Highly chemo-, regio-, and stereoselective introduction of a cis-double bond into a thia-analogue of stearic acid

Buist, Peter H.; Dallmann, H.; Rymerson, R. T.; Seigel, Peter M.

doi:10.1016/s0040-4039(01)81007-8

Cited by 21 publications

(7 citation statements)

References 6 publications

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“…TsCl was recrystallized from hexane/CHCl 3 before use. 8-Sulfanyloctanoic and 10-sulfanyldecanoic acids were prepared from the corresponding, commercially available bromo acids as described in [10]. In a similar manner, 7-sulfanylheptanoic and 9-sulfanylnonanoic acid were obtained from 7-bromoheptanoic acid and 9-bromononanoic acid, resp.…”

Section: Experimental Partmentioning

confidence: 99%

“…Use of DAST ((diethylamino)sulfur trifluoride) in this step was compromised by the fact that a significant reaction at the S-atom occurred to give the sulfoxy by-product. The intermediate alcohols 1a ± 1d were readily available via alkylation of the appropriate wthioacid [10] with the 3,4,5,6-tetrahydro-2H-pyran-2-yl (THP)-protected w-hydroxy alkyl bromides of the correct chain length. Oxidation of 2a ± 2d with 1 or 2 equiv.…”

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confidence: 99%

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ω‐Fluoro Thiafatty Acids: New Mechanistic Probes of Desaturase‐Mediated Reactions

Hodgson

Lao

Dawson

et al. 2003

Helvetica Chimica Acta

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Dedicated to Duilio Arigoni on the occasion of his 75th birthday A series of 18-fluoro thiastearates were prepared and incubated with a yeast D9-desaturating system. The relative efficiency of desaturase-mediated sulfoxidation was monitored via 19 F-NMR analysis of the sulfoxide products, and a strong preference for oxo transfer to the S-atom occupying the 9-position was confirmed. The oxidation profile obtained in this manner matched that of analogous experiments with non-fluorinated substrates. These results form the basis of a versatile 19 F-NMR-based method for mapping the position of the putative diiron oxidant relative to substrate, and has potential application to the study of membrane-bound desaturases in vitro.1. Introduction. ± Fatty acid desaturases are an important superfamily of enzymes found in a wide variety of aerobic organisms [1]. The first desaturation reaction to be studied in detail was the conversion of stearoyl CoA to oleyl CoA as it occurs in baker×s yeast (Scheme 1, a) [2]. Interest in this particular enzyme system has risen recently with the discovery that enhanced stearoyl CoA D9 desaturase (SCD) activity in mammals occurs in a number of disorders, including obesity, diabetes, and other metabolic diseases [3]. Thus, the development of mechanism-based SCD inhibitors would have potential therapeutic significance. A major stumbling block to progress in this area is that stearoyl CoA D9 desaturase is membrane-bound and difficult to isolate in purified form. However, some important mechanistic information has been obtained on the structurally related yeast enzyme [4], which can be conveniently studied in vivo by an appropriate experimental design. A KIE study showed that the H-atom at C(9) of substrate is removed first in an isotopically sensitive step, followed by rapid cleavage of the CÀH bond at C(10) [5]. This result correlates well with the observation that desaturase-mediated oxo transfer occurs most efficiently when a S-atom occupies the 9-position of a thiastearoyl substrate (Scheme 1, b) [6]; the enantioselectivity of sulfoxidation matches the stereochemistry (syn, pro-R) of the corresponding parent reaction [7] [8]. Taken together, these results strongly suggest that the putative diiron oxidant involved in yeast D9 desaturase mediated oxidation is asymmetrically located between C(9) and C(10) of substrate.The success of the thia-analogue approach in providing critically important information on desaturase-active-site topology prompted us to consider modifications to the probe that would obviate the need to isolate milligram amounts of product for

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Section: Experimental Partmentioning

confidence: 99%

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confidence: 99%

ω‐Fluoro Thiafatty Acids: New Mechanistic Probes of Desaturase‐Mediated Reactions

Hodgson

Lao

Dawson

et al. 2003

Helvetica Chimica Acta

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“…Unlike the membrane-bound, non-heme monoiron consists of comparing the relative efficiency of 0x0 transfer to A9 desaturases of which the S. cerevisiae and rat liver 9-vs. 10-thia substrate analogues (Scheme 1). Using Regiochemical 'Thia test ' via selective S-alkylation of the appropriate w-mercaptoalpreparation of 3e required the use of 4-(trifluoromethy1)phekanoic acids using previously published procedures (8 (9)). In each spectrum, methyl ester using one equivalent of m-chloroperoxybenzoic the ' 9~ resonance of the sulfoxy acid products3 appeared at acid-CH2CI2 (4) followed by hydrolysis using 2 N ethanolic lower field (A6 = 0.3 -0.5 ppm) than the signal due to the cor-KOH.…”

Section: [Traduit Par La Redaction]mentioning

confidence: 99%

Use of¹⁹F NMR as a direct probe of Δ⁹desaturase cryptoregiochemistry: a feasibility study

Buist¹,

Marecak²,

Dawson³

et al. 1996

Can. J. Chem.

