Dynamic Kinetic Resolution and Desymmetrization

Song and coworkers have developed a series of cinchona-derived dimeric squaramides and have studied their application in dynamic kinetic resolution reaction 

H-4— o o o MeOH MTBE,25 C.24h 51% overall yield Me02C CO2H H-)— 

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Kinetic Resolution, Dynamic Kinetic Resolution, and Desymmetrization... 

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. 

Most work on this subject is based on the use of alcohols as reagents in the presence of enantiomerically pure nucleophilic catalysts [1, 2]. This section is subdivided into four parts on the basis of classes of anhydride substrate and types of reaction performed (Scheme 13.1) - desymmetrization of prochiral cyclic anhydrides (Section 13.1.1) kinetic resolution of chiral, racemic anhydrides (Section 13.1.2) parallel kinetic resolution of chiral, racemic anhydrides (Section 13.1.3) and dynamic kinetic resolution of racemic anhydrides (Section 13.1.4). 

The most powerful approaches, which can be used with several different enzyme systems, lead to a single enantiomer as the product in high yield and do not rely on a classic resolution approach in which the unwanted enantiomer is discarded. These approaches include dynamic kinetic resolutions, der-acemizations, and asymmetric and desymmetrization reactions (49, 50). In some cases, a chemical catalyst may be available to recycle the unwanted isomer in the same reactor vide infra). It is sometimes possible to racemize the unwanted isomer of the substrate and then to perform the reaction again (51). 

Cinchona-Based Organocatalysts for Desymmetrization of meso-Compounds and (Dynamic) Kinetic Resolution of Racemic Compounds... 

In this chapter, we attempt to review the current state of the art in the applications of cinchona alkaloids and their derivatives as chiral organocatalysts in these research fields. In the first section, the results obtained using the cinchona-catalyzed desymmetrization of different types of weso-compounds, such as weso-cyclic anhydrides, meso-diols, meso-endoperoxides, weso-phospholene derivatives, and prochiral ketones, as depicted in Scheme 11.1, are reviewed. Then, the cinchona-catalyzed (dynamic) kinetic resolution of racemic anhydrides, azlactones and sulfinyl chlorides affording enantioenriched a-hydroxy esters, and N-protected a-amino esters and sulftnates, respectively, is discussed (Schemes 11.2 and 11.3). 

This chapter presented the current stage of development in the desymmetrization of mt >o-com pounds and (dynamic) kinetic resolution of racemic compounds in which cinchona alkaloids or their derivatives are used as organocatalysts. As shown in many of the examples discussed above, cinchona alkaloids and their derivatives effectively promote these reactions by either a monofunctional base (or nucleophile) catalysis or a bifunctional activation mechanism. Especially, the cinchona-catalyzed alcoholytic desymmetrization of cyclic anhydrides has already reached the level of large-scale synthetic practicability and, thus, has already been successfully applied to the synthesis of key intermediates for a variety of industrially interesting biologically active compounds. However, for other reactions, there is still room for improvement... 

Desymmetrization and Dynamic Kinetic Resolution Processes Using Covalent and Non-covalent Strategies... 

Suzuki-Miyaura coupling (Scheme 13.6). Detailed studies revealed that the transmetalation step is stereospeeifle and this step is likely to be stereochemistry determining. They also believe that the stereoselective transmetalation might oeeur either by a desymmetrization if both boronates are equivalent or by a dynamic kinetic resolution if the geminal boron atoms are not equivalent. 

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. 

ENANTIOPURE COMPOUNDS RESOLUTIONS, DESYMMETRIZATIONS, AND DYNAMIC KINETIC RESOLUTIONS... 

The most common application of hydrolase-catalyzed reactions is the preparation of enantiopure compounds. The three possible routes are kinetic resolutions, desymmetrizations and dynamic kinetic resolutions (Figure 5.3 [21-23]). The choice of substrate determines the possible routes. If the substrate is a racemate, then the choice is either a kinetic resolution or a dynamic kinetic resolution. If the substrate is a meso or prochiral compound, then the route is a desymmetrization. Since racemates are more numerous than meso or prochiral compounds, the most common routes are resolutions. 

Three routes to enantiopure compounds using hydrolase-catalyzed reactions, (a) Kinetic resolution starts with racemic substrate and converts one enantiomer into product. This separation yields one enantiomer as the product alcohol and one as the starting acetate, both with a maximum yield of 50%. (b) Desymmetrization of a prochiral compound transforms one of prochiral groups to yield a chiral product with a maximum yield of 100%. (c) A dynamic kinetic resolution combines rapid racemization of racemic starting material with a hydrolase catalyzed acylation of one enantiomer. The maximum yield is 100%. 

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. 

The enantioselective acylation of alcohols, and amine reactions by lipases and esterases in organic synthesis with examples of classical and dynamic kinetic resolutions of racemates, are shown, giving attention to the desymmetrization of meso-compoxmds. 

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