Microbiological transformations. Part 39: Determination of the regioselectivity occurring during oxirane ring opening by epoxide hydrolases: a theoretical analysis and a new method for its determination

Moussou, Philippe; Archelas, Alain; Baratti, J.; Furstoss, R.

doi:10.1016/s0957-4166(98)00122-0

Cited by 77 publications

(44 citation statements)

References 26 publications

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“…Three similar and interesting enan tioconvergent processes were described using fungal EHs from B. sulfurescens ATCC7159 [115], Aspergillus terreus [58], and the metagenome-derived EH Kau2 [32]. Indeed, it was observed that the two antipodes were hydrolyzed with a low enantio selectivity (E-value = 10) and an opposite regioselectivity, leading to the formation of the same (1R,2R)-diol in almost optically pure form and nearly quantitative yield (Figure 8.16).…”

Section: Cis-and Trans-β-methylstyrene Oxidementioning

confidence: 99%

Epoxide Hydrolases and their Application in Organic Synthesis

2016

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c h a p t e r 8 INTRODUCTIONOrganic chemists have become interested in enzymes as catalysts due to their high efficiencies and specificities. Moreover, recent progress in molecular biology and enzyme-related research areas enabled and simplified the production and purifica tion of recombinant enzymes in large quantities and their engineering toward tailormade biocatalysts using straightforward mutagenesis and screening techniques. This is also true for epoxide hydrolases (EHs), as evidenced by the many published research papers about the synthetic applications of naturally occurring or engi neered EHs. EHs catalyze the opening of oxirane rings, generating a vicinal diol as the final product ( Figure 8.1). From a synthetic chemistry point of view, the most valuable EHs are those with either (i) high enantioselectivities or (ii) a combination of low enantio preference with a high level of enantioconvergence. While the former generate enan tiopure epoxides with a maximum yield of 50% in a kinetic resolution process, the latter produce ideally an enantiopure diol product with a theoretical yield of 100%. Thus, EHs provide convenient access to enantiopure epoxides or diols from racemic epoxides. Furthermore, the enantiopure diols can then often be chemically trans formed back to the corresponding epoxides with no effect on the enantiomeric excess (ee). High values of enantioselectivity or enantioconvergence are a consequence of particular enzyme-substrate interactions, which can be modulated by specific reac tion conditions or through the exchange of specific amino acids of the biocatalyst. The final stereochemical outcome of an EH-catalyzed reaction depends solely on the regioselectivity coefficients, which determine the absolute configuration and the ee of the diol product when the reaction reaches 100% conversion. During the reaction, the oxirane ring of each enantiomer is often attacked at either carbon atom, resulting in a mixture of diol enantiomers (Figure 8.2). Unfortunately, several authors used the product-derived E-value, E P (calculated from c and ee P using Sih's equation; see Ref.[1]) for characterizing the stereochemistry of the diol formation of an EH-mediated hydrolysis reaction [2,3]. This is wrong and misleading for epoxide-opening reac tions since there are two possible positions of attack for each oxirane enantiomer. The ideal enantioconvergent EH leads to deracemization of a racemic mixture of an epox ide and exhibits reversed regioselectivity for either substrate enantiomer, that is,

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Section: Cis-and Trans-β-methylstyrene Oxidementioning

confidence: 99%

Epoxide Hydrolases and their Application in Organic Synthesis

2016

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“…Hence, the regioselectivity of this attack can be different from one enantiomer to the other. [13] As a consequence, the absolute configuration and the ee of the formed diol (eep) depend upon two combined factors, that is, the enantioselectivity and the regioselectivity of the oxirane ring opening. This leads to the conclusion that Sihs [14] [E = fA C H T U N G T R E N N U N G (c,eep)] and Straathofs [15] [E = fA C H T U N G T R E N N U N G (ees,eep)] equations, both implying the ee of the product, can generally not be used without previous determination of the regioselectivity coefficients.…”

Section: Theoretical Commentsmentioning

confidence: 99%

“…This leads to the conclusion that Sihs [14] [E = fA C H T U N G T R E N N U N G (c,eep)] and Straathofs [15] [E = fA C H T U N G T R E N N U N G (ees,eep)] equations, both implying the ee of the product, can generally not be used without previous determination of the regioselectivity coefficients. [13] However, in the special case of spiroepoxide 1, these restrictions are not to be considered, since neither carbon atom of the oxirane ring is a stereogenic centre. Indeed, the chirality of the molecule is not born by the epoxide moiety itself, but by the two carbon atoms adjacent to the oxirane (i.e., the ones bearing a vinyl group) which are, in each specific enantiomer, of identical absolute configuration [i.e., (R,R) or (S,S)].…”

