Yinlong Guo

Palladium-Catalyzed Oxidative Aryltrifluoromethylation of Activated Alkenes at Room Temperature

A palladium-catalyzed intramolecular oxidative aryltrifluoromethylation reaction of activated alkenes has been explored. The reaction allows for an efficient synthesis of a variety of CF(3)-containing oxindoles. Preliminary mechanistic study indicated that the reaction involves a C(sp(3))-Pd(IV)(CF(3)) intermediate, which undergoes reductive elimination to afford a C(sp(3))-CF(3) bond.

Palladium-Catalyzed Intermolecular Aminofluorination of Styrenes

A novel palladium-catalyzed intermolecular aminofluorination of styrenes, with N-fluorobenzenesulfonimide (NFSI) functioning not only as a fluorinating reagent but also as an aminating reagent, has been developed. The reaction afforded vicinal fluoroamine products with very high regioselectivity. This transformation may involve fluoropalladation of styrene as a key step for C-F bond formation. The bidental nitrogen ligand is crucial to achieving the transformation successfully.

Highly Selective Pd-Catalyzed Intermolecular Fluorosulfonylation of Styrenes

A novel Pd-catalyzed intermolecular regio- and diastereoselective fluorosulfonylation of styrenes has been developed under mild conditions. This reaction exhibits a wide range of functional-group tolerance in styrenes and arylsulfinic acids to afford various β-fluoro sulfones. Preliminary mechanistic study reveals an unusual mechanism, in which a high-valent L2Pd(III)F species side-selectively reacts with a benzylic carbon radical to deliver a C-F bond. This pathway is distinct from a previously reported radical fluorination reaction.

N-Trifluoromethylthio-dibenzenesulfonimide: A Shelf-Stable, Broadly Applicable Electrophilic Trifluoromethylthiolating Reagent

The super electrophilicity of a shelf-stable, easily prepared trifluoromethylthiolating reagent N-trifluoromethylthio-dibenzenesulfonimide 7 was demonstrated. Consistent with the theoretical prediction, 7 exhibits reactivity remarkably higher than that of other known electrophilic trifluoromethylthiolating reagents. In the absence of any additive, 7 reacted with a wide range of electron-rich arenes and activated heteroarenes under mild conditions. Likewise, reactions of 7 with styrene derivatives can be fine-tuned by simply changing the reaction solvents to generate trifluoromethylthiolated styrenes or oxo-trifluoromethylthio or amino-trifluoromethylthio difunctionalized compounds in high yields.

A highly sensitive isotope-coded derivatization method and its application for the mass spectrometric analysis of analytes containing the carboxyl group

A novel isotope labeling reagent d(0)-/d(6)-2, 4-dimethoxy-6-piperazin-1-yl pyrimidine (DMPP) has been developed for derivatization toward the carboxyl group based on carbodiimide chemistry for mass spectrometry (MS) analysis. The strengths of this derivatization strategy involve fast labeling (15s), low chemical background and general access to most carboxylic analytes. This has been demonstrated using a series of compounds containing carboxylic acids, including peptides and proteins. To enhance the MS response of the derivatized analytes, the design of DMPP has been based on integration of the theoretical consideration of high gas-phase hydrogenation capacity and hydrophobicity. In addition, the high abundance product ions at m/z 225 and m/z 231 from d(0)-/d(6)-DMPP labeled carboxylic acids indicate high efficiency of the gas-phase cleavage induced by the labeling reagent. Quantitative determination of these ions can also be used in single reaction monitoring to achieve extremely high sensitivity toward the target analytes. This has subsequently been used to determine trace free fatty acids in human urine. Furthermore, the DMPP labeled peptides also provide additional sequence information in MALDI-MS/MS because of the formation of sequence-related isotope fragment ions. This DMPP-oriented labeling technique is expected to be a promising tool for the MS detection of many varieties of compounds containing carboxyl groups.

Analysis of low molecular weight compounds by MALDI-FTICR-MS

This review focuses on recent applications of matrix-assisted laser desorption ionization-Fourier-transform ion cyclotron resonance mass spectrometry (MALDI-FTICR-MS) in qualitative and quantitative analysis of low molecular weight compounds. The scope of the work includes amino acids, small peptides, mono and oligosaccharides, lipids, metabolic compounds, small molecule phytochemicals from medicinal herbs and even the volatile organic compounds from tobacco. We discuss both direct analysis and analysis following derivatization. In addition we review sample preparation strategies to reduce interferences in the low m/z range and to improve sensitivities by derivatization with charge tags. We also present coupling of head space techniques with MALDI-FTICR-MS. Furthermore, omics analyses based on MALDI-FTICR-MS were also discussed, including proteomics, metabolomics and lipidomics, as well as the relative MS imaging for bio-active low molecular weight compounds. Finally, we discussed the investigations on dissociation/rearrangement processes of low molecular weight compounds by MALDI-FTICR-MS.

