Oxidation-reduction deracemization process

Figure 5.2 Cyclic deracemization process involving sequential enzyme-catalyzed oxidation and nonenzymatic reduction.

Note at the outset that asymmetric catalysis in the synthesis of fine chemicals is rarely a single-step process that converts a reactant directly to the final product. It is usually one of the steps in a total synthesis but is often the key step. Hence the analysis of the overall yield will be based on the methods described in Chapter 5. There are many types of reactions where asymmetric catalysis can be applied. The most important of these are C-C bond-forming reactions such as alkylation or nucleophilic addition, oxidation, reduction, isomerization, Diels-Alder reaction, Michael addition, deracemization, and Sharpless expoxidation (of allyl alcohols). A few representative examples (homogeneous and heterogeneous) are given in Table 9.6. 

Assuming that the enzymatic reaction is highly enantioselective, then even after only four cycles the enantiomeric excess will have reached 93.4% whereas after seven catalytic cycles the enantiomeric excess is >99% (Figure 5.3). This type of deracemization is really a stereoinversion process in that the reactive enantiomer undergoes stereoinversion during the process. One of the challenges of developing this type of process is to find conditions under which the enzyme catalyst and chemical reactant can coexist, particularly in the case of redox chemistry in which the coexistence of an oxidant and reductant in the same reaction vessel is difficult to achieve. For this... 

An elegant four-enzyme cascade process was described by Nakajima et al. [28] for the deracemization of an a-amino acid (Scheme 6.13). It involved amine oxidase-catalyzed, (i )-selective oxidation of the amino acid to afford the ammonium salt of the a-keto acid and the unreacted (S)-enantiomer of the substrate. The keto acid then undergoes reductive amination, catalyzed by leucine dehydrogenase, to afford the (S)-amino acid. NADH cofactor regeneration is achieved with formate/FDH. The overall process affords the (S)-enantiomer in 95% yield and 99% e.e. from racemic starting material, formate and molecular oxygen, and the help of three enzymes in concert. A fourth enzyme, catalase, is added to decompose the hydrogen peroxide formed in the first step which otherwise would have a detrimental effect on the enzymes. 

Deracemization by stereoinversion is a process in which one form (S of the racemic starting material (Rf -i- Sf) is enantioselectively transformed into an intermediate (Si) which can in turn react to give the form of opposite configuration (Rf). An example of this method could be the selective oxidation of one enantiomer of a racemic secondary alcohol and the subsequent reduction with a catalyst of opposite stereopreference [2]. 

Asymmetric synthesis of amines is a synthetically important research area due to the broad range of applications of chiral amines in fhe field of pharmaceuticals [134]. Amine oxidases are a versatile class of catalysts, which turned out to be very suitable for the preparation of chiral amines by means of desymmetrization or deracemization reactions. With respect to the latter, a racemic amine is enantioselectively oxidized by the amine oxidase, and simultaneously the in situ-formed imines or iminium ions, respectively, are reduced in a nonenantioselective chemical reduction process (with typically a borohydride) back to the racemic amine [135]. The key catalyst for such a... 

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