Fluorous Reagents Research Articles

Fluorous-paired derivatization approach towards highly sensitive and accurate determination of long chain unsaturated fatty acids by liquid chromatography-tandem mass spectrometry

Long chain unsaturated fatty acids (LCUFAs) are emerging as critical contributors to inflammation and its resolution. Sensitive and accurate measurement of LCUFAs in biological samples is thus of great value in disease diagnosis and prognosis. In this work, a fluorous-derivatization approach for UPLC-MS/MS quantification of LCUFAs was developed by employing a pair of fluorous reagents, namely 3-(perfluorooctyl)-propylamine (PFPA) and 2-(perfluorooctyl)-ethylamine (PFEA). With this method, the LCUFAs in biological samples were perfluoroalkylated with PFPA and specifically retained on a fluorous-phase LC column, which largely reduced matrix interferences-induced quantitation deviation. Moreover, PFEA-labeled LCUFAs standards were introduced as one-to-one internal standards to farthest ensure unbiased results. Application of the proposed method enabled a reliable determination of eight typical LCUFAs with high sensitivity (LLOQ ranged from 30 amol to 6.25 fmol) and low matrix interferences (almost less than 10%). Such a high sensitivity could facilitate the determination of small-volume and low-concentration bio-samples. Further metabolic characterization of these targeted LCUFAs was monitored in OVA-induce asthma mice, requiring only 5 μL serum sample. Our results showed that asthmatic attack led to significant disturbances not only in the concentrations but also in the ratio among these LCUFAs. In view of the favorable advantages in sensitivity and accuracy, the present fluorous-paired derivatization approach will be expected to serve as a new avenue for dissecting the physiological and clinical implications of LCUFAs, thereby shedding light on the management of diseases related to their disturbances.

Fluorous Derivatization Method for Selective Analysis of Curcumin with Liquid Chromatography-Tandem Mass Spectrometry

Curcumin has been shown to be pharmacologically active in the prevention and treatment of various human diseases. In this study, we developed a fluorous derivatization method for selective analysis of curcumin with liquid chromatography (LC)tandem mass spectrometry (MS/MS). Curcumin was derivatized with the thiol-containing fluorous reagent (1H,1H,2H,2Hperfluoro-1-decanethiol) under mild conditions via Michael addition reaction, and the obtained derivative was introduced to a fluorous LC column (Fluofix-II 120E, 150 × 2.0 mm i.d., 5 μm, Wako). The selectively retained fluorous-derivatized curcumin on the column was also enabled highly sensitive detection with negative electrospray ionization MS/MS. Pretreatment of human serum sample was used protein precipitation with CH3CN. The calibration curve obtained by the present method showed good linearity (r2 = 0.9998) in the range of 7.4-442 ng/mL serum, and the limit of detection (S/N = 3) and limit of quantification (S/N = 10) were 1.8 ng/mL serum and 6.1 ng/mL serum, respectively. The present method was successfully applied to the analysis of curcumin in human serum sample.

Highly selective analysis of biogenic-related compounds utilizing fluorous chemistry

Perfluoroalkyl-containing compounds are highly fluorous, meaning that they have a remarkable affinity for one another and effectively exclude non-fluorous species. Utilizing this unique property, we have developed a fluorous derivatization with a liquid chromatographic analysis method for highly selective analysis of target analytes. Although most previous methods focused on extremely sensitive detection-oriented derivatization, the fluorous derivatization method involves highly specific separation for analytes. This method includes perfluoroalkylation of analytes with a fluorous reagent, and separation of the derivatives using a perfluoroalkyl-modified stationary phase LC column. The derivatives can be selectively retained on the fluorous-phase LC column, whereas the non-fluorous derivatives are poorly retained under the same separation conditions. The combination of this method with LC-tandem mass spectrometry (MS/MS) is very useful for complex biological sample analysis, because matrix-induced suppression effects, which are a common problem in LC-MS/MS analysis arising from components of a biological endogenous matrix, have not been observed. We have successfully applied this method to precise and accurate LC-MS/MS analysis of some biogenic compounds, such as sialic acids and biogenic amines, in complex biological samples.

ChemInform Abstract: “Propylene Spaced” Allyl Tin Reagents: A New Class of Fluorous Tin Reagents for Allylations under Radical and Metal-Catalyzed Conditions.

