Nature of the Electronic Factor Governing Diastereofacial Selectivity in Some Reactions of Rigid Saturated Model Substrates

Adcock, William; Trout, Neil A.

doi:10.1021/cr980380v

Cited by 74 publications

(51 citation statements)

References 172 publications

(307 reference statements)

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“…1). The direction of the Dd effects for increasingly electron-withdrawing substituents (shielding) match previous observations for rigid cycloalkyl systems [14].…”

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confidence: 86%

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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“…1). The direction of the Dd effects for increasingly electron-withdrawing substituents (shielding) match previous observations for rigid cycloalkyl systems [14].…”

supporting

confidence: 86%

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

Hodgson

Lao

Dawson

et al. 2003

Helvetica Chimica Acta

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“…Interestingly, the direction of the υ effects for increasingly electron-withdrawing substituents (shielding) correlate well with those observed for rigid cycloalkyl systems. 6 The various factors responsible for long-range substituent effects on 19 F chemical shifts have been reviewed recently. 6 In anticipation of in vitro experiments using relatively small amounts of substrate, we examined the υ effects as a function of concentration and found these were essentially invariant over a wide range (30 µM-30 mM).…”

Section: Resultsmentioning

confidence: 99%

“…6 The various factors responsible for long-range substituent effects on 19 F chemical shifts have been reviewed recently. 6 In anticipation of in vitro experiments using relatively small amounts of substrate, we examined the υ effects as a function of concentration and found these were essentially invariant over a wide range (30 µM-30 mM). However, we would like to emphasize that for analyses involving micromolar concentrations of analyte, we have found that it is critically important to use CDCl 3 which had been passed through a short alumina column to remove impurities such as DCl.…”

Section: Resultsmentioning

confidence: 99%

Use of ¹⁹F NMR spectroscopy to probe enzymatic oxidation of fluorine‐tagged sulfides

Behrouzian

Hodgson

Savile

et al. 2002

Magnetic Reson in Chemistry

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A novel19 F NMR-based method for monitoring the enzymatic oxidation of thia fatty acid analogues is presented. Our approach is based on the observation that methyl !-monofluorinated 9-thia-and 10-thiaoctadecanoates and their S-oxide and S-dioxide derivatives are easily distinguishable via their 1 H-decoupled 19 F spectra. These long-range substituent effects were used to probe the regio-and chemoselectivity of stearoyl ACP (acyl carrier protein) 1 9 desaturase-mediated sulfoxidation. The results clearly demonstrate that mono-oxygenation of a 10-thia analogue ACP 1 9 desaturase was more efficient than that of a 9-thia substrate. A product previously undetected by TLC was observed for the first time in the product mixture obtained from 18-fluoro-9-thiaoctadecanoyl-ACP.

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“…Chemists have long recognized that there are two basic mechanisms by which a polar group conveys its influence on a remote probe in saturated systems, the r-(through-bond) inductive effect and field (through-space) inductive effect (Robinson, 1932;Dewar and Grisdale, 1962;Reynolds, 1980). Since Kirkwood and Westheimer (1938) highlighted the electrostatic field model, the importance of the field inductive effect has been gradually established via numerous experimental and theoretical studies (Adcock and Trout, 1999;Nolan and Linck, 2000;Otto and Zdene'k, 2007). In many cases it is difficult to accurately ascribe substituent effects to either mechanism.…”

Section: The Effects Of Functional Group On Equilibrium Fractionationmentioning

confidence: 99%

Equilibrium 2H/1H fractionations in organic molecules. II: Linear alkanes, alkenes, ketones, carboxylic acids, esters, alcohols and ethers

Wang

Sessions

Nielsen

et al. 2009

Geochimica et Cosmochimica Acta

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Nature of the Electronic Factor Governing Diastereofacial Selectivity in Some Reactions of Rigid Saturated Model Substrates

Cited by 74 publications

References 172 publications

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

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

Use of ¹⁹F NMR spectroscopy to probe enzymatic oxidation of fluorine‐tagged sulfides

Equilibrium 2H/1H fractionations in organic molecules. II: Linear alkanes, alkenes, ketones, carboxylic acids, esters, alcohols and ethers

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Nature of the Electronic Factor Governing Diastereofacial Selectivity in Some Reactions of Rigid Saturated Model Substrates

Cited by 74 publications

References 172 publications

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

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

Use of 19F NMR spectroscopy to probe enzymatic oxidation of fluorine‐tagged sulfides

Equilibrium 2H/1H fractionations in organic molecules. II: Linear alkanes, alkenes, ketones, carboxylic acids, esters, alcohols and ethers

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Use of ¹⁹F NMR spectroscopy to probe enzymatic oxidation of fluorine‐tagged sulfides