Diastereoselective intermolecular radical addition to nitrones

The intermolecular radical addition to chiral nitrones 2, 4, 5, and 16 was studied. The isopropyl radical addition to Oppolzer's camphorsultam derivative 2 of glyoxylic nitrone proceeded with excellent diastereoselectivity to give the desired isopropylated product 3a accompanied by the diisopropylated product 3b. A high degree of stereocontrol in the reaction of cyclic nitrone 4 was achieved. The ethyl radical addition to nitrone 4 with triethylborane afforded the desired ethylated product 9a accompanied by the diethylated product 10a and the ethylated nitrone 11a. To evaluate the utility of cyclic nitrone 4, several alkyl radicals were employed in the addition reaction, which afforded the alkylated products 9b-d with excellent diastereoselectivities. In the presence of Mg(ClO(4))(2), the ethyl radical addition to BIGN 16 afforded selectively syn isomers. In contrast, the alkyl radical addition to 16 took place even in the absence of Lewis acid to give anti isomers.     

Asymmetric synthesis of alpha-amino acids based on carbon radical addition to glyoxylic oxime ether

The first asymmetric synthesis of alpha-amino acids based on diastereoselective carbon radical addition to glyoxylic imine derivatives is reported. The addition of an isopropyl radical, generated from i-PrI, Bu(3)SnH, and Et(3)B in CH(2)Cl(2) at 25 degrees C, to achiral glyoxylic oxime ether 1 proceeded regioselectively at the imino carbon atom of the oxime ether group to give an excellent yield of the C-isopropylated product 2. The competitive reaction using glyoxylic oxime ether 1 and aldoxime ether 4 showed that the reactivity of the glyoxylic oxime ether toward nucleophilic carbon radicals was enhanced by the presence of a neighboring electron-withdrawing substituent. Thus, the alkyl radical addition to glyoxylic oxime ether 1 proceeded smoothly even at -78 degrees C, in contrast to the unactivated aldoxime ether 4. A high degree of stereocontrol in the carbon radical addition to the glyoxylic oxime ether was achieved by using Oppolzer's camphorsultam as a chiral auxiliary. The stannyl radical-mediated reaction of the camphorsultam derivative 6 with an isopropyl radical at -78 degrees C afforded a 96:4 diastereomeric mixture, 7a, of the C-isopropylated product. The reductive removal of the benzyloxy group of the major diastereomer (R)-7a, by treatment with Mo(CO)(6) and the subsequent removal of the sultam auxiliary by standard hydrolysis, afforded the enantiomerically pure D-valine (R)-12 without any loss of stereochemical purity. To evaluate the new methodology, a variety of alkyl radicals were employed in the addition reaction which gave the alkylated products 7 with excellent diastereoselectivity, allowing access to a wide range of enantiomerically pure natural and unnatural alpha-amino acids. Even in the absence of Bu(3)SnH, treatment of 6 with alkyl iodide and Et(3)B at 20 degrees C gave the C-alkylated products 7 with moderate diastereoselectivities. The use of Et(2)Zn as a radical initiator, instead of Et(3)B, was also effective for the radical reaction. The enantioselective isopropyl radical addition to 1 using (R)-(+)-2, 2'-isopropylidenebis(4-phenyl-2-oxazoline) and MgBr(2) gave excellent chemical yield of the valine derivative 2 in 52% ee.     

Behavior of nitroxyl radical in the polymerization process forming copolymers bearing diarylnitrone pendants and photocontrol of refractive indices for these copolymers

To establish the reaction condition under which the radical copolymerization of methyl methacrylate (MMA) with α‐(2‐hydroxy‐4‐methacryloyloxyphenyl)‐N‐(2,6‐dimethylphenyl)nitrone (HMDN) proceeds smoothly to give photoreactive copolymers, the effects of the nitrone chromophore on the extent to which the radical polymerization of MMA is inhibited were investigated. It was found that the reversible addition of initiating radical to the CH?N⁺(? O^?) moiety in the nitrone chromophore readily occurs to give the nitroxyl radical. It was also found that the latter radical undergoes an efficient coupling reaction with propagating radical to inhibit the radical copolymerization of MMA with HMDN. However, on raising the reaction temperature and the radical concentration, the copolymerization was successfully carried out. This polymerization condition allowed us to prepare the HMDN/MMA, HMDN/styrene, and HMDN/cyclohexyl acrylate copolymers in good yields. The photoirradiation of the copolymer film prepared on a silicon wafer lowered its refractive index by 0.003–0.023, depending on the relative composition of the diarylnitrone chromophore in these copolymers. © 2005 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 44: 88–97, 2006     

Zinc-mediated carbon radical addition to glyoxylic imines in aqueous media for the synthesis of alpha-amino acids

The addition of carbon radicals to glyoxylic imines was studied using zinc dust as a radical initiator. The zinc-mediated radical reaction of glyoxylic oxime ethers and hydrazones proceeded smoothly to give the alkylated products via a carbon-carbon bond-forming process in aqueous media. The reaction of the oxime ethers and hydrazones having an Oppolzer's camphorsultam group provided the corresponding alkylated products, which could be converted into enantiomerically pure alpha-amino acids. The diastereoselectivities observed in the reaction of hydrazones were better than those obtained in the reaction of oxime ethers.     

