西田 篤司

Lundurine A, B, C, and D (1-4) were isolated from a Malaysian plant Kopsia tenuis by Kam and co-workers in 1995. They might be new seeds for anticancer drugs because selective anti-melanoma activities of Lundurine B and D have been reported. In addition, its unique hexacyclic skeleton including cyclopropane-fused indoline is attractive for synthetic organic chemists. Therefore, we have been studying total synthesis of Lundurines. According to Toke's protocol, iodine-mediated intramolecular cyclopropanation using 11 was studied (Table 1). Proper selection of solvent and temperature was important to prepare 10 with high yield and diastereoselectivity (entry 2, 6). 10 was converted into a cyclopropane-fused indoline 9 in 4 steps in good yield (Scheme 1). It is notable that 9 was unstable under acidic conditions, and removal of Boc group induced a cleavage of cyclopropane to give a quinoline 14 (Scheme 2). This tetracyclic lactone 9 was readily converted into a silyl enol ether 20 as a precursor of ring closing metathesis (Scheme 4, 5). Grubbs catalyst 2^<nd> generation was powerful enough for this cyclization to afford a tetracyclic cyclohexanone 6 after desilylation. To construct D and F heterocycles, introduction of nitrogen group on E ring was required (Scheme 6). Overman rearrangement seemed suitable for this purpose, because its intramolecular fashion might overcome some potential steric hindrance around E ring. Indeed, the rearrangement proceeded under heating condition to afford mixture of two diastereomers 26. Further investigations about construction of D and F rings are in progress. We recently started the second generation study on a synthesis of the tetracyclic structure of Lundurines using a new synthetic strategy: SmI_2-mediated reductive cyclopropanation (Figure 2). The key cyclization was proceeded well with addition of LiBr and afforded tetracyclic compound 27 (Scheme 7). This methodology enabled us to prepare 27 in shorter steps and higher yield.

We have developed a novel and efficient method for the preparation of unstable tetramethylzirconium and its application to the synthesis of tetrakis(N-methylethylamido)zirconium and dimethylbis(indenyl)zirconium using a microflow system. © 2012 The Chemical Society of Japan.

This account describes the cyanopalladation of simple and nonactivated alkynes and their application to various cyclization and cycloaddition protocols. A unique feature of cyanopalladation is the direct nucleophilic cyanation with an external CN source such as TMSCN of simple alkynes, which can be effectively activated by Pd(II) under molecular oxygen. There are two possible pathways: syn- and anti-cyanopalladation, which are strongly influenced by the structure of the substrates. The former is usually the major pathway because nucleophilic cyanation is favored to occur at the less hindered alkynyl carbon. The latter could be controlled by the Markovnikov rule, with cyanide directly attacking the π-complex of alkynyl carbons from the site opposite Pd(II). Once the cyanoalkenyl Pd(II) species are formed by cyanopalladation, these intermediates act as useful precursors for sequential carbon-carbon bond-forming reactions, such as 5-exo and 6-endo cyclizations and [4+2] cycloaddition. Cyclization is triggered by regio- and stereoselective cyanopalladation, and [4+2] cycloaddition gives up to five stereogenic centers through the formation of four C-C bonds in a single operation. The reaction pathways and the origin of stereochemistry are also described. 1 Introduction 2 Catalytic 1,2-Dicyanation 2.1 Terminal Alkynes 2.2 Internal Alkynes 2.3 Synthetic Applications 3 Dicyanative Cyclization 3.1 5-exo Cyclization 3.2 Diyne Cyclization 3.2.1 Terminal Diynes 3.2.2 Internal Diynes 3.3 6-endo Cyclization 4 Dicyanative [4+2] Cycloaddition 5 Conclusion. © Georg Thieme Verlag KG · Stuttgart · New York.

Although Ito-Saegusa oxidation gives defined α,β-unsaturated ketones from silyl enol ether of ketones controlled by the position of the sp2 carbon of the silyl enol ether, the formation of a regioisomeric product that was oxidized abnormally was observed. The structural requirements for the substrates, the conditions, and a plausible mechanism are presented. © 2011 Elsevier Ltd. All rights reserved.

Several bicyclic compounds were synthesized by the Diels-Alder reaction using aminodiene and a cyclic dienophile. The stereochemistries of the obtained adducts were determined by X-ray crystallography or NMR analysis. The stereoselectivity of this Diels-Alder reaction was based on the interaction of molecular orbitals between the diene and dienophile. The reactivities of these Diels-Alder reactions were estimated, and the generality of this reaction is discussed. © 2011 Elsevier Ltd. All rights reserved.