Abstract A new generation of propylene-spaced fluorous allyltin reagents [(Rf(CH 2 ) 3 ) 3 SnCH 2 CHCH 2 ] is described. These succeed in radical allylations where their lower homologs (ethylene-spaced) fail, and they provide improved performance in transition metal catalyzed allylations. The reagents and byproducts are readily separated by simple fluorous-organic liquid-liquid or solid-liquid extractions.

One-step synthesis of high-purity fluorous-capped inorganic nanoparticles

Making use of the fact that perfluorohydrocarbon, and hydrocarbon solvents become miscible at high temperatures, highly pure inorganic nanoparticles capped with fluorous labels have been generated in a one-step synthesis. The procedure involves taking the reactants in a hydrocarbon+perfluorohydrocarbon mixture along with a fluorous reagent and carrying out the reaction at elevated temperatures. On cooling the reaction mixture, fluorous-capped inorganic nanoparticles dispersed in the perfluorohydrocarbon are obtained.

Second-Generation Tags for Fluorous Chemistry Exemplified with a New Fluorous Mitsunobu Reagent

A new fluorous DEAD reagent bearing two perfluoro-tert-butyloxy groups with propylene spacers shows excellent promise for use in fluorous Mitsunobu reactions. Pure target products were obtained in good yields after removing fluorous byproducts by FSPE. The new reagent serves as a prototype for a greener second generation of fluorous reagents bearing tags that are not expected to degrade in the environment to compounds that are highly persistent or that bioaccumulate in higher organisms.

ライトフルオラスタグを基点とする有機反応プロセスの簡略化

Organic molecules bearing small fluorous tags (C6F13, C8F17) are called light fluorous molecules. Light fluorous reagents, scavengers and catalysts are especially convenient since they typically induce reactions of organic substrates under the same conditions as their non-fluorous relatives, but are reliably removed from crude reaction products by fluorous solid phase extraction. Herein we report light fluorous versions of Grubbs-Hoveyda metathesis catalysts, Mukaiyama reagent, and Fmoc reagent. These exhibit the expected reactivity profile, are readily recovered from reaction mixtures by fluorous solid phase extraction. In addition, we describe reverse-fluorous solid phase extraction. In a reversal of the roles of solid and liquid phases in standard fluorous solid phase extraction, a mixture is charged to a polar solid phase (standard silica gel) and then eluted with a fluorous solvent. The organic components of the mixture are retained, while the fluorous components pass.

Preparation of a fluorous protecting group and its application to the chemoenzymatic synthesis of sialidase inhibitor

2-(Perfluorohexyl)ethoxymethyl chloride was prepared as a novel fluorous protecting reagent. Neu5Ac aldolase-catalyzed chemoenzymatic transformation of N-acetyl-D-mannosamine to Neu5Ac derivatives was achieved successfully by using the fluorous reagent not only for hydroxy group protection but also for fluorous tagging. This chemoenzymatic method was applied to the synthesis of 2-deoxy-2,3-didehydrosialic acid 1 known as a potent sialidase inhibitor.

フルオラスケミストリーを用いるキラル化合物の分離・合成および天然物合成への利用

Organic compounds that bear perfluoroalkyl substituents such as CH2CH2CnF2n+1 (n=4-10) and the fluorine atom contents of which are higher than 60 wt% are soluble in perfluorocarbon like FC-72 (CF3 (CF2) 4CF3) but insoluble in common organic solvents. The unique nature has been applied to a simple and quick separation of organic products from a fluorous reagent, or a fluorous product from organic reagents, and to immobilization of a fluorous catalyst in the fluorous phase of a fluorous and organic biphase system. Using a fluorous silica gel column, fluorous compounds that bear only a single fluorous substituent can easily be separated from organic compounds but also themselves can be separated by HPLC depending upon their fluorine atom contents. Here we describe catalytic enantioselective reactions using fluorous BINOL and BINAP in the biphase system, separation of enantiomers of fluorous chiral alcohols and α-amino acid derivatives by HPLC with a β-cyclodextrin chiral column and a total synthesis of macrolactam bistratamide H using a new fluorous protecting group, 2-tris (pefluorodesyl) silylethoxycarbonyl.