Prediction of Acute Cellular Renal Allograft Rejection by Urinary Metabolomics Using MALDI-FTMS

The present study investigated small molecule analysis of urinary samples as a noninvasive method to detect acute cellular renal allograft rejection. Matrix-assisted laser desorption/ionization Fourier transform mass spectrometry (MALDI-FTMS) was used to analyze 15 urinary samples from transplant patients with different grades of biopsy showing improved clinical acute cellular rejection (ACR) and 24 urinary samples from 8 transplant patients without evidence of rejection. Seven small molecules demonstrated highly successful diagnostic performance (m/z): 278.1 (t = 3.398, p = 0.004), 293.0 (t = 2.169, p = 0.048), 294.1 (t = 2.154, p = 0.05), 382.2 (t = 2.961, p = 0.010), 383.3 (t = 2.270, p = 0.040), 402.2 (t = 2.994, p = 0.010), 424.0 (t = 2.644, p = 0.019). Kidney transplant patients with ACR could be distinguished from those without ACR using four individual small molecules with a specificity of 100%. In conclusion, the combination of MALDI-FTMS technology with a clear definition of patient groups can detect urine small molecule associated with ACR.

Carbon Nanotubes (2,5-Dihydroxybenzoyl Hydrazine) Derivative as pH Adjustable Enriching Reagent and Matrix for MALDI Analysis of Trace Peptides

A functionalized carbon nanotube (CNT), CNT 2,5-dihydroxybenzoyl hydrazine derivative, was synthesized and used as both pH adjustable enriching reagent and matrix in matrix assisted laser desorption/ionization mass spectrometry (MALDI-MS) analysis of trace peptides. The derivative reagent, 2,5-dihydroxybenzoyl hydrazine, introduced phenolic hydroxyl and phenyl groups to the surface of the CNT. The former group can provide adjustable surface charge and a source of protons for chemical ionization, and the latter helps to keep strong ultraviolet absorption for enhancing pulsed laser desorption and ionization. It was found that the functionalized CNT was less twisted in a basic condition (pH 10.5), which afforded an increased surface area to volume ratio for adsorption towards trace peptides. However, functionalized CNT becomes deposited in an acidic condition (pH 5) and can be isolated readily from the sample solutions once the nanoparticles have trapped the target analytes, thus providing a novel and convenient alternative method for quick isolation. Compared with the previously reported method on enriching analytes using the pristine CNT, it is observed that the detection limit for analytes can be greatly improved due to enhancing adsorption capacity of the functionalized CNT. Moreover, peptide mixture at concentration as low as 0.01 pg/µL still can be detected after enrichment mediated by the functionalized CNT, while it is difficult to be detected without enrichment at concentration 0.1 pg/µL using α-cyano-4-hydroxycinnamic acid (CHCA) as matrix. Therefore, high efficiency of adsorption and enrichment towards trace peptides can be achieved by adjusting pH value of the functionalized CNT dispersion.

Neighboring group participation of phosphine oxide functionality in the highly regio- and stereoselective iodohydroxylation of 1,2-allenylic diphenyl phosphine oxides.

Two sets of reaction conditions were established to enable the highly regio- and stereoselective iodohydroxylation of 1,2-allenylic diphenyl phosphine oxides, yielding (E)-2-iodo-3-hydroxy-1-alkenyl diphenyl phosphine oxides with very high stereoselectivity. The scope of this reaction was examined extensively. Notably, studies on the reactivity of optically active substrates indicated that the axial chirality in the starting allenes may be efficiently transferred to the center chirality of the products with no discernible loss of enantiopurity. Due to the importance of phosphine-containing compounds, both as reagents and ligands, this reaction shows potentials in organic synthesis. Investigations using ESI-MS technology on the (18)O-labeled product, which was prepared using (18)O-water as the solvent, indicated that the (18)O atom was bound to phosphorus in the final product and the oxygen atom of the hydroxyl comes from the phosphinyl functionality of the allene reactant. These results provided solid evidence for the formation of a five-membered cyclic intermediate from the neighboring group participation of the diphenylphosphinyl group. To the best of our knowledge, this is the first time that the neighboring group participation of this type of group was observed.

Monitoring Enzyme Reaction and Screening of Inhibitors of Acetylcholinesterase by Quantitative Matrix-Assisted Laser Desorption/ Ionization Fourier Transform Mass Spectrometry

A matrix-assisted laser desorption/ionization Fourier transform mass spectrometry (MALDI-FTMS)-based assay was developed for kinetic measurements and inhibitor screening of acetylcholinesterase. Here, FTMS coupled to MALDI was applied to quantitative analysis of choline using the ratio of choline/acetylcholine without the use of additional internal standard, which simplified the experiment. The Michaelis constant (Km) of acetylcholinesterase (AChE) was determined to be 73.9 µmol L−1 by this approach. For Huperzine A, the linear mixed inhibition of AChE reflected the presence of competitive and noncompetitive components. The half maximal inhibitory concentration (IC50) value of galantamine obtained for AChE was 2.39 µmol L−1. Inhibitory potentials of Rhizoma Coptidis extracts were identified with the present method. In light of the results the referred extracts as a whole showed inhibitory action against AChE. The use of high-resolution FTMS largely eliminated the interference with the determination of ACh and Ch, produced by the low-mass compounds of chemical libraries for inhibitor screening. The excellent correlation with the reported kinetic parameters confirms that the MS-based assay is both accurate and precise for determining kinetic constants and for identifying enzyme inhibitors. The obvious advantages were demonstrated for quantitative analysis and also high-throughput characterization. This study offers a perspective into the utility of MALDI-FTMS as an alternate quantitative tool for inhibitor screening of AChE.