Palladium-catalyzed dicyanative [4 + 2] cycloaddition using various ene-enynes was investigated. The key species in this process is a cyanoallene intermediate that is obtained by the cyanopalladation of conjugated enynes followed by 5-exo-cyclization. To achieve an efficient [4 + 2] cycloaddition reaction, both the smooth generation of this species and critical control of regioselectivity in the 6-endo-cyclization step are quite important. A study of the substrate scope revealed that the reaction is strongly affected by the steric bulk of the substituents on the enyne and alkene units and prefers to give trans-fused cycloadducts. The stereochemistry of olefins was reasonably transferred to the corresponding products. Further study proved that this transformation includes not a thermal [4 + 2] cycloaddition process via 1,2-dicyanoalkenes generated in situ but rather a palladium-mediated stepwise cyclization sequence to control a maximum of five contiguous stereogenic centers in a single operation. An intermolecular version using methyl acrylate with conjugated cyclic enynes and TMSCN also gave the corresponding [4 + 2] cycloadducts in a regioselective manner. © 2010 American Chemical Society.

Ceramide-1-phosphate (C1P) regulates cellular functions including arachidonic acid (AA) metabolism and modulates cell fate. The mechanism by which C1P is taken up is unclear, and the development of lipophilic analogs may be useful for regulating C1P's actions. We synthesized new mono- and di-methyl-ester (MM and DM, respectively) analogs of C1P with N-acyl chains of different lengths, and examined their effects on AA release and cell toxicity. Short-N-acyl-DM-C1P analogs including C5- and C6-DM-C1P, but not long-N-acyl-DM-C1P analogs, inhibited the release of AA mediated by α type cytosolic phospholipase A2 (cPLA2α) in Chinese hamster ovary (CHO) cells and the enzymatic activity. Short-N-acyl-DM-C1P analogs including C6-DM-C1P caused morphological changes with cell toxicity 24h after the treatment in three cells lines (CHO, L929, and RLC-18 cells), although the role of AA in the toxicity was not clear. Neither long-N-acyl-DM-C1P analogs nor MM-C1P analogs including C6-MM-C1P affected cPLA2α activity and cell toxicity. Similar to C6-ceramide having a 4-nitrobenzo-2-oxa-1,3-diazole (NBD) group on a C6-N-acyl chain (NBD-C6-ceramide), NBD-C6-DM-C1P and C6-DM-C1P-NBD (with a C6-N-acyl chain and an NBD-labeled C14-alkyl chain) were accumulated in the Golgi complex, although less C6-DM-C1P-NBD than NBD-C6-DM-C1P was taken up. NBD-C6-ceramide was converted to various metabolites including NBD-C6-sphingomyelin, but both NBD-C6-DM-C1P and C6-DM-C1P-NBD were stable in cells within 2h. The short-N-acyl-DM-C1P analogs acted directly as an inhibitor of cPLA2α and an inducer of cell toxicity, and may be useful for the regulation of ceramide/C1P-regulated responses. © 2010 Elsevier Inc.

A new continuous-flow system for C-H borylation has been developed. An insoluble catalyst prepared from chloro(1,5-cyclooctadien)iridium(I) dimer and 2,2′-bipyridine-4,4′-dicarboxylic acid in the presence of bis(pinacolato)diboron exhibited high reactivity under continuous-flow processing without the loss of expensive iridium metal. © 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Figure presented The catalytic asymmetric total synthesis of platyphyllide has been accomplished. A key highly substituted cyclohexene derivative has been obtained by the catalytic asymmetric Diels-Alder reaction of Danishefsky diene with an electron-deficient alkene. The Diels-Alder adduct was converted to a protected cyclohexane-1,3-dione in chiral form by catalytic Ito-Saegusa oxidation. Although the reported structure of platyphyllide was successfully synthesized, the optical rotation was opposite that of the natural compound. The absolute configuration of natural (-)-platyphyllide is revised to be a (6S,7S)-enantiomer. © 2010 American Chemical Society.

