Benzyl radical addition reaction through the homolytic cleavage of a benzylic C-H bond.

Direct generation of a benzyl radical by C-H bond activation of toluenes and the addition reaction of the resulting radical to an electron deficient olefin were developed. The reaction of dimethyl fumarate with toluene in the presence of Et(3)B as a radical initiator at reflux afforded 2-benzylsuccinic acid dimethyl ester in good yield.

Palladium-catalyzed cross coupling reaction of N-alkoxyimidoyl bromides and its application to one-pot synthesis of N-arylamines.

The synthetic utility of N-alkoxyimidoyl halides is demonstrated using the palladium-catalyzed cross-coupling reaction. The Sonogashira and Suzuki-Miyaura coupling reactions of N-alkoxyimidoyl bromides produced versatile ketoxime ethers in good to excellent yields. A one-pot reaction of the imidoyl bromides with arylboronic acid and allylmagnesium bromide to produce N-arylamines via Suzuki-Miyaura coupling followed by domino reaction involving sequential addition-eliminative rearrangement-addition reactions was developed.

Efficient entry into 2-substituted tetrahydroquinoline systems through alkylative ring expansion: stereoselective formal synthesis of (+/-)-martinellic acid.

A new efficient synthesis of 2-substituted tetrahydroquinolines has been achieved by the domino reaction of N-indanyl(methoxy)amines, which consists of three types of reactions: elimination of an alcohol, the rearrangement of an aryl group, and the addition of an organolithium or magnesium reagent. The synthetic utility of this approach is demonstrated by the stereoselective formal synthesis of (+/-)- martinellic acid.

Highly effective synthetic methods for substituted 2-arylbenzofurans using [3,3]-sigmatropic rearrangement: short syntheses of stemofuran a and eupomatenoid 6.

A new and efficient synthesis of 2-arylbenzofurans has been achieved via a route involving acylation and subsequent [3,3]-sigmatropic rearrangement of oxime ethers. Its synthetic utility is demonstrated by a short synthesis of stemofuran A and eupomatenoid 6 in which no procedure for protection of the phenolic hydroxyl groups is needed. [reaction--see text]

Indium-mediated intermolecular alkyl radical addition to electron-deficient C [double bond] N bond and C [double bond] C bond in water.

[reaction: see text] The intermolecular alkyl radical addition to imine derivatives was studied in aqueous media by using indium as a single-electron-transfer radical initiator. The one-pot reaction based on radical addition to glyoxylic hydrazone provided a convenient method for preparing the alpha-amino acids. The indium-mediated radical addition to an electron-deficient C=C bond also proceeded effectively to provide the new carbon-carbon bond-forming method in aqueous media.

Addition of electrophilic and heterocyclic carbon-centered radicals to glyoxylic oxime ethers.

[reaction: see text] Stabilized primary radicals can be formed from alkyl halides in an atom transfer process with Et(3)B. This process depends on the strength of the carbon-halogen bond and the stability of the resulting primary radical. Radicals formed from benzyl iodide and ethyl iodoacetate add to glyoxylic oxime ethers; however, more electrophilic radicals do not. Glyoxylic oxime ethers are also good radical acceptors for heterocyclic carbon-centered secondary radicals, giving novel alpha-amino acid derivatives.

Indium-mediated tandem radical addition-cyclization-trap reactions in aqueous media.

[reaction: see text] Tandem carbon-carbon bond-forming reactions were studied by using indium as a single-electron-transfer radical initiator. The radical addition-cyclization-trap reaction of a substrate having a vinyl sulfonamide group and an olefin moiety proceeded smoothly in aqueous media. The radical addition-cyclization reaction of hydrazone gave the functionalized cyclic products.

Asymmetric synthesis of alpha-amino acids: indium-mediated reactions of glyoxylic oxime ether in aqueous media.

The indium-mediated allylation and alkylation reactions of the Oppolzer camphorsultam derivative of glyoxylic oxime ether proceeded with excellent diastereoselectivity in aqueous media, providing a variety of enantiomerically pure alpha-amino acids.

Novel intermolecular carbon radical addition to a nitrone: asymmetric synthesis of alpha-amino acids.

A nitrone was used as a synthetically useful radical acceptor in carbon-carbon bond-forming radical reactions; the intermolecular addition of alkyl radicals to chiral glyoxylic nitrone was studied; a high degree of stereocontrol in radical addition to glyoxylic nitrone was achieved to provide a new method for asymmetric synthesis of alpha-amino acids.

Radical Cyclization in Heterocycle Synthesis. 6.(1) A New Entry to Cyclic Amino Alcohols via Stannyl Radical Cyclization of Oxime Ethers Connected with Aldehydes or Ketones.

