Enantioconvergent hydrolysis

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

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.

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

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. 

Also, the scope of suitable substrates has been explored. Thus, it was shown that substituted styrene derivatives such as various para-substituted styrene oxides [204] as well as )3-disubstituted derivatives [176] could be accommodated by one or both of these fungi. In the latter case, an interesting enantioconvergent hydrolysis of cz5-methyl substituted styrene oxide was observed, affording an 85% preparative yield of enantiopure (lP,2A)-diol. Further screening conducted on various other fungal strains indicated that this type of enzyme does indeed seem to be widespread within the fungal world [149,205]. 

Finally, a chemoenzymatic enantioconvergent procedure led to (S)-ibuprofen in four steps and 47% overall yield (Fig. 11.2-20). The latter compound is a widely used antiinflammatory drug and pain remedy and is one of the top ten drugs sold worldwide l,HH. In the key step, the conditions for the enantioconvergent hydrolysis of para-iso-butyl-a-methylstyrene oxide was optimized (elevated substrate concentration at +4 °C) to afford the non-reacted epoxide in >95 % ee[136l After separation from the epoxide, the formed diol (70% ee) was recycled via a two-step sequence via the corresponding bromohydrin, which was cyclized back to give ( )-epoxide. The latter material was subjected to repeated biocatalytic resolution in order to improve the economy of the process. 

Scheme 2.3 Enantioconvergent hydrolysis of styrene epoxides by Vigna radiata epoxide hydrolases.

Figure 2.7 Regioselectivity of VrEHl in enantioconvergent hydrolysis of (R)- and (S )-pNSO. For the (R)-pNSO enantiomer, VrEHl mainly attacks the Cj, position of the epoxide, resulting in retention of the configuration and formation of (R)-diol with 87% probability, while it attacks the position affording (S)-diol with merely 13% probability. On the other hand, for (Sl-pNSO, VrEHl mainly attacks (83%), resulting in inversion of the configuration and formation of (R)-diol, whereas it attacks affording (S )-diol with 17% probability.

In order to circumvent the disadvantages of kinetic resolution, several protocols were developed towards the enantioconvergent hydrolysis of epoxides, which lead to a single enantiomeric vicinal diol as the sole product from the racemate. 

Scheme 4.49 Enantioconvergent hydrolysis of racemic sulfate esters using a sulfatase.

Steinreiber, A., Mayer, S.R, Saf, R. and Faber, K. (2001) Biocatalytic asymmetric enantioconvergent hydrolysis of trisubstituted oxiranes. Tetrahedron Asymmetry, 12,1519-1528. 

Scheme 14 IQnetics of the enantioconvergent hydrolysis of rac-ci5-2-heptene oxide elucidated by 0-labeling experiments.

A crude enzyme preparation from the antennae of 1-day-old male gypsy moth (Lymantria dispar) was found to catalyze the enantioconvergent hydrolysis of ( )-disparlure 3.25 to the corresponding (7/ ,5J )-diol. However, for a single experiment, the antennae of 50 gypsy moths were required to provide just enough enzyme for the reaction, even at prolonged incubation times. It is obvious that this excludes these enzymes from practical applications. 

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