SmI(2)-promoted radical addition of nitrones to alpha,beta-unsaturated amides and esters: synthesis of gamma-amino acids via a nitrogen equivalent to the ketyl radical

[reaction: see text] Alkyl nitrones undergo radical addition reactions to a series of alpha,beta-unsaturated amides and esters when subjected to samarium diiodide via a nitrogen equivalent to a ketyl radical anion. This reaction conveniently provides access to a variety of functionalized gamma-amino acids. The methodology was extended to the asymmetric synthesis of 4-substituted gamma-amino acids, via the nitrone radical addition reaction to acrylates/amides possessing a chiral auxiliary.     

EPR/spin trapping study of the spontaneous addition of dioxygen on a dienol

The spontaneous addition of triplet oxygen on dienol 1, yielding endoperoxide 2, was followed by EPR/spin trapping. The use of nitroso and nitrone spin traps allowed the detection of two radical centers, showing that this reaction could likely follow a radical pathway.     

Addition of alkyl radicals, generated from carboxylic acids via photochemical decarboxylation, to glyoxylic oxime ether: a mild and efficient route to α-substituted α-aminoesters

Radical addition to a glyoxylic oxime ether was accomplished under mild conditions using an alkyl radical generated from a free carboxylic acid via photochemical decarboxylation. The photoreaction provided an efficient route to α-substituted α-aminoesters from carboxylic acids and oxime ether.     

UVA-ketoprofen-induced hemoglobin radicals detected by immuno-spin trapping

Ketoprofen (3-benzoyl-alpha-methylbenzeneacetic acid, KP) is a widely used nonsteroidal anti-inflammatory drug (NSAID) that causes both phototoxicity and photoallergy. Here, we investigated the formation of hemoglobin radicals, in both purified hemoglobin and red blood cells (RBC), induced by ultraviolet A (UVA)-KP by using "immuno-spin trapping," a novel approach that combines the specificity of spin trapping with the sensitivity of antigen-antibody interactions. The methemoglobin (metHb) radicals react covalently with 5,5-dimethyl-1-pyrroline N-oxide (DMPO) to form nitroxyl radical adducts that are oxidized to the corresponding nitrone adducts, which in turn are specifically recognized by antiserum against DMPO nitrone. We found that the formation of nitrone adducts in metHb depended on the UVA dose, the KP concentration and the presence of DMPO, as determined by enzyme-linked immunosorbent assay and Western blotting. Adduct formation decreased when irradiation was carried out in the presence of catalase or nitrogen, suggesting that H2O2 plays a key role in KP-UVA-induced metHb radical formation. KP in the dark did not generate metHb radical-derived nitrone adducts, whereas UVA alone resulted in the formation of metHb radical-derived nitrone adducts that increased with UVA dose from 4 to 10 J/cm2. However, KP (25 and 200 microM) plus UVA (4 and 10 J/cm2) resulted in a significant increase in the formation of metHb radical-derived nitrone adducts as compared with UVA or KP alone, indicating that KP photosensitized the production of the metHb radicals in the presence of UVA. In contrast, no metHb radical-derived nitrone adduct was detected in the absence of DMPO, even though KP and UVA were present. We also detected the hemoglobin radical formation in RBC as well as in hemolysates. The endogenous antioxidants and exogenous reduced glutathione inhibited the protein radical formation. These studies have shown that the immuno-spin-trapping technique can be used to detect radical damage in proteins as a result of photosensitizing reactions. The successful detection of protein radical formation caused by KP photosensitization could help further understand the photoallergic effect of this NSAID.     

A DFT study on the 1,3-dipolar cycloaddition reactions of C-(methoxycarbonyl)-N-methyl nitrone with methyl acrylate and vinyl acetate

In the 1,3-dipolar cycloaddition of glyoxylic nitrones with electron-poor and electron-rich alkenes, the configurational instability of the nitrone leads to parallel models when regio- and stereoselectivities are rationalized. The energetics of the cycloaddition reactions have been investigated through molecular orbital calculations at the B3LYP/6-31-G(d) theory level. By studying different reaction channels and reagent conformations, leading to a total of sixteen transition structures for each dipolarophile, the regio- and stereochemical preferences of the reaction are discussed.     

