalyzed by the... 

A dynamic kinetic resolution reaction involves the interconversion of the enantiomers of a starting material under conditions where one enantiomer is converted selectively into product. This principle is shown in Fig. 9-1, where a conventional kinetic resolution reaction and a dynamic kinetic resolution reaction are compared. In both cases enantiomer A reacts to form product B more quickly than enantiomer A. However, in the conventional kinetic resolution, enantiomer A is simply left behind as unreacted starting material. In the dynamic kinetic resolution, A and A are in equilibrium, which allows for the possibility that all of the starting material will be converted into product B. The reaction conditions must be chosen that whilst the starting material enantiomers (A/A ) undergo rapid equilibration (racemization), the product B must be inert to racemization. 

The asymmetric processes discussed so far in this chapter have focused on reactions that create non-racemic, chiral products from achiral reagents by selective reaction at one prochiral face or position over the other. However, these principles can also be applied to reactions that separate enantiomers of an existing racemic mixture, channel both enantiomers of such a mixture to a single enantiomeric product, or that select between reaction at one of two diastereotopic functional groups in an achiral substrate. These reactions are also synthetically valuable and are called kinetic resolutions, dynamic kinetic resolutions, and desymmetrizations. An understanding of these reactions draws from the principles established so far in this chapter, but they also require some additional principles to be established that apply in a specific way to these classes of asymmetric transformations. Thus, the remainder of Chapter 14 introduces the fundamentals of these classes of asymmetric catalysis. 

The synthesis of jS-hydoxy-a-amino acids is important since these compounds are incorporated into the backbone of a wide range of antibiotics and cyclopeptides such as vancomycins. These highly functional compounds are also subject to dynamic kinetic resolution (DKR) processes, as the stereocenter already present in the substrate epimerizes under the reaction conditions and hence total conversions into single enantiomers are possible. These transformations can be iy -selective ° for N-protected derivatives as shown in Figure 1.27 when using a mthenium-BlNAP catalyzed system and anfi-selective when the jS-keto-a-amino acid hydrochloride salts are reduced by the iridium-MeOBlPHEP catalyst as shown in Figure 1.28. One drawback is that both these reductions use 100 atm hydrogen pressure. 

By extending the substrate design, a dynamic kinetic resolution of the a-fluoroketones [14] was demonstrated [31]. The reaction shown in Scheme 10.5 accompanied the equihbration between the enantiomers of the substrate that was faster than the hydrogenation process, to produce the threo-isomer with high selectivities. 

A number of different groups have recently investigated the dynamic kinetic resolution of racemic chiral amines [35, 36] using an enantioselective lipase (often CAL B or Novozyme 435) in combination with a chemocatalyst that effects racemi zation of the unreactive amine enantiomer under the reaction conditions. A key issue vdth these types of DKR processes is finding conditions under which the bio and chemocatalysts can function efficiently together. The catalytic cycle for a DKR is shown in Figure 14.26 in which it is essentia] to identify methods for selective racemization of the substrate but not the product. 

As we shall see further in Chapter 28, a kinetic resolution is the more rapid reaction of one enantiomer of starting material over the other. In the absence of anything fancy (like a dynamic kinetic resolution) they are limited to 50% yield of product (or starting material). But because a desymmetrisation starts with one achiral molecule (instead of a pair of enantiomers) this limitation is removed as are other complications we face in kinetic resolutions such as the build up of the wrong enantiomer which makes selectivity more difficult. However, it is worth noting that desymmetrisation and kinetic resolutions are brothers in the stereochemical world. 

Fulling and Sih reported one of the earliest examples to exploit racemization of carboxylic acid derivatives in order to achieve a dynamic kinetic resolution1311. The anti-inflammatory drug Ketorolac was prepared by hydrolysis of the corresponding ester. Whilst most lipases afforded the undesired enantiomer preferentially, a protease from Streptomyces griseus afforded the required (S)-enantiomer of product with good selectivity. The substrate was particularly prone to racemization since the intermediate enolate is well stabilized by resonance effects, although a pH 9 7 buffer was required to achieve a useful dynamic resolution reaction. Thus the acid was formed with complete conversion and with 76 % enantiomeric excess. 

