Enantiospecific synthesis of methyl 11,12- and 14,15-epoxyeicosatrienoate

doi:10.1016/S0040-4039(01)81200-4

Tetrahedron Letters

Volume 25, Issue 23, 1984, Pages 2443-2446

https://doi.org/10.1016/S0040-4039(01)81200-4 Get rights and content

Abstract

The methyl esters of the cytochrome P-450 epoxygenase metabolites 11(S),12(R)-and 14(R),15(S)-epoxyeicosatrienoic acid and some analogues were prepared enantiospecifically from 15(S)-HETE derived precursors.

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Enantioselective high-performance liquid chromatography analysis of oxygenated polyunsaturated fatty acids
2019, Free Radical Biology and Medicine
Citation Excerpt :
According to the results shown in Table 3, for three out of four racemic mixtures, enantioresolution was achieved with RP eluent systems, while 0.014% (v) 2-propanol in n-hexane was necessary to get 14,15-EET methyl ester enantiomers almost baseline separated. To apprise the enantiomeric elution order (EEO) with the optimal analysis conditions, the authors prepared enantiomerically pure 5,6-cis-, 8,9-cis-, 11,12-cis-and 14,15-cis-EETs via total asymmetric synthesis procedures [77–79]. Instead, racemic standards were achieved from arachidonic acid reported methods [80,81].
Oxygenated polyunsaturated fatty acids (PUFAs)play an outstanding role in the physiological and pathological regulation of several biological processes. These oxygenated metabolites can be produced both enzimatically, yielding almost pure enantiomers, and non-enzymatically. The free radical-mediated non-enzymatic oxidation commonly produces racemic mixtures which are used as biomarkers of oxidative stress and tissue damage. The biological activity of oxygenated PUFAs is often associated with only one enantiomer, making it necessary of availing of lipidomics platforms allowing to disclose the role of single enantiomers in health and disease.
Polysaccharide-based chiral stationary phases (CSPs) play a dominating part in this setting. As for the cellulose backbone, 4-methylbenzoate derivatives exhibit very high chiral recognition ability towards this class of compounds. Concerning the phenylcarbamate derivatives of cellulose and amylose, the tris(3,5-dimethylphenylcarbamate) variants show the best enantioresolving ability for a variety of oxygenated PUFAs. Moreover, also the amylose tris(5-chloro-2-methylphenylcarbamate)-based selector produces relevant chromatographic performances.
The extreme versatility of those CSPs mostly depends on their compatibility with the most relevant elution modes: normal- and reversed-phase, as well as polar organic/ionic-mode.
In this review article, a selection of enantioseparation studies of different oxygenated PUFAs is reported, with both tris(benzoates) and tris(phenylcarbamates) of cellulose and amylose.
Stereospecific synthesis of trans-arachidonic acids
2001, Bioorganic and Medicinal Chemistry Letters
Practical, enantiospecific syntheses of 14,15-EET and leukotoxin B (vernolic acid)
2001, Tetrahedron Letters
Human cytochromes P450
1999, Molecular Aspects of Medicine
The cytochrome P450 proteins (CYPs) are a family of haem proteins resulting from expression of a gene super-family that currently contains around 1000 members in species ranging from bacteria through to plants and animals. In humans, about 40 different CYPs are present and these play critical roles by catalyzing reactions in: (a) the metabolism of drugs, environmental pollutants and other xenobiotics; (b) the biosynthesis of steroid hormones; (c) the oxidation of unsaturated fatty acids to intracellular messengers; and (d) the stereo- and regio-specific metabolism of fat-soluble vitamins. This review deals with aspects of cytochrome P450s of relevance to human physiology, biochemistry, pharmacology and medicine. Topics reviewed include: pharmacogenetics of CYPs, induction and inhibition of these haem proteins, their role in metabolism of endogenous compounds such as steroids and eicosanoids, the effect of disease on CYP function, CYPs and cancer, and CYPs as targets of antibodies in immune-mediated diseases.
Metabolism of epoxyeicosatrienoic acids by cytosolic epoxide hydrolase: Substrate structural determinants of asymmetric catalysis
