Microbiological Transformations 43. Epoxide Hydrolases as Tools for the Synthesis of Enantiopure α-Methylstyrene Oxides:  A New and Efficient Synthesis of (S)-Ibuprofen

Abstract

Biohydrolysis of various α-methylstyrene oxide derivatives, differently substituted at the aromatic ring, was investigated using 10 epoxide hydrolases from different origins. Our results indicate that the enantioselectivity of these biohydrolyses strongly depends on the nature of the enzyme and of the substituent. Using some of these enzymes, this approach allows to prepare these epoxides in high optical purity. The potentiality to perform efficient preparative-scale resolution using such a biocatalyst was illustrated by the four-step synthesis of (S)-ibuprofen, a nonsteroidal antiinflammatory drug and household pain killer, one of the top-ten drugs sold worldwide. Using a combined chemoenzymatic strategy, we were thus able to set up a four-step enantioconvergent procedure allowing for the synthesis of this compound in optically pure form and with a 47% overall yield, including the resolution process, due to a possible recycling of the formed diol via chemical racemisation.

Colorimetric Assays for Quantitative Analysis and Screening of Epoxide Hydrolase Activity

“…The calculated ratio V SO[R] / V SO[S] is 9.5, a value in the same order of magnitude of the enantioselectivity constant, E, determined in different conditions with usual methods (Pedragosa-Moreau et al 1993, Cleij et al 1999. Therefore, the velocity ratio gives a good indication on the EH selectivity and can be used in screening on enantioselectivity.…”

Epoxide Hydrolases and their Application in Organic Synthesis

“…One year later, the same authors studied the biohydrolysis of seven differently substituted α-methylstyrene oxide derivatives, including the para-bromo-α-methyl styrene oxide, using ten different EHs [14]. The best results were obtained with the rac H…”

“…Enantiopure epoxides and diols are chiral intermediates or building blocks, which can be used for the synthesis of biologically active compounds such as antibi otics [4], antifungal drugs [5], antiandrogens [6], receptor agonists and antagonists [7][8][9], 11-heterosteroids [10], HIV protease inhibitors [11,12], nonsteroidal antiinflammatory drugs [13,14], and other natural products [15][16][17][18][19]. An EH-triggered cascade reaction enabled the asymmetric synthesis of two antitumor agents, which occur naturally in Panax ginseng [20].…”

Biocatalysis as an alternative for the production of chiral epoxides: A comparative review

“…1, and Tables 1 and 2). Several preparative-scale EH-catalyzed hydrolytic kinetic resolutions have been reported for the synthesis of enantiopure intermediates such as Eliprodil and (S)-Ibuprofen [148,149].…”

“…Most of the bacterial EHs showed a preference for the (S)-2,2-disubstituted enantiomer, providing the (R)-epoxides with over 99% ee [176,[180][181][182][183]. EHs with the opposite enantioselectivity to yield (S)-epoxides are also available ( Table 2, entry 2) [149,161,[183][184][185], an illustration of which is the synthesis of (S)-p-isobutyl-␣-methyl styrene oxide (96% ee) that serves as an intermediate for (S)-Ibuprofen catalyzed with a strain of A. niger [149]. In the EH-catalyzed resolution of trans-2,3-disubstituted epoxides (17), mixed enantio-preference is common, which can provide enantio-complementary chiral epoxides simply by the choice of the appropriate enzymes or EH-containing strains ( [158,161,186], while the opposite enantio-preference with high selectivity is rare.…”