Hiroyuki Ishibashi

Iron-Catalyzed Redox Radical Cyclizations of 1,6-Dienes and Enynes

Treatment of 1,6-dienes and enynes with FeCl(3) or Fe(Pc) in the presence of NaBH(4) and air or O(2) causes radical cyclization to give five-membered carbo or heterocyclic compounds, into which a halogen atom or hydroxyl group was introduced.

Iron-mediated radical halo-nitration of alkenes.

Radical halo-nitration of alkenes using iron(III) nitrate nonahydrate and halogen salt has been developed. The present reaction proceeds by radical addition of nitrogen dioxide generated by thermal decomposition of iron(III) nitrate nonahydrate and subsequent trapping of the resultant radical by a halogen atom in the presence of halogen salt. Application of this method to synthesis of nitroalkenes is also described. The practicality of the present method using nontoxic and inexpensive iron reagents has been shown by the application to broad alkenes.

Iron-mediated radical nitro-cyclization reaction of 1,6-dienes.

Sequential steps that involved radical addition of a nitro group to 1,6-dienes promoted by the thermal decomposition of iron nitrate(III) nonahydrate, cyclization, and trapping of the resulting terminal radicals by a chlorine atom in the presence of chloride salt afforded five-membered-ring compounds. The present reaction provides a practical method for the synthesis of nitro compounds due to its simple experimental procedure and its use of nontoxic and inexpensive iron reagents.

A New Synthesis of 2,3-Di- or 2,3,3-Trisubstituted 2,3-Dihydro-4-pyridones by Reaction of 3-Ethoxycyclobutanones and N-p-Toluenesulfonyl Imines Using Titanium(IV) Chloride: Synthesis of (±)-Bremazocine

N-p-Toluenesulfonyl (Ts) aldimines reacted with 3-ethoxycyclobutanones by catalysis of titanium(IV) chloride to afford 2,3-di- or 2,3,3-trisubstituted N-Ts-2,3-dihydro-4-pyridones. Synthesis of (+/-)-bremazocine was efficiently accomplished by using this method.

Synthesis of the Core of Actinophyllic Acid Using a Transannular Acyl Radical Cyclization

A synthetic study of actinophyllic acid based on an original strategy has been described. A transannular acyl radical cyclization allowed us to obtain a key bicyclo[3.3.2] framework, and construction of a core of the target alkaloid has been accomplished by subsequent introduction of a C2 unit.

Asymmetric Synthesis of 2,3-Dihydro-4-pyranones by Reaction of Chiral 3-Alkoxycyclobutanone and Aldehydes

Chiral cyclobutanone which had ethyl l-lactate as a chiral auxiliary at the 3-position reacted with aldehydes to give 2,3-dihydro-4-pyranones in up to 93% ee by combined use of titanium(IV) chloride and tin(II) chloride.

Iodine-mediated α-acetoxylation of 2,3-disubstituted indoles.

A new method for direct α-functionalization of 2,3-disubstituted indoles has been developed. The present reaction provides α-acetoxy indole derivatives regioselectively under mild conditions using commercially available and nontoxic iodine reagents. This reaction is a useful synthetic tool because obtained α-acetoxy products can be transformed into various functionalized indoles by substitution reactions with nucleophiles.

Brønsted acid catalyzed asymmetric reduction of ketones and acyl silanes using chiral anti-pentane-2,4-diol.

Ketones and acyl silanes were reduced to the corresponding alcohols by a simple procedure employing anti-1,3-diol and a catalytic amount (5 mol %) of 2,4-dinitrobenzenesulfonic acid in benzene at reflux. Asymmetric induction reached up to >99% ee when a chiral pentane-2,4-diol of 97% ee was used.

Identification of stemonamide synthetic intermediates as a novel potent anticancer drug with an apoptosis-inducing ability.

We previously demonstrated that Pim‐3, a protooncogene with serine/threonine kinase activity, was aberrantly expressed in malignant lesions but not in normal tissues of endoderm‐derived organs, including pancreas, liver, colon and stomach. Moreover, aberrantly expressed Pim‐3 can prevent tumor cell apoptosis by inactivating a proapoptotic molecule, Bad, and enhancing the expression of an antiapoptotic molecule, Bcl‐XL. These observations prompted us to speculate that a chemical targeting Pim‐3 kinase may be a good candidate for a novel type of anticancer drug. Hence, we screened various low‐molecule compounds by examining their capacity to inhibit Pim‐3 kinase activity in vitro. We observed that some synthetic intermediates of stemonamide can inhibit in vitro activities of Pim‐3 kinase and its related kinases, such as Pim‐1 and Pim‐2. Moreover, these compounds inhibit in vitro cell proliferation of various human pancreatic, hepatocellular and colon cancer cell lines. Furthermore, the compounds can induce apoptosis of human pancreatic cancer cell lines in vitro by reducing the amount of phospho‐Ser112‐Bad, but not total amounts of Bad and Pim‐3. Finally, when the compound was administered to nude mice injected with a human pancreatic cancer cell line, it retarded tumor growth by increasing apoptotic cell numbers and decreasing proliferating cell numbers without causing serious adverse effects on blood counts. These observations indicate that the chemicals and its related compounds may be effective for the treatment of tumors of endoderm‐derived organs, particularly the pancreas.

Syntheses of (±)-Serratine, (±)-Lycoposerramine T, and (±)-Lycopoclavamine B

The first total syntheses of (±)-serratine, (±)-lycoposerramine T, and (±)-lycopoclavamine B have been accomplished. The functionalized octahydroindane skeleton of these natural products was constructed by an efficient Diels-Alder reaction of an α-alkynylcyclopentenone and the stereoselective introduction of a tertiary hydroxyl group. Two of these natural products were divergently synthesized from the same synthetic intermediate at a later stage.