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"F NMR can be used to monitor the relative efficiency with which various fluorinated aromatic sulfides are oxidized by the A9 desaturating system of Saccharomyces cerevisiae. Thus the sulfoxy acids produced from methyl S-(4-(trifluoromethy1)benzyl)-8-mercaptooctanoate (34, methyl S-(4-(trifluoromethyl)phenyl-2-ethyl))-8-mercaptooctanoate (3e), and methyl S-(4-(trifluorornethyl)benzyl)-9-mercaptononanoate (4c) were observed in the supernatant of S. cerevisiae cultures at concentrations of -140, -45, and -10 pM, respectively. This paper lays the methodological basis for a novel, in vitro "thia test" of cryptoregiochemistry and provides further experimental evidence that the yeast A9 desaturase initiates oxidation of stearoyl CoA at C-9.Key words: I9F NMR, desaturase, chiral sulfoxidation, hydrocarbon activation. The biological syn-dehydrogenation (desaturation) of fatty have determined (4) that the yield of sulfoxide products acids as exemplified by the A9 desaturase-mediated wansforobtained upon incubation of 9-thia fatty acids, such as 3a-C, is rnation of stearoyl COA (1) to give oleyl c o~ (2) is a remarkconsistently higher than yields obtained with the correspondable example of enzymic selectivity (1). A possible ing IO-thia analogues (4a,b) (Scheme 2). We have interpreted mechanism (2, 3) for this process involves regioselective this data to mean that yeast A9 desaturation is initiated at C-9hydrogen abstraction by an iron 0x0 species, followed by carof the parent stearoyl substrate. Renewed interest in the mechbocation formation and subsequent proton elimination anism of fatty acid desaturation has arisen recently with the (Scheme 1). We have devised a simple ''this test" for deterisolation and characterization of the soluble, plant A9 desatumining the site of initial oxidation (cryptoregiochemistry) that rases (5). Unlike the membrane-bound, non-heme monoiron consists of comparing the relative efficiency of 0x0 transfer to A9 desaturases of which the S. cerevisiae and rat liver 9-vs. 10-thia substrate analogues (Scheme 1). Can.

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“…8-Thiooctanoic acid was prepared from 8-bromooctanoic acid as previously described. 18 Tetrahydrofuran (THF) and diethyl ether (Et 2 O) were freshly distilled from Na-benzophenone ketyl. All air-and moisture-sensitive reactions were performed under N 2 .…”

Section: Experimental General Methodsmentioning

confidence: 99%

Stereochemistry of 10-sulfoxidation catalyzed by a soluble Δ9 desaturase

et al. 2010

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The stereochemistry of castor stearoyl-ACP Delta(9) desaturase-mediated 10-sulfoxidation has been determined. This was accomplished by (19)F NMR analysis of a fluorine-tagged product, 18-fluoro-10-thiastearoyl ACP S-oxide, in combination with a chiral solvating agent, (R)-AMA. Sulfoxidation proceeds with the same stereoselectivity as hydrogen removal from the parent stearoyl substrate. These data validate the use of thia probes to determine the stereochemistry and cryptoregiochemistry of desaturase-mediated oxidations.

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Highly chemo-, regio-, and stereoselective introduction of a cis-double bond into a thia-analogue of stearic acid

Cited by 21 publications

References 6 publications

ω‐Fluoro Thiafatty Acids: New Mechanistic Probes of Desaturase‐Mediated Reactions

ω‐Fluoro Thiafatty Acids: New Mechanistic Probes of Desaturase‐Mediated Reactions

Use of¹⁹F NMR as a direct probe of Δ⁹desaturase cryptoregiochemistry: a feasibility study

Stereochemistry of 10-sulfoxidation catalyzed by a soluble Δ9 desaturase

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Highly chemo-, regio-, and stereoselective introduction of a cis-double bond into a thia-analogue of stearic acid

Cited by 21 publications

References 6 publications

ω‐Fluoro Thiafatty Acids: New Mechanistic Probes of Desaturase‐Mediated Reactions

ω‐Fluoro Thiafatty Acids: New Mechanistic Probes of Desaturase‐Mediated Reactions

Use of19F NMR as a direct probe of Δ9desaturase cryptoregiochemistry: a feasibility study

Stereochemistry of 10-sulfoxidation catalyzed by a soluble Δ9 desaturase

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Use of¹⁹F NMR as a direct probe of Δ⁹desaturase cryptoregiochemistry: a feasibility study