Development of diastereoselective birch reduction-alkylation reactions of bi- and tricyclic beta-alkoxy-alpha,beta-unsaturated ketones.

Diastereoselective Birch reduction-alkylation reactions of bicyclic beta-alkoxy-alpha,beta-unsaturated carbonyl compounds and tricyclic analogues were investigated. Although the relative configuration of the product was altered according to the structure of the starting material, stereoselectivity of the reaction could be accounted for by similar reaction pathways. The product from the tricyclic beta-alkoxy-alpha,beta-unsaturated carbonyl compound corresponded to the trichothecene skeleton.

Generation and suppression of 3-/4-functionalized benzynes using zinc ate base (TMP-Zn-ate): new approaches to multisubstituted benzenes.

We present full details of our new methods for preparing functionalized benzynes with lithium di-alkyl(2,2,6,6-tetramethylpiperidino)zincate (R2Zn(TMP)Li) through deprotonative zincation as a key reaction. In this system, by choosing appropriate ligands for the zincate, either regioselective zincation of functionalized haloaromatics or the generation of substituted benzynes can be controlled in good yields with excellent chemoselectivity, using the same substrate. Zincation with (t)Bu2Zn(TMP)Li followed by electrophilic trapping or zincation with Me2Zn(TMP)Li followed by nucleophilic or diene trapping is shown to be a powerful tool for the chemoselective preparation of 1,2,3-/1,2,4-trisubstituted benzene derivatives.

Palladium-catalyzed C-H activation/intramolecular amination reaction: a new route to 3-aryl/alkylindazoles.

A method for the catalytic C-H activation of hydrazone compounds followed by intramolecular amination is described. It requires the use of a catalytic amount of Pd(OAc)2 in the presence of Cu(OAc)2 and AgOCOCF3, which efficiently effects the cyclization to afford variously substituted indazoles. The reactions proceed under relatively mild conditions and thus tolerate a variety of functional groups, including alkoxycarbonyl and cyano groups and halogen atoms.

Regiocontrolled intramolecular cyclizations of carboxylic acids to carbon-carbon triple bonds promoted by acid or base catalyst.

We systematically investigated, for the first time, the relationship between regioselectivity and acid/base effects in the cyclization reactions between carboxylic acids and carbon-carbon triple bonds. We found novel acid- and base-promoted cyclizations to selectively give isocoumarin or pyran-2(2H)-one and phthalide or furan-2(5H)-one skeletons, respectively, and established a catalytic version of regioselective heterocyclic ring synthesis. Density functional theory calculations and application to a short route to thunberginol A were also described.

Cyclization reactions of homopropargyl azide derivatives catalyzed by PtCl4 in ethanol solution: synthesis of functionalized pyrrole derivatives.

[Structure: see text] PtCl4-catalyzed cyclization reactions of homopropargyl azide derivatives to pyrrole rings were investigated. Using ethanol as solvent with 2,6-di-tert-butyl-4-methylpyridine as the base was found to be the best set of conditions for effecting this ring-closing reaction. These reaction conditions can be applied to the preparation of functionalized pyrrole derivatives, with no effect on the functional groups.

Highly regioselective palladium-catalyzed annulation reactions of heteroatom-substituted allenes for synthesis of condensed heterocycles.

We have developed a highly regioselective synthesis of heterocycles via palladium-catalyzed annulation reaction of heteroatom-substituted allenes. Various aryl halides were reacted and one regioisomer was observed exclusively in all reactions. In addition, subsequent functionalizations of annulated products were carried out using alkyl metal reagents, and the introduction of alkyl moieties was accomplished.

New synthetic method for indole-2-carboxylate and its application to the total synthesis of duocarmycin SA.

The sequential coupling and cyclization reactions between aryl halides and methyl propiolate were investigated. The electron-withdrawing groups on the aromatic ring are essential for producing the methyl indole-2-carboxylate derivatives. On the other hand, the presence of an extra methyl propiolate and Pd(PPh3)4 were required to provide an efficient catalytic system for the cyclization reactions.

Development of a catalytic electron transfer system mediated by transition metal ate complexes: applicability and tunability of electron-releasing potential for organic transformations.

We have developed a catalytic electron transfer (ET) system composed of a transition metal ate complex (Me3M(II)Li; M = Co(II), Mn(II), Fe(II)) and magnesium. This system (catalytic Me3M(II)Li/Mg) turned out to be effective for various ET reactions, such as the desulfonylation of N-phenylsulfonyl amides, and others (the chemoselective cleavage of O-allyl groups, the reduction of nitro groups, the partial reduction of diketones, and the reductive coupling of diphenyliodonium salt). The ET ability of this system can be tuned by changing the ligands of the ate complexes.