Scheme 7. Examples for Enantiomer Separations by Crystallization with TADDOLs. Besides the original TADDOL (from tartrate acetonide and PhMgX), Toda et al. [44] have often used the cyclopentanone- and cyclohexanone-derived analogs. The dynamic resolution (resolution with in-situ recychng) of 2-(2-methoxyethyl)cyclohexanone was reported by Tsunoda et al. The resolved compounds shown here are only a small selection from a large number of successful resolutions, which include alcohols, ethers, oxiranes, ketones, esters, lactones, anhydrides, imides, amines, aziridines, cyanohydrins, and sulfoxides. The yields given refer to the amount of guest compound isolated in the procedure given. Since we are not dealing with reactions (for which we use % es to indicate enantioselectivity with which the major enantiomer is formed), we use % ep (enantiomeric purity of the enantiomer isolated from the inclusion...

Asymmetric catalysis may also be achieved by the kinetic resolution of racemic substrates, where one enantiomer of starting material is selectively converted into product, leaving the other enantiomer unreacted, in some instances, both enantiomers of a starting material are converted into the same enantiomer of product, i.e. dynamic kinetic resolution. Most reactions fit into one of the categories identified in Figures 1.1-1.3, even if the exact structure is not represented. 

Allyl acetates 1/ent-l that possess identical R groups undergo aUyUc substitution via an achiral intermediate 2. Both enantiomers of starting material proceed via the same intermediate. In the absence of any controlling influence, approach of the nucleophile via pathways a and b is equally likely, and a racemic product 3/ent-3 will be formed (Scheme 1). However, the opportunity for an asymmetric catalytic reaction exists if the reaction can be channeled through one pathway selectively. Overall, the process represents a dynamic resolution, since a racemic starting material is converted into an enan-tiomericaUy emiched product. 

Other examples include OKR of racemic secondary alcohols (Scheme 25A), oxidative desymmetrizations of meso-diols, etc. The kinetic resolution is generally defined as a process where two enantiomers of a racemic mixture are transformed to products at different rates. Thus, one of the enantiomers of the racemate is selectively transformed to product, whereas the other is left behind. This method allows to reach a maximum of 50% yield of the enantiopure remaining sec-alcohol. To overcome this fim-itation, a modification of the method, namely dynamic kinetic resolution (DKR), was introduced. In this case, the kinetic resolution method is combined with a racemization process, where enantiomers are interconverted while one of them is consumed (e.g., by esterification. Scheme 25B). Therefore, a 100% theoretical yield of one enantiomer can be reached due to the constant equifibrium shift. In most of the proposed DKR processes, several catalytic systems, e.g., enzymes and transition-metal catalysts, work together. Both reactions (transfer hydrogenation of ketones and the reverse oxidation of secondary alcohols using ketone as a hydrogen acceptor) can be promoted by a catalyst. The process can involve a temporary oxidation of a substrate with hydrogen transfer to a transition-metal complex. 

The Kabachnik-Fields reaction is a three-component hydrophosphonylation of imines formed in the reaction mixture from carbonyl compounds and amines [75]. In 2008, List and coworkers reported on such a reaction catalyzed by chiral phosphoric acids that combines a dynamic kinetic resolution with the concomitant generation of a new stereogenic center (Scheme 42.30). The resolution is possible when chiral racemic aldehydes 135 are used. This is because the imine formed in the first step of the reaction is in equilibrium with its achiral enamine tautomer, thereby racemizing the starting material continuously. Since one of the two enantiomers is selectively activated by the chiral phosphoric acid catalyst, the addition of phosphite 136 affords the exclusive formation of one diastereomer. All phos-phonate products 137 were obtained with good yields and moderate to excellent diastereo- and enantioselectivity [76]. 

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