Fluorous reagents and scavengers versus solid-supported reagents and scavengers, a reaction rate and kinetic comparison

Reactions using fluorous reagents and scavengers are compared side-by-side with their solid-supported counterparts. Fluorous triphenylphosphine is used in the bromination reaction of alcohols, fluorous thiol is used as an electrophile scavenger for alpha-bromoketones, fluorous isatoic anhydride is used as a nucleophile scavenger for primary and secondary amines. Reactions involving fluorous reagents and scavengers occur in homogeneous media with solution-phase reaction kinetics. Reactions with solid-supported reagents and scavengers occur in a heterogeneous media, and the reaction kinetics are greatly affected by the nature of the solid-support and reaction environment. Significantly larger amounts of reagents and more time are usually required to complete the solid-supported reaction.

Highlights of Applications in Synthesis and Catalysis: Synthetic Applications of Fluorous Reagents

AbstractFor Abstract see ChemInform Abstract in Full Text.

Second Generation Fluorous DEAD Reagents Have Expanded Scope in the Mitsunobu Reaction and Retain Convenient Separation Features.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Second Generation Fluorous DEAD Reagents Have Expanded Scope in the Mitsunobu Reaction and Retain Convenient Separation Features

First generation fluorous DEAD reagent bis(perfluorohexylethyl)azo dicarboxylate (C(6)F(13)(CH(2))(2)O(2)CN=NCO(2)(CH(2))(2)C(6)F(13), F-DEAD-1) has been shown to underperform relative to diisopropylazodicarboxylate in difficult Mitsunobu reactions involving hindered alcohols or less acidic pronucleophiles (phenols). Two new second generation fluorous reagents bearing propylene spacers instead of the ethylene spacers show expanded reaction scope while retaining the easy fluorous separation features. Byproducts from "half fluorous" reagent perfluorooctylpropyl tert-butyl azo dicarboxylate (C(8)F(17)(CH(2))(3)O(2)CN=NCO2(t)Bu, F-DEAD-2) can be removed by fluorous flash chromatography, and byproducts from bis(perfluorohexylpropyl)azo dicarboxylate (C(6)F(13)(CH(2))(3)O(2)CN=NCO(2)(CH(2))(3)C(6)F(13), F-DEAD-3) can be removed by fluorous solid-phase extraction. The new reagents promise to provide general and complementary solutions for separation problems in Mitsunobu reactions without restricting reaction scope.

Use of benzyloxycarbonyl (Z)-based fluorophilic tagging reagents in the purification of synthetic peptides

Three novel fluorous reagents (i.e. 1– 3 ), derived from benzyl chloroformate (Z-Cl), have been synthesized and used for the tagging of peptides prepared following a Fmoc-based solid-phase approach. It is shown that the implementation of a benzyloxycarbonyl (Z)-based fluorophilic tag facilitates purification of peptides using fluorous reverse phase chromatography.

ChemInform Abstract: Parallel Synthesis with Fluorous Reagents and Reactants

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Parallel synthesis with fluorous reagents and reactants

Fluorous reagents and reactants provide emerging new options in parallel synthesis because they are easily prepared, reacted, and then separated from the desired reaction products. Some background information on fluorous reaction and separation techniques is provided, and the utility of fluorous reagents and reactants is illustrated with a number of case studies that feature both liquid-liquid and solid-solid separations. © 1999 John Wiley & Sons, Inc. Med Res Rev, 19, No. 5, 432–438, 1999.

Parallel synthesis with fluorous reagents and reactants.

Fluorous reagents and reactants provide emerging new options in parallel synthesis because they are easily prepared, reacted, and then separated from the desired reaction products. Some background information on fluorous reaction and separation techniques is provided, and the utility of fluorous reagents and reactants is illustrated with a number of case studies that feature both liquid-liquid and solid-solid separations.

Organic/Fluorous Phase Extraction: A New Tool for the Isolation of Organometallic Complexes

Strategies for isolating and purifying organometallic complexes are limited. The use of the unique solubility properties of fluorous reagents allows for purification by fluorous/organic phase extraction. An 85% yield of pure (Rfh)3SnCp* (1, Rfh = (CH2)2(CF2)5CF3) was isolated by filtration and extraction with FC-72 (fluorinated hexanes) of the reaction of (Rfh)3SnBr with Cp*Li. The reaction of 1 with TaCl5 and NbCl5 gave the alkylated products Cp*TaCl4 and Cp*NbCl4, respectively. These products were isolated from the reaction mixtures in good yields by simple extraction with a biphasic combination of FC-72 and a nonfluorinated solvent.