Section: Theoretical Commentsmentioning

confidence: 99%

Epoxide Hydrolase‐Catalysed Kinetic Resolution of a Spiroepoxide, a Key Building Block of Various 11‐Heterosteroids

et al. 2007

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Two microbial epoxide hydrolases -i.e., Aspergillus niger (AnEH) and Rhodococcus erythropolis (the so-called "Limonene EH": LEH) were used to achieve, for the first time, the biocatalysed hydrolytic kinetic resolution (BHKR) of spiroepoxide rac-1. This compound is a strategic key building block allowing the synthesis of 11-heterosteroids. Interestingly enough, the two enzymes exhibited opposite and therefore complementary enantioselectivity allowing us to isolate the residual (R,R)-1 (from AnEH) and the residual (S,S)-1 (from LEH) in nearly enantiopure forms (> 98 %). Their absolute configurations were determined by X-ray crystallography. An opposite regioselectivity of the oxirane ring opening for both enantiomers of substrate 1, determined using H 2 18O labelling and chiral GC-MS analysis, was also observed, corresponding to an attack at the less substituted carbon atom using AnEH, and at the most substituted carbon atom using LEH. A chemical process-improving methodology was also developed. This allowed us to obtain both enantiomers of the substrate in high enantiomeric purity (99 %) and optimised quantity. In the case of the AnEH, the use of a biphasic (water/isooctane) reaction medium allowed us to increase the global substrate concentration up to 200 g/ L. The preparation of both enantiomers of 1 clearly paves the way to the preparative scale synthesis and biochemical evaluation of the corresponding 11-heterosteroid enantiomers.

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“…This can formally occur at both carbon atoms of the oxirane ring, and we have previously shown that, depending on the regioselectivity coefficients, this will govern the stereochemical outcome of the reaction. [19,20] In order to check this point the E value was calculated, at different conversion values of rac-1, on the basis of the ee of the residual epoxide and of the formed diol. This led to very similar values (E = 14, 14, 15 and 15), indicating that the oxirane ring was attacked with a high regioselectivity on one single carbon atom.…”

Section: Determination Of Various Reaction Parameters Semi-preparatimentioning

confidence: 99%

Enzymatic Transformations 62. Preparative Scale Synthesis of Enantiopure Glycidyl Acetals using an Aspergillus niger Epoxide Hydrolase‐Catalysed Kinetic Resolution

2006

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Abstract:The hydrolytic kinetic resolution of five glycidaldehyde acetal derivatives was examined using the recombinant Aspergillus niger epoxide hydrolase as biocatalyst. This could successfully be performed, at room temperature, using solely demineralised water as solvent and following a two-phase methodology allowing us to operate at a global substrate concentration as high as 200 g/L in the reactor. The observed E values were shown to be modest to excellent, depending on the structure of the acetal moiety, indicating that it is possible to achieve this resolution very efficiently just by choosing the right substituents. Both the unreacted (R)-epoxide and the formed (S)-diol could thus be obtained in good to excellent ee (ee > 99 % for the epoxide). For the best substrates, the reaction could be performed within a few hours by using a biocatalyst over substrate molecular ratio of about 9 to 10 × 10 À4 mol %. The turnover frequency (TOF) as well as the total turnover number (TON) of the enzyme proved to be excellent as compared to chemical catalysts -reaching respectively values in the order of 6 × 10 2 mol sub/mol enz/ min and 6 × 10 4 mol sub/mol enz. The space-time yield of the best (two-phase) reactor could thus reach a value as high as 56 g/L/hour. As a demonstration experiment, a 50-g scale resolution of glycidaldehyde 2,2-dimethyltrimethylene acetal was performed.

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Microbiological transformations. Part 39: Determination of the regioselectivity occurring during oxirane ring opening by epoxide hydrolases: a theoretical analysis and a new method for its determination

Cited by 77 publications

References 26 publications

Epoxide Hydrolases and their Application in Organic Synthesis

Epoxide Hydrolases and their Application in Organic Synthesis

Epoxide Hydrolase‐Catalysed Kinetic Resolution of a Spiroepoxide, a Key Building Block of Various 11‐Heterosteroids

Enzymatic Transformations 62. Preparative Scale Synthesis of Enantiopure Glycidyl Acetals using an Aspergillus niger Epoxide Hydrolase‐Catalysed Kinetic Resolution

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