Synthesis and EPR spin trapping properties of a new isoindole-based nitrone: 1,1,3-trimethylisoindole N-oxide (TMINO)

Here we describe the synthesis and characterisation of a new isoindole-based nitrone spin trap, 1,1,3-trimethylisoindole N-oxide (TMINO). This nitrone and its radical adducts (isoindoline nitroxides) exhibit enhanced stability with respect to other commonly used spin traps and their adducts. We also report EPR trapping studies of this new nitrone with some carbon- and oxygen-centred radicals including alkyl, aryl, hydroxyl and benzoyloxyl systems. The narrow EPR line-widths and stability of the resulting nitroxide spin adducts allowed the detection of the expected radicals as well as secondary and minor radical components in the reaction mixtures.     

Embedding multiple site‐specific functionalities into polymer chains via nitrone‐mediated radical coupling reactions

A facile method to generate polymer materials with embedded functional groups at known and precise positions along the polymer backbone is described. In the presented approach, well‐defined bifunctional poly(isobornyl acrylate)s preformed via atom transfer radical polymerization (ATRP) containing α,ω‐bromo end groups are reactivated and subsequently coupled in a stepwise manner via the nitrone‐mediated radical coupling (NMRC) technique. The generated polymers contain on average four nitrone moieties at evenly spaced locations. The number of embedded functionalities, and thus, the size of the polymer is limited by disproportionation reactions occurring during the nitroxide termination sequence. Using the nitrone as a functional carrier, secondary functionalities can be incorporated into the polymer with ease. To exemplify such an approach, an alkyne‐functionalized nitrone is used to construct a multisegment structure via NMRC reactions followed by postmodification of the obtained polymers with 3‐mercaptopropionic acid via UV‐induced thiol‐yne reactions. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011     

NMR and EPR studies of the reaction of nucleophilic addition of (bi)sulfite to the nitrone spin trap DMPO

The reaction of the nitrone spin trap 5,5‐dimethylpyrroline‐N‐oxide (DMPO) with sodium (bi)sulfite in aqueous solutions was investigated using NMR and EPR techniques. Reversible nucleophilic addition of (bi)sulfite anions to the double bond of DMPO was observed, resulting in the formation of the hydroxylamine derivative 1‐hydroxy‐5,5‐dimethylpyrrolidine‐2‐sulfonic acid, with characteristic ¹H and ¹³C NMR spectra. The reaction mechanism was suggested and corresponding equilibrium constants determined. The mild oxidation of the hydroxylamine results in the formation of an EPR‐detected spectrum identical with that for the DMPO adduct with sulfur trioxide anion radical. The latter demonstrates that a non‐radical addition reaction of (bi)sulfite with DMPO may contribute to the EPR detection of SO₃^?? radical. This possibility must be taken into account in spin trapping analysis of sulfite radical. Copyright © 2003 John Wiley & Sons, Ltd.     

Carbon-carbon bond construction on solid support: triethylborane-induced radical reactions of oxime ethers

The triethylborane-induced solid-phase radical reaction was studied. The solid-phase radical reaction of oxime ether anchored to Wang resin proceeded smoothly to give the α-amino acid derivatives. The carbon-carbon bond-forming radical reaction of TentaGel OH resin-bound glyoxylic oxime ether proceeded even in aqueous media.     

Relevance of a prereaction for the in situ NMP of styrene using the C‐Phenyl‐N‐tert‐butylnitrone/2,2′‐azobis(isobutyronitrile) pair

In this article, we compare two routes for carrying out in situ nitroxide‐mediated polymerization of styrene using the C‐phenyl‐N‐tert‐butylnitrone (PBN)/2,2′‐azobis(isobutyronitrile) (AIBN) pair to identify the best one for an optimal control. One route consists in adding PBN to the radical polymerization of styrene, while the other approach deals with a prereaction between the nitrone and the free radical initiator prior to the addition of the monomer and the polymerization. The combination of ESR and kinetics studies allowed demonstrating that when the polymerization of styrene is initiated by AIBN in the presence of enough PBN at 110 °C, fast decomposition of AIBN is responsible for the accumulation of dead polymer chains at the early stages of the polymerization, in combination with controlled polystyrene chains. On the other hand, PBN acts as a terminating agent at 70 °C with the formation of a polystyrene end‐capped by an alkoxyamine, which is not labile at this temperature but that can be reactivated and chain‐extended by increasing the temperature. Finally, the radical polymerization of styrene is better controlled when the nitrone/initiator pair is prereacted at 85 °C for 4 h in toluene before styrene is added and polymerized at 110 °C. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 1085–1097, 2009     

