Deracemization chemoenzymatic

Stereoinversion Stereoinversion can be achieved either using a chemoenzymatic approach or a purely biocatalytic method. As an example of the former case, deracemization of secondary alcohols via enzymatic hydrolysis of their acetates may be mentioned. Thus, after the first step, kinetic resolution of a racemate, the enantiomeric alcohol resulting from hydrolysis of the fast reacting enantiomer of the substrate is chemically transformed into an activated ester, for example, by mesylation. The mixture of both esters is then subjected to basic hydrolysis. Each hydrolysis proceeds with different stereochemistry - the acetate is hydrolyzed with retention of configuration due to the attack of the hydroxy anion on the carbonyl carbon, and the mesylate - with inversion as a result of the attack of the hydroxy anion on the stereogenic carbon atom. As a result, a single enantiomer of the secondary alcohol is obtained (Scheme 5.12) [8, 50a]. 

Scheme 5.14 Chemoenzymatic enantioconvergent deracemization of secondary alcohols via hydrolysis of their sulfate esters.

Finally, natural (i )-(-)-mevalonolactone, a key intermediate from a broad spectrum of cellular biological processes and their regulation, was synthesised via eight steps in 55% overall yield and > 99% ee (Scheme 19). In the key step, the aforementioned enantioconvergent chemoenzymatic deracemization route was applied. Thus, 2-methyl-2-benzyl-oxirane ( )-2 g was deracemized on a large scale (10 g) using lyophilized cells of Nocardia EHl and sulfuric... 

Chemoenzymatic processes involving oxidizing enzymes have been reported particularly for specific chemical syntheses. For example, industrially important amino acids can be deracemized by exploiting the enantioselectivity of amino acid oxidases a commercial process has recently been developed in which efficient... 

During the past few years great efforts have been made to overcome the 50% threshold of enzyme-catalyzed KRs. Among the methods developed, deracemization processes have attracted considerable attention. Deracemizations are processes during which a racemate is converted into a non-racemic product in 100% theoretical yield without intermediate separation of materials [5]. This chapter aims to provide a summary of chemoenzymatic dynamic kinetic resolutions (DKRs) and chemoenzymatic cyclic deracemizations. 

It should be mentioned that the great majority of dynamic kinetic resolutions reported so far are carried out in organic solvents, whereas all cyclic deracemizations are conducted in aqueous media. Therefore, formally, this latter methodology would not fit the scope of this book, which is focused on the synthetic uses of enzymes in non-aqueous media. However, to fully present and discuss the applications and potentials of chemoenzymatic deracemization processes for the synthesis of enantiopure compounds, chemoenzymatic cyclic de-racemizations will also be briefly treated in this chapter, as well as a small number of other examples of enzymatic DKR performed in water. 

The first example of chemoenzymatic DKR of allylic alcohol derivatives was reported by Williams et al. [37]. Cyclic allylic acetates were deracemized by combining a lipase-catalyzed hydrolysis with a racemization via transposition of the acetate group, catalyzed by a Pd(II) complex. Despite a limitation of the process, i.e. long reaction times (19 days), this work was a significant step forward in the combination of enzymes and metals in one pot Some years later, Kim et al. considerably improved the DKR of allylic acetates using a Pd(0) complex for the racemization, which occurs through Tt-allyl(palladium) intermediates. The transesterification is catalyzed by a lipase (Candida antarctica lipase B, CALB) using isopropanol as acyl acceptor (Scheme 5.19) [38]. 

In Section 5.3.1, chemoenzymatic cyclic deracemizations or stereoinversions are categorized according to the type of substrate, namely amino acids, hydroxy acids,... 

An important breakthrough was made very recently in this area. A chemoenzymatic method developed by Turner has allowed the cyclic deracemization of tertiary amines [80]. Enantiopure tertiary amines cannot be obtained via DKR. One of the variants obtained by directed evolution of the monoamine oxidase from Aspergillus niger showed high activity and enantioselectivity toward cyclic tertiary amines (Scheme 5.40). 

Faber, K. Chemoenzymatic deracemization of ( )-2,2-disubstituted oxiranes. Tetrahedron 1998, 54, 859-874. 

Scheme 13.19 Chemoenzymatic deracemization with D-amino acid oxidase and chemical reduction.

Fig. 21. Deracemization of p-nitrostyrene oxide by a chemoenzymatic process. Application to the synthesis of (R)-Nifenalol [211]...

R. V.A. Orm, W. Kroutil, K. Faber, Deracemization of (+/-)-2,2-disubstituted epoxides via enantioconvergent chemoenzymatic hydrolysis using Nocardia EHl epoxide hydrolase and sulfuric acid. Tetrahedron Lett. 38 (1997) 1753-1754. 

In 1996, Archer et al. reported a highly enantioselective chemoenzymatic resolution of rac-l-methyl-l,2-epoxycyclohexane using whole cells of Corynebacterium C12, giving rise to the (li ,2S)-epoxide in >99% ee (30% )deld) and the (lS,2S)-diol in 92% ee (42% yield) [134]. Further, an additional efficient chemoenzymatic deracemization process was run in tandem using the EH from Corynebacterium C12 and perchloric acid for the acid-catalyzed ring opening of the residual epoxide (Figure 8.25). 

Chemoenzymatic resolution and deracemization of rac-1-methyl-1,2-epoxycyclohexane using whole cells of Corynebacterium C12. 

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