Oxidation of chiral 9-fluorinated substrates by castor stearoyl-ACP Δ9 desaturase yields novel products

Behrouzian, Behnaz; Dawson, Brian; Buist, Peter H.; Shanklin, John

doi:10.1039/b100035g

Cited by 12 publications

(23 citation statements)

References 11 publications

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“…-J\^ Deprotection of each enantiomer was performed using ( 15)-(+)-10-camphorsulfonic acid in methanol at 0°C to obtain the target compounds. The *H NMR (Figure 2.15), 13 C NMR (Figure 2.16), 19 F NMR (Figure 2.17) and mass spectral (Figure 2.18) data of the products were similar to that of the products prior to deprotection and were consistent with the proposed structures. Evidence of incomplete deprotection of the alcohol was also observed in the H NMR spectrum (0.88 and 0.03 ppm).…”

Section: Synthesis Of Fluorine-tagged Chiral Sulfoxide Standardssupporting

confidence: 69%

“…As noted earlier, further support for the configurational assignments was obtained by comparing the trends in the 'H and 13 C NMR spectra with the data for corresponding butyl and propyl sulfinate esters as found in the literature (Tables 2.1 and 2.2). [ ' Diastereomeric ratios were determined through 19 F NMR spectroscopy, using the integration of the fluorine signals as the diastereomers featured slightly different chemical shifts.…”

Section: Synthesis Of Fluorine-tagged Chiral Sulfoxide Standardssupporting

confidence: 58%

“…[54] The vinyliodide was lithiated using n-BuLi and methyl 9-oxononanoate was added to obtain (10E) methyl 9hydroxy-10-octadecanoate (7% yield). 13 The assigned structures of the products were confirmed using mass spectra, 'H and C NMR. The structural data for both compounds were similar to that previously reported.…”

Section: Synthesis Of Methyl (10z)-and (102s)-9-hydroxy-10-octadecenoatementioning

confidence: 96%

“…This enzyme produces a 10-sulfoxide product from a 10-thiasubstrate (Figure 2.2). [15 To study the stereochemistry of 10-sulfoxidation, an to-fluoro, CIO thia fatty acid analogue was employed and the corresponding 10-sulfoxide product was isolated as the Clalcohol after reductive workup (Figure 2.2). The stereochemistry of this product was studied using 19 F NMR in combination with the CSA, (7?…”

Section: Efforts To Determine the Enantioselectivity Of Soluble A 9 Desaturasemediated Sulfoxidationmentioning

confidence: 99%

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Mechanistic studies of desaturase-mediated oxidations

Tremblay¹

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The study of the mechanism of fatty acid desaturases often requires the use of synthetic probes and/or standards. In this work, a general procedure for preparing chiral fluorine-tagged dialkyl sulfoxides was developed using DAG methodology. 18-fluoro-(10S)sulfoxy-1-octadecanol, 18-fluoro-(10i?)-sulfoxy-l-octadecanol, 15-fluoro-(l 15)-sulfoxypentadecane, and 15-fluoro-(lli?)-sulfoxypentadecane were prepared. These standards were used in the determination of the stereochemistry of enzymatically produced sulfoxides arising from the introduction of fluorine-tagged thia fatty acid analogues to a soluble and a membrane-bound A 9 desaturase.In this study, it has been shown that the Pirkle binding model is successful for predicting the direction of induced non-equivalence of fluorine-tagged dialkyl sulfoxide enantiomers by ! H NMR using the chiral solvating agents AMA, MPAA and TFAE. However, the observed non-equivalence of 19 F NMR signals of these sulfoxides under similar conditions is dependent on the nature of the chiral reagent used.The identification of the products of a triple mutant, T117R/G188L/D280K of the castor A 9 desaturase was also undertaken using synthetic standards in combination with GC-MS. (10Z)-and (10£)-9-hydroxy-10-octadecenoate and (9Z)-and (9£)-ll-hydroxy-9octadecenoate were synthesized by known methods. The dienoic fatty acid esters, methyl 9Z,ll£'-octadecadienoate with a minor component of methyl 9is,ll£'-octadecadienoate were prepared in a 9:1 ratio and a mixture of 9Z,llZ-octadecadienoate and methyl 9£',11Zoctadecadienoate were also prepared. in Chemoselectivity 12Chapter 2: Results and Discussion 2.1 Determination of the enantioselectivity of soluble A 9 desaturase-mediated sulfoxidation using fluorine-tagged substrates 16 2.1.1 Introduction 16 V 2.1.1.1 Use of 'H-decoupled 19 F NMR in the study of desaturase-mediated oxidation 16 2.1.1.2 Efforts to determine the enantioselectivity of soluble A 9 desaturasemediated sulfoxidation \j 2.1.2 Project goals 20 2.1.3 Synthesis of fluorine-tagged chiral sulfoxide standards 21 2.1.3.1 Synthesis of (105)-and (107v)-18-fluoro-10-sulfoxy-l-octadecanol 26 2.1.3.2 Synthesis of (US)-and (117?)-15-fluoro-ll-sulfoxypentadecane 36 2.1.4 Synthesis of (R) and (S) (9-anthryl)methoxyacetic acid (AMA) 41 2.1.5 NMR experiments 45 2.1.5.1 Assignment of the absolute configuration of 18-fluoro-10-sulfoxy-loctadecanol produced by a soluble A 9 desaturase 45 2.1.5.2 Investigation of the role of the C1 hydroxyl group on the CSA induced NMR non-equivalences 48 2.1.5.3 Assignment of the absolute configuration of methyl 15-fluoro-l 1sulfoxypentadecanoate produced by growing S. cerevisae cultures 49 2.1.5.4 Investigation of the effect of dilution on the direction of induced non-equivalence 51 2.1.5.5 A study of the direction of induced non-equivalence in 'H and 'H-decoupled 19 F NMR for various chiral solvation reagents 52 2.1.6 Conclusions and future directions 55 2.2 Study of the catalytic diversity of an acyl-ACP desaturase mutant 57 2.2.1 Introduction 57 2.2.2 Project go...