Oxime ethers connected by a tether to aldehydes or ketones efficiently cyclize via stannyl radical addition-cyclization to provide a new entry to cyclic amino alcohols. Upon treatment with tributyltin hydride in the presence of AIBN, oxime ethers connected with either an aldehyde or a ketone via a nitrogen atom smoothly underwent stannyl radical addition-cyclization to give five- to seven-membered cis- and trans-heterocyclic amino alcohols of which the trans-isomers were major products. The newly found radical cyclization provides a novel method for preparing not only bifunctionalized heterocyclic compounds but also adjacently functionalized amino alcohols carrying two quaternary carbons.

Phosphatidylcholine hydroperoxide levels in human plasma are lower than previously reported.

The quantification of PC hydroperoxide (PCOOH) in human plasma was studied by HPLC with chemiluminescence detection (HPLC-CL). We identified for the first time the monohydroperoxide of 1-palmitoyl-2-linoleoyl-PC hydroperoxide (PC 16:0/18:2-OOH) in plasma by LC-MS and HPLC-CL. The standard compound, PC 16:0/18:2-OOH (synthetic PCOOH), as well as PCOOH from egg yolk, was used. Comparison of the PCOOH concentration in each participant's plasma as determined by use of a Finepak SIL NH2 column with 2-propanol/methanol/water as the mobile phase (system A, the conventional method) gave a higher concentration than did an LC-18-DB column with methanol containing 0.01% triethylamine (system B). The mean PCOOH concentration for the 43 healthy volunteers was 55.1+/-30.4 pmol/mL (mean+/-SD) for system A and 16.3+/-9.9 pmol/mL for system B. Moreover, the main peak of the plasma extract appeared at a different time from that of synthetic PCOOH or egg yolk PCOOH in system A, whereas in system B plasma sample retention time practically corresponded to that of standard PCOOH. These findings confirm that the PCOOH plasma concentration is not so high as previously reported.

Synthesis of dihydrobenzofurans with quaternary carbon center under mild and neutral conditions.

A new method has been developed for the construction of dihydrobenzofurans from O-aryloxime ethers bearing an α-cyano group using a sequential regioselective isomerization/[3,3]-sigmatropic rearrangement/cyclization reaction in MeOH without any catalysts under neutral conditions at ambient temperature. The current transformation provides environmentally benign and atom-economical access to a variety of dihydrobenzofurans containing a quaternary carbon from readily available cyclic and acyclic oxime ethers.

Direct synthesis of trisubstituted isoxazoles through gold-catalyzed domino reaction of alkynyl oxime ethers.

Alkynyl oxime ether underwent a gold-catalyzed domino reaction involving cyclization and subsequent Claisen-type rearrangement to afford trisubstituted isoxazoles in a direct, efficient, and regioselective manner. The products were successfully applied to the synthesis of unusual heterocycles as an illustration of the potential utility of the reaction.

Two novel domino reactions triggered by thiyl-radical addition to vinylcyclopropyl oxime ether.

Two domino reactions of vinylcyclopropyl oxime ethers involving (i) thiyl radical addition, ring-opening, and hydroxylation reactions and (ii) thiyl radical addition, ring-opening, and aldol-type reactions were developed.

Aerobic hydroxylation of N-borylenamine: triethylborane-mediated hydroxyalkylation of alpha,beta-unsaturated oxime ether.

Intermolecular hydroxyalkylation of alpha,beta-unsaturated imines involving Et3B-mediated regioselective alkyl radical addition and subsequent hydroxylation with molecular oxygen has been developed, in which N-borylenamine generated by trapping of the enaminyl radical with Et3B was a key intermediate in the proposed aerobic hydroxylation mechanism.

Development of new synthetic reactions for nitrogen-containing compounds and their application.

Nitrogen-containing compounds are core parts not only of natural and synthetic medicines but also of biologically active compounds including natural products. This review focuses on the development of new synthetic reactions for nitrogen-containing compounds via three methodologies: the reductive photocycloaddition reaction of enamides, radical addition reaction, and nucleophilic addition reaction. Newly developed reactions were successfully applied to the synthesis of various types of nitrogen-containing compounds including medicines, lead compounds to new drugs, natural alkaloids, and others.

Total synthesis of (-)-martinellic acid via radical addition-cyclization-elimination reaction.

The asymmetric total synthesis of martinellic acid, the first pyrrolo[3,2-c]quinoline alkaloid found in nature, is described. Three key steps in our synthesis of (-)-martinellic acid are the Bu(3)SnH-promoted radical addition-cyclization-elimination (RACE) reaction of an oxime ether with an alpha,beta-unsaturated ester to generate the pyrrolo[3,2-c]quinoline core, a chemoselective lactam carbonyl reduction, and guanidinylation under Mitsunobu reaction conditions. The key radical cyclization has also been investigated by using SmI(2). (-)-Martinellic acid was synthesized from commercially available methyl 4-bromo-3-methylbenzoate in fewer steps than previous syntheses and in an improved overall yield.