硝酮化合物对9-氰蒽荧光猝灭作用的研究

本工作对硝酮化合物猝灭9-氰蒽荧光的机制进行了研究,发现不同的9-氰蒽/硝酮体系可能经历包括电子转移、能量转移及竞争吸收等不同的猝灭过程。其中α,N-二苯基硝酮对荧光猝灭遵循电子转移机制,分别形成猝灭剂和敏化剂的离子自由基,但硝酮正离子自由基不能导致环化反应发生,结果还表明：硝酮化合物的四π电子1,3偶极结构在猝灭过程中起主要作用,因此当光环化反应破环1,3偶极结构生成氧氮丙啶时,即失去其原有的猝灭能力,导致已被猝灭的荧光重新回复。     

Reactivity of superoxide radical anion with cyclic nitrones: role of intramolecular H-bond and electrostatic effects

Limitations exist among the commonly used cyclic nitrone spin traps for biological free radical detection using electron paramagnetic resonance (EPR) spectroscopy. The design of new spin traps for biological free radical detection and identification using EPR spectroscopy has been a major challenge due to the lack of systematic and rational approaches to their design. In this work, density functional theory (DFT) calculations and stopped-flow kinetics were employed to predict the reactivity of functionalized spin traps with superoxide radical anion (O2*-). Functional groups provide versatility and can potentially improve spin-trap reactivity, adduct stability, and target specificity. The effect of functional group substitution at the C-5 position of pyrroline N-oxides on spin-trap reactivity toward O2*- was computationally rationalized at the PCM/B3LYP/6-31+G(d,p)//B3LYP/6-31G(d) and PCM/mPW1K/6-31+G(d,p) levels of theory. Calculated free energies and rate constants for the reactivity of O2*- with model nitrones were found to correlate with the experimentally obtained rate constants using stopped-flow and EPR spectroscopic methods. New insights into the nucleophilic nature of O2*- addition to nitrones as well as the role of intramolecular hydrogen bonding of O2*- in facilitating this reaction are discussed. This study shows that using an N-monoalkylsubstituted amide or an ester as attached groups on the nitrone can be ideal in molecular tethering for improved spin-trapping properties and could pave the way for improved in vivo radical detection at the site of superoxide formation.     

A dual sensor spin trap for use with EPR spectroscopy

Redox active metal ions, carbon-centered radicals, and oxygen-centered radicals are important to oxidative stress. A radical detector combining a nitrone spin trap, a phenol, and a cyclopropane radical clocklike unit was prepared and used with EPR spectroscopy to detect and distinguish between hydroxyl radicals, methyl radicals, and iron(III) ions. Iron(III) reacts with the phenol unit inducing opening of the cyclopropane ring and cyclization to generate a stable nitroxyl radical.     

Preparation of alpha-(2,2-diphenylhydrazino)lactones and related compounds by radical cyclization: use of glyoxylic acid hydrazone derivatives

Glyoxylic acid diphenylhydrazone (2a) and the corresponding O-benzyloxime (2b) are easily esterified in high yield by beta-bromo alcohols. The resulting esters undergo radical cyclization to alpha-(2,2-diphenylhydrazino)- or alpha-[(phenylmethoxy)amino]lactones on treatment with tributyltin hydride. Esters for radical cyclization were also made using a beta-(phenylseleno) alcohol and an enol ether. Several derivatives of glyoxylic acid were evaluated, but none was as effective as 2a or 2b. The imine 28 was prepared by an indirect route; it undergoes radical cyclization with displacement of the nitrogen substituent (28 --> 30) so that an alpha-amino lactone can be generated by acid hydrolysis of the cyclization product.     

An electron spin resonance study of radicals from chloramine-t-1 : Spin trapping of radicals produced in acid media

Under acid conditions aqueous solutions of chloramine-T form nitrogen-centred radicals via loss of the chlorine atom. The nitrogen radicals produced have been studied by ESR spectroscopy using the spintrapping method. Adducts of the spin trap phenyl-t-butyl nitrone are oxidized by chloramine-T in acid media to give a paramagnetic product in which the unpaired electron interacts with two inequivalent nitrogen atoms. The spin trap 5,5-dimethyl-2-pyrrolidine-1 -oxide is oxidized rapidly to 5,5-dimethyl-2-pyrrolidone-1-oxyl by chloramine-T under acid onditions. The water soluble trap α-4-pyridyl-1-oxide-N-t-butyl nitrone forms a stable nitroxide adduct with a nitrogen radical of chloramine-T in acid solution. Identical results were obtained with chloramine-B (sodium salt of N-chlorobenzene sulfonamide), indicating the involvement of the N-chloramine group in radical formation.     

On the formation of arseno aminoxyls (nitroxides) by spin trapping of arseno radicals

The ·AsO₂ radical is detected by spin trapping using 2-methyl-2-nitrosopropane producing a new aminoxyl spin adduct. As0₄·^2? is trapped as an oxygen-centered radical by phenyl $\text{tert}$-butyl nitrone.