Chemoenzymatic asymmetric total syntheses of a constituent of Jamaican rum and of (+)-Pestalotin using an enantioconvergent enzyme-triggered cascade reaction

Mayer, Sandra F.; Steinreiber, Andreas; Goriup, Marian; Saf, Robert; Faber, Kurt

doi:10.1016/s0957-4166(02)00124-6

Cited by 13 publications

(11 citation statements)

References 12 publications

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“…In 2002 Faber and coworkers described a chemoenzymatic route to two natural products, a constituent of Jamaican rum and the (+)-antipode of the gibberellin synergist (−)-pestalotin, starting from rac-cis-1-chloro-2,3-epoxyheptane [17]. …”

Section: Pestalotin: Jamaican Rum Constituentmentioning

confidence: 99%

“…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].…”

Section: Introductionmentioning

confidence: 99%

“…Enantiopure epoxides and diols are chiral intermediates or building blocks which can be used for the synthesis of biologically active compounds, such as antibiotics (Ueberbacher et al, 2005), antifungal drugs (Monfort et al, 2004), antiandrogens (Fujino et al, 2007), receptor agonists and antagonists (Pedragosa-Moreau et al, 1997;Genzel et al, 2002;Monterde et al, 2004), 11-heterosteroids (Bottalla et al, 2007), HIV-protease inhibitors (Zhang et al, 1995;Pedragosa-Moreau et al, 1996a), nonsteroidal anti-inflammatory drugs (Chen et al, 1993;Cleij et al, 1999) and other natural products (Kroutil et al, 1997b;Orru et al, 1998b;Steinreiber et al, 2001c;Mayer et al, 2002a;Edegger et al, 2004). An EH-triggered cascade reaction enabled the asymmetric synthesis of two antitumor agents which occur naturally in Panax ginseng (Mayer et al, 2002b).…”

Section: Introductionmentioning

confidence: 99%

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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: Pestalotin: Jamaican Rum Constituentmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Epoxide Hydrolases and their Application in Organic Synthesis

2016

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“…There are only a few references in the recent literature, which refer to this enzyme [60,78]. Other EH producing R. ruber strains used in recent studies were DSM44540, DSM44541, DSM44539, DSM43338, SM1789, and SM1790 [62,[78][79][80][81]. There are significant differences in the activity and enantioselectivity of the EHs produced by the different R. ruber strains [62,79,81].…”

Section: Commercially Available Epoxide Hydro-lasesmentioning

confidence: 99%

Diversity of Epoxide Hydrolase Biocatalysts

Labuschagne¹

2006

COC

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Chiral epoxides and their derivatives are versatile intermediates for the synthesis of enantiopure organic chemicals. Chiral epoxides can be obtained through asymmetric epoxidation using either chemical catalysts or epoxidizing enzymes such as monooxygenases or chloroperoxidases. Alternatively hydrolytic kinetic resolution of racemic epoxides can yield a mixture containing, in an ideal situation, a single enantiomer of the remaining epoxide and a single enantiomer of the formed diol. Occasionally catalysts with complementary enantioselectivities and opposite regioselectivities can give through enantioconvergent hydrolysis one diol enantiomer in > 90% yield. Hydrolyses can also be performed with either metal catalysts or biological catalysts, mainly epoxide hydrolases. Epoxide hydrolases show great promise for the preparative scale hydrolysis of epoxides, because they are easy-to-use biocatalysts that accept a wide range of substrates, that do not require co-factors and that show improved activity when the substrate is present as a second water immiscible phase. X-ray structures for one fungal, one bacterial and two mammalian epoxide hydrolases are available as well as gene sequences for more than ninety five epoxide hydrolases. Expression systems in Escherichia coli and other hosts have also been developed and different assays suitable for high throughput screening have been developed and tested. The latter developments also made possible the first attempts at catalyst improvement through site directed mutagenesis and directed evolution. This review will give a comparative overview of the different types of epoxide hydrolases, which recently gave promising results for hydrolytic kinetic or enantioconvergent resolution of different types of epoxides and of results obtained with various recombinant epoxide hydrolases.

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“…Enantiocomplementary hydrolases include esterases, lipases, and proteases,13 epoxide hydrolases,14 hydantoinases,15 and lactamases 16. Serine proteases and lipases have approximately mirror‐image active sites and thus usually prefer opposite enantiomers of secondary alcohols and primary amines (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Enantiocomplementary Enzymatic Resolution of the Chiral Auxiliary: cis,cis‐6‐(2,2‐Dimethylpropanamido)spiro[4.4]nonan‐1‐ol and the Molecular Basis for the High Enantioselectivity of Subtilisin Carlsberg

et al. 2004

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cis,cis-(+/-)-6-(2,2-Dimethylpropanamido)spiro[4.4]nonan-1-ol, 1, a chiral auxiliary for Diels-Alder additions, was resolved by enzyme-catalyzed hydrolysis of the corresponding butyrate and acrylate esters. Subtilisin Carlsberg protease and bovine cholesterol esterase both showed high enantioselectivity in this process, but favored opposite enantiomers. Subtilisin Carlsberg favored esters of (1S,5S,6S)-1, while bovine cholesterol esterase favored esters of (1R,5R,6R)-1, consistent with the approximately mirror-image arrangement of the active sites of subtilisins and lipases/esterases. A gram-scale resolution of 1-acrylate with subtilisin Carlsberg yielded (1S,5S,6S)-1 (1.1 g, 46 % yield, 99 % ee) and (1R,5R,6R)-1-acrylate (1.3 g, 44 % yield, 99 % ee) although the reaction was slow. The high enantioselectivity combined with the conformational rigidity of the substrate made this an ideal example to identify the molecular basis of the enantioselectivity of subtilisin Carlsberg toward secondary alcohols. When modeled, the favored (1S,5S,6S) enantiomer adopted a catalytically productive conformation with two longer-than-expected hydrogen bonds, consistent with the slow reaction rate. The unfavored (1R,5R,6R) enantiomer encountered severe steric interactions with catalytically essential residues in the model. It either distorted the catalytic histidine position or encountered severe steric strain with Asn155, an oxyanion-stabilizing residue.

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Chemoenzymatic asymmetric total syntheses of a constituent of Jamaican rum and of (+)-Pestalotin using an enantioconvergent enzyme-triggered cascade reaction

Cited by 13 publications

References 12 publications

Epoxide Hydrolases and their Application in Organic Synthesis

Epoxide Hydrolases and their Application in Organic Synthesis

Diversity of Epoxide Hydrolase Biocatalysts

Enantiocomplementary Enzymatic Resolution of the Chiral Auxiliary: cis,cis‐6‐(2,2‐Dimethylpropanamido)spiro[4.4]nonan‐1‐ol and the Molecular Basis for the High Enantioselectivity of Subtilisin Carlsberg

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