1995, Archives of Biochemistry and Biophysics
The metabolism of cis-epoxyeicosatrienoic acids (EETs), methyl cis-epoxyeicosatrienoates, and cis-epoxyeicosanoic acids by cytosolic epoxide hydrolase was studied to identify substrate structural features important for stereoselective metabolism and chiral diol formation. 14(R), 15(S)-, 11(S),12(R)-, and 8(S),9(R)-EET, the predominant enantiomers present endogenously in rat organs, were metabolized at substantially higher rates than their antipodes. With the exception of 8(R),9(S)-EET (K_m = 41 μM), differences in enantiomer hydration rates appear to be caused by K_m-independent factors since the apparent K_m values for the enantiomers of 14,15-, 11,12-, and 8(S),9(R)-EET were similar (between 3 and 5 μM). Chiral analysis of the diols resulting from enzymatic hydration of homochiral EETs showed that the regio and/or stereochemistry of water addition was EET regioisomer dependent. For the 11,12-EET enantiomers, water addition was nonregioselective; whereas, with both 8,9-EET antipodes water addition occurred predominantly at C9. Importantly, for 14,15-EET the regiochemistry of water addition was enantiomer-dependent. Only with 14(R),15(S)-EET did enzymatic hydration result in regiospecific addition at C15. Hence, enantioselective EET hydration is determined, principally, by enantiomer specific differences in rates of catalytic turnover and/or substrate binding parameters. On the other hand, the chirality of the diol products is determined by EET enantiomer-dependent differences in the regiochemistry of enzymatic oxirane cleavage and water addition. Esterification resulted in an overall reduction in the rates of epoxide hydration for all three EET-methyl esters (59, 89, and 68% of the EET rate for 8,9-, 11,12-, and 14,15-EET-methyl ester, respectively) and in the loss of regioselectivity during methyl 8(S),9(R)-EET oxirane cleavage. Catalytic EET hydrogenation reduced the rates of EET hydration (56, 45, and 23% of the EET rates for 8,9-, 11,12-, and 14,15-epoxyeicosanoic acids, respectively). Compared to 14,15-EET, enzyme catalyzed hydration of 14,15-epoxyeicosanoic acid was less regioselective and yielded products with a substantially lower chiral purity. Based on these data, as well as on the documentation of 14(R),15(R)-dihydroxyeicosatrienoic acid as an endogenous constituent of rat urine we concluded that: (1) cytosolic epoxide hydrolase plays a significant role in the regio- and stereoselective metabolism of endogenous EETs; (2) differences in the affinities and/or turnover rates of the enzyme for the individual EET antipodes may be responsible for enantioselective EET metabolism; and (3) for 14,15- and 8,9-EET, regioselective and/or enantioselective oxirane water addition is responsible for asymmetric diol formation. The protein spatial coordinates responsible for the asymmetry of EET hydration and diol formation must be circumscribed by a highly structured active site capable of recognizing, regio- and stereospecifically, overall substrate polarity, freedom of CC bond rotation, and/or protein-substrate π-π dipole interactions.
Direct resolution of epoxyeicosatrienoic acid enantiomers by chiral-phase high-performance liquid chromatography
1994, Journal of Chromatography B: Biomedical Sciences and Applications
A chromatographic method was developed to separate enantiomers of four regioisomeric epoxyeicosatrienoic acids (EETs), which are cytochrome P-450 monooxygenase products of arachidonic acid. Enantiomers of individual epoxyeicosatrienoic acids were separated by chiral-phase HPLC using Chiralcel OD columns. In contrast to the pre-derivatization of EETs, the method is simple and convenient. It can be readily used in analytical studies and in preparative applications. The method can also be applied to the separation of methyl ester derivatives of epoxyeicosatrienoic acid enantiomers.

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Enantiospecific synthesis of methyl 11,12- and 14,15-epoxyeicosatrienoate

Abstract

Biochem. biophys. Res. Comm.

Proc. Natl. Acad. USA

Biochem. Biophys. Res. Comm.

J. Amer. Chem. Soc.

J. Amer. Chem. Soc.

Tetrahedron Letters

Tetrahedron Letters