Development of an efficient procedure for indole ring synthesis from 2-ethynylaniline derivatives catalyzed by CuII salts and its application to natural product synthesis.

The development of efficient methods for the indole synthesis catalyzed by Cu(II) salts and its applications were investigated. Cu(OAc)(2) has been proved to be the best catalyst for the synthesis of various 1-p-tolylsulfonyl or 1-methylsulfonylindoles, which have both electron-withdrawing and electron-donating groups on the aromatic ring and C2 position of indoles. For the primary aniline derivatives, Cu(OCOCF(3))(2) showed good activities, while Cu(OAc)(2) was a good catalyst for the cyclization of secondary anilines.

Convenient indole synthesis from 2-iodoanilines and terminal alkynes by the sequential Sonogashira reaction and the cyclization reaction promoted by tetrabutylammonium fluoride (TBAF).

The sequential Sonogashira reaction and the cyclization reaction of various 2-iodoanilines and terminal alkynes in the presence of a palladium catalyst and tetrabutylammonium fluoride (TBAF) gave the corresponding 2-substituted indoles in good yields.

Synthesis of betulin derivatives and their protective effects against the cytotoxicity of cadmium.

The protecting effect of betulin against cadmium toxicity was investigated using 11 kinds of analogues. It was elucidated by analyzing the analogue activities that both hydroxyl groups on C-3 and C-28 and the isopropenyl group on C-19 played important roles for expressing efficient activities. In addition, the cytotoxicity of betulin was also reduced by being functionalized using the above functional group.

Generation of functionalized asymmetric benzynes with TMP-zincates. Effects of ligands on selectivity and reactivity of zincates.

We have developed new methods for preparing functionalized benzynes through deprotonative zincation as a key reaction using R2Zn(TMP)Li, and we also describes dramatic ligand effects on the benzyne formation. Deprotonative zincation of various meta-substituted bromobenzenes with Me2Zn(TMP)Li proved effective for the one-pot generation of various 3-functionalized benzynes, particularly those electrophilic substituents such as ester, amide, and cyano. On the other hand, zincation with tBu2Zn(TMP)Li, followed by electrophilic trapping (with I2) proved a powerful tool for the preparation of 1,2,3-trisubstituted aromatic compounds.

New mu-opioid receptor agonists with phenoxyacetic acid moiety.

New muq-opioid receptor (MOR) agonists containing 4-hydroxypiperidine, piperidine and piperazine moieties were synthesized and evaluated to find a peripheral opioid analgesic. Among the synthesized compounds, 12-[1-[3-(N,N-dimethylcarbamoyl)-3,3-diphenylpropyl]-4-hydroxypiperidin-4-yl]phenoxy]acetic acid (8: SS620) having phenoxyacetic acid and 4-hydroxypiperidine moieties showed the highest agonist potency on the MOR in an isolated guinea-pig ileum preparation, and it also had selectivity to the human MOR expressed in Chinese hamster ovary (CHO)-K1 cells compared with the same types of delta- and kappa-opioid receptors (DOR and KOR). In addition, compound 8 showed a 10 times more potent MOR agonist activity than loperamide.

Synthesis of 2,3-disubstituted indole using palladium(II)-catalyzed cyclization with alkenylation reaction.

The reaction of ethyl 2-ethynylphenylcarbamate derivative with alkenes in the presence of a palladium(II) catalyst, copper dichloride and tetrabutylammonium fluoride (TBAF) produced 2-substituted 3-ethenylindoles during refluxing. The intramolecular cyclization reaction of ethyl 2-ethynylphenylcarbamates, which have an ethenyl part in the ethynyl group, was also used to produce carbazole derivatives.

A concise synthesis of furostifoline by tetrabutylammonium fluoride-promoted indole ring formation.

Furostifoline, a furo[3,2-a]carbazole alkaloid, was synthesized in 10% overall yield in four steps from 2-acetyl-3-bromofuran. The key step of this synthesis was the 2-substituted indole formation with tetrabutylammonium fluoride (TBAF) from 2-(2-propenyl)-3-((2-ethoxycarbonylamino)phenylethynyl)furan, which was easily prepared from ethyl 2-ethynylphenylcarbamate with 3-bromo-2-(2-propenyl)furan by the Sonogashira reaction.