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Section: Synthesis Of Fluorine-tagged Chiral Sulfoxide Standardssupporting

confidence: 69%

Section: Synthesis Of Fluorine-tagged Chiral Sulfoxide Standardssupporting

confidence: 58%

Section: Synthesis Of Methyl (10z)-and (102s)-9-hydroxy-10-octadecenoatementioning

confidence: 96%

Section: Efforts To Determine the Enantioselectivity Of Soluble A 9 Desaturasemediated Sulfoxidationmentioning

confidence: 99%

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Mechanistic studies of desaturase-mediated oxidations

Tremblay¹

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“…In insect sex pheromones we (10-12) and others (13,14) demonstrated that replacements of hydrogen atom(s) by fluorine mimic, potentiate, or inhibit the action of the natural products. Recently, Behrouzian et al (15,16) studied the desaturation of both enantiomers of 9-fluoroderivatives of stearic acid by stearoyl acyl carrier protein ∆ 9 desaturase isolated from castor seed oil and gained valuable insights into the enantioselectivity of this enzyme in dehydrogenation and oxidation reactions. In our case, we were interested in studying the activity of those mono-and gem-difluoroderivatives of myristic acids bearing the fluorine substitution at the C8-C11 positions.…”

mentioning

confidence: 99%

Synthesis of fluorinated analogs of myristic acid as potential inhibitors of egyptian armyworm (Spodoptera littorialis) Δ¹¹ desaturasedesaturase

Abad

Villorbina

Fabriás

et al. 2003

Lipids

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To study the activity of the different desaturases present in the pheromone biosynthetic pathway of the Egyptian armyworm, Spodoptera littoralis, we prepared a series of mono- and gem-difluorinated analogs of myristic acid with halogen substitution at the C8-C11 positions of the aliphatic chain via specifically positioned dithiane precursors. Thus, transformation of dithianes by treatment with N-bromosuccinimide in the presence of H2O followed by reduction with LiAlH4 afforded the appropriate alcohols, which reacted with diethylaminosulfur trifluoride to give rise to the corresponding monofluoroderivative intermediates. Alternatively, the introduction of the gem-difluoro functionality was carried out by reaction of the appropriate dithiane intermediate with 1,3-dibromo-5,5-dimethylhydantoin in the presence of HF/pyridine. The activity of these fluorinated FA as substrates and inhibitors of the desaturases involved in the biosynthesis of the sex pheromonal blend of S. littoralis has been studied. In this case, 11-fluorotetradecanoic acid elicited a moderate inhibitory activity of delta11 desaturase.

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Enzymatic Catalytic Promiscuity and the Design of New Enzyme Catalyzed Reactions

Bornscheuer

Kazlauskas

2012

Enzyme Catalysis in Organic Synthesis

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Oxidation of chiral 9-fluorinated substrates by castor stearoyl-ACP Δ9 desaturase yields novel products

Cited by 12 publications

References 11 publications

Mechanistic studies of desaturase-mediated oxidations

Mechanistic studies of desaturase-mediated oxidations

Synthesis of fluorinated analogs of myristic acid as potential inhibitors of egyptian armyworm (Spodoptera littorialis) Δ¹¹ desaturasedesaturase

Enzymatic Catalytic Promiscuity and the Design of New Enzyme Catalyzed Reactions

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Oxidation of chiral 9-fluorinated substrates by castor stearoyl-ACP Δ9 desaturase yields novel products

Cited by 12 publications

References 11 publications

Mechanistic studies of desaturase-mediated oxidations

Mechanistic studies of desaturase-mediated oxidations

Synthesis of fluorinated analogs of myristic acid as potential inhibitors of egyptian armyworm (Spodoptera littorialis) Δ11 desaturasedesaturase

Enzymatic Catalytic Promiscuity and the Design of New Enzyme Catalyzed Reactions

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Synthesis of fluorinated analogs of myristic acid as potential inhibitors of egyptian armyworm (Spodoptera littorialis) Δ¹¹ desaturasedesaturase