Cyclic Deracemization

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

Figure 5.3 Progression of an ideal cyclic deracemization process.

Finally in this section on deracemization via cyclic oxidation/reduction methods, there has been some limited work carried out on the deracemization of secondary alcohols. Soda et al. [22] employed lactate oxidase in combination with sodium borohydride to deracemize D/i-lactate (18) via the intermediate pyruvate (19) (Figure 5.12). 

Other racemization systems that may be amenable to conversion to deracemization processes in future have recently been reported by Faber and coworkers [33]. Resting cells of L. paracasei have been used for biocatalytic racemization of open-chain and cyclic dialkyl-, alkyl-aryl-, and diaryl-substituted acyloins (29/30) (Figure 5.20). Both... 

Upon mutagenesis of the monoamine oxidase from Aspergillus niger (MAO-N) within several rounds of directed evolution [65], variant biocatalysts were identified with largely expanded substrate acceptance, enabling also the deracemization of tertiary amines incorporating straight-chain and cyclic structural motifs [66]. 

Biocatalytic Deracemization Dynamic Resolution, Stereoinversion, Enantioconvergent Processes and Cyclic Deracemization, in Biocatalysts in the Pharmaceutical and Biotechnology industries, (ed. R.N. Patel), CRC Press, Boca Raton, pp. 27-51. 

In order to extend the approach to include deracemization of chiral secondary amines, this group carried out directed evolution on the monoamine oxidase (MAO) enzyme MAO-N (Scheme 2.32). A new variant was identified with improved catalytic properties towards a cyclic secondary amine 64, the substrate used in the evolution experiments. This new variant had a single point mutation, lle246Met, and was found to have improved catalytic properties towards a number of other cyclic secondary amines. The new variant was used in the deracemization of rac-64 yielding (R)-64 in high yield and enantiomeric excess [34]. 

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. 

This approach transforms a racemic compound into the enantiomerically pure form of the same compound. Cyclic deracemizations have been achieved for... 

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,... 

Scheme 5.35 Chemo-enzymatic deracemization of cyclic amino acids.

Deracemization of acyclic amino acids is more difficult than that of cyclic ones because of the higher instability of the imino acid intermediates toward hydrolysis (Scheme 5.36). 

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). 

E.3.2.2. Deracemization of Cyclic Substrates Although the ambiguity of synlanti geometry can be removed by the rigidity of the cyclic framework, the interaction between the ligand and a cyclic allyl substrate becomes quite different from that of acyclic systems because relatively... 

TABLE 8E.8. Deracemization of Cyclic Ally Substrates with Heteroatom Nucleophiles... 

Carr, R., Alexeeva, M., Dawson, M. J., Gotor-Fernandez, V., Humphrey, C. E., and Turner, N. J. 2005. Directed evolution of oxidase for the preparative deracemization of cyclic secondary amines. Chem. Bio. Chem.,6, 637-639. 

Kroutil, W., and Faber, K. 1998. Deracemization of compounds possessing a sec-alcohol or -amino group through a cyclic oxidation-reduction sequence a kinetic treatment. Tetrahedron Asymm., 9(16), 2901-2913. 

Chiral allenes can also be deracemized by photosensitization. Thus 2,3 pentadiene 28 was photoderacemized upon sensitization with the chiral aromatic steroid, 21,22-dihydroneoergosterol 29 to give 3.4% ee at the pss [16]. Cyclic allene 30 was also subjected to photoderacemization sensitized by (— )-menthy or ( — )-bomyl benzene(di)carboxylate, but the ees obtained were low (< 5%... 

Reactions with Oxygen Nucleophiles. The hist report of the reaction of oxygen nucleophiles was for the deracemization of cyclic allylic ethers, for example, the palladium(0)-catalyzed reaction of 2-cyclohexeny 1-1 -methyl carbonate with sodium pivalate afforded the pivalate ester in 94% yield and 92% ee. This reaction was extended to other cyclic allylic carbonates. 

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