Enantioconvergence

A number of previous reviews [2-6] have dealt with both deracemization and enantioconvergent processes and hence this chapter will focus primarily on the recent literature. 

Figure 5.1 Schematic illustration of (a) dynamic kinetic resolution, (b) deracemization, and (c) enantioconvergent processes.

As outlined above, enantioconvergent processes require two separate reaction pathways in order to transform a racemic substrate into a single product enantiomer. This is accomplished by employing a catalyst, which transforms one of the substrate enantiomers to the product with retention of configuration. Concurrently, another catalyst, with opposite enantioselectivity and opposite regioselectivity, transforms the other substrate enantiomer with inversion of configuration (Figure 5.24). 

Furstoss et al. have reported their studies on the use of an epoxide hydrolase with four styrene oxide derivatives (Figure 5.26) [39]. The (R)-diol (43) was obtained in 91% ee at 100% conversion from racemic (42), demonstrating an enantioconvergent... 

Figure 5.25 Enantioconvergent hydrolysis of epoxides (35) to the corresponding diols (36) using mung bean epoxide hydrolase.

An enantioconvergent transformation leads to a single enantiomeric product from a racemate [51]. Each enantiomer is transformed via independent pathways by the same catalyst or by two different catalysts (Figure 6.6). For example, the hydrolysis of epoxides may proceed with high regio- and stereoselectivity vdth inversion or retention of configuration. Several enantioconvergent transformations of epoxides are reported in the last section of this chapter. 

Enantioconvergent hydrolysis of para-chlorostyrene oxide (Figure 6.67) using a one-pot sequential bienzymatic strategy provided the corresponding (R)-diol in high yield (96% ee, yield = 93%) [186]. The second enzyme was added after about 50% conversion because the first one was sensitive to inhibition by the (R)-diol. 

Figure 6.66 Enantioconvergent hydrolysis of styrene oxides using two biocatalysts.

Figure 6.68 Enantioconvergent hydrolysis of m-chlorostyrene oxide using a single biocatalyst.

The enantioconvergent biohydrolysis of m-chlorostyrene oxide (Figure 6.68) in the presence of a recombinant S. tuberosum EH afforded the corresponding (JJ)-diol in a nearly quantitative yield [187]. The (S)-epoxide was attacked at the benzylic (more substituted) carbon whereas the (R)-epoxide was attacked at the terminal (less substituted) carbon. 

Figure 6.69 An enantioconvergent enzyme-triggered cascade reaction.

Figure 6.70 Enantioconvergent hydrolysis of a trisubstituted epoxide using a single enzyme.

The enantioconvergent biohydrolysis of sterically demanding trisubstituted oxiranes has also been reported [189,190]. For instance, the enantioconvergent hydrolysis of a trisubstituted rac-epoxide (Figure 6.70) was a key step in the chemoenzymatic synthesis of a volatile constituent of the beer aroma [190]. 

Figure 6.72 shows an enantioconvergent multistep process leading to an enantio-pure epoxide. The racemic epoxide was resolved by A. niger EH leading to the (R)-diol and the residual (S)-epoxide with excellent optical purity [195]. The chemical... 

Figure 6.71 Enantioconvergent hydrolysis of a 2,2-disubstituted epoxide by combined bio- and chemocatalysts.

Figure 6.72 An enantioconvergent process leading to an enantiopure epoxide.

Biooxidative deracemization of racemic sec-alcohols to single enantiomers [47,48] is complementary to combined metal-assisted lipase-mediated strategies [49,50]. In general, deracemization can be realized by either an enantioconvergent, a dynamic kinetic resolution, or a stereoinversion process. The latter concept is particularly appealing, as only half of the substrate needs to be converted, as the remaining half already represents the product with correct stereochemistry. 

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

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. 

Lee, E.Y. and Shuler, M.L. (2007) Molecular engineering of epoxide hydrolase and its application to asymmetric and enantioconvergent hydrolysis. Biotechnology and Bioengineering, 98, 318-327. 

---