A palladium-catalyzed dicyanative [4+2] cycloaddition reaction using dienynes with TMSCN under aerobic conditions is described. This new reaction triggered by the cyanopalladation of terminal alkynes includes regioselective direct cyanation to C-C triple bonds by TMSCN to give --allyl Pd intermediates, which promotes 5- exo followed by 6- endo cyclization. This protocol enables (1) the formation of four C-C bonds through one operation, (2) the construction of highly functionalized cyclohexene rings, and (3) the generation of five contiguous stereogenic centers in one operation. The intermolecular cycloaddition reaction between a conjugated enyne and methyl acrylate also proceeded in a regioselective fashion to give multifunctionalized carbocycles. © 2010 American Chemical Society.

A stereoselective dicyanative 5-exo- and 6endo-cyclization using various enynes has been investigated. The mode of cyclization is critically controlled by the structure of the substrates. For example, N-allyl derivatives prefer 5-exo-cyclization, while methacryloyl amides are transformed to the corresponding lactams with tetra substituted carbons at the alpha-position via 6-endo-cyclization. Both reactions include syn-cyanopalladation to carbon≡carbon triple bonds in the initial step, and sequential cyclization followed by reductive elimination in one operation enables the construction of the highly functionalized nitrogen heterocycles. The scope of suitable substrates and a proposed mechanism are also described. © 2010 Wiley-VCH Verlag GmbH & Co. KGaA.

Aromatic C-H borylation using [IrCl(COD)]2 and 2,2′-bipyridinedicarboxylic acids was studied. 2,2′-Bipyridine-4,4′-dicarboxylic acid was complexed with [IrCl(COD)]2 in the presence of bis(pinacolato)diboron. The resulting iridium catalyst could be readily separated from the reaction mixture by simple filtration, and the recovered catalyst under a nitrogen atmosphere was still active and could be reused more than 10 times. © 2009.

The synthesis and utility of the novel axially chiral bis-urea ligand BINUREA are described. A complex of this urea ligand with ytterbium triflate and DBU can be used in the catalytic enantioselective Diels-Alder reaction of Danishefsky-type diene and electron-deficient olefins to give the adducts in good to excellent yield and enantiomeric excess (ee). © 2009 Elsevier Ltd. All rights reserved.

A. steric and electronic effect: on enamide/ene metathesis, a novel preparation of 2-substituted indoles and 3-substituted indoles using enamide-ene metathesis as a key reaction, and its application to the synthesis of indoniethacin are described. © Wiley-VCH Verlag GmbH &amp; Co. KGaA.

A stereoselective 1,2-dicyanation of various alkynes in the presence of trimethylsilyl cyanide (TMSCN) by palladium(II) catalysis under aerobic conditions is investigated. This reaction includes two cyanation pathways, syn- and anti-cyanopalladation to alkynes that are activated by Pd(II). High syn-selectivity was observed in the reaction using terminal alkynes that have bulky substituents at a propargyl position and aliphatic internal alkynes. Furthermore, a dramatic acceleration was observed with substrates having an N-arenesulfonyl functionality at a propargyl position, this indicates that both sulfoxide and carbon-carbon triple bond act as Lewis bases to Pd(II). © 2009 Wiley-VCH Verlag GmbH & Co. KGaA.

Essential oxygen: The title transformation involves two different modes of cyanation, syn and anti cyanopalladation, as the key steps in this catalytic reaction. These processes enable successful dicyanative cyclization of diyne and enyne derivatives (see scheme). © 2009 Wiley-VCH Verlag GmbH & Co. KGaA.

A new palladium-catalyzed cyclization of N-alkenyl-o-haloanilines with selective isomerization of a double bond followed by formal 5-endo-trig cyclization was developed. A variety of fused and 2-substituted indoles were synthesized from enaminoesters prepared by condensation of β-ketoesters and o-iodoaniline. © 2008 Elsevier Ltd. All rights reserved.

Sphingolipid metabolites including ceramide, sphingosine, and their phosphorylated products [sphingosine-1-phosphate (S1P) and ceramide-1-phosphate] regulate cell functions including arachidonic acid (AA) metabolism and cell death. The development of analogs of S1P may be useful for regulating these mediator-induced cellular responses. We synthesized new analogs of S1P and examined their effects on the release of AA and cell death in L929 mouse fibrosarcoma cells. Among the analogs tested, several compounds including DMB-mC11S [dimethyl (2S,3R)-2-tert-butoxycarbonylamino-3 -hydroxy-3-(3 '-undecyl)phenylpropyl phosphate] and DMB-mC9S [dimethyl (2S,3R)-2-tert- butoxycarbonylamino-3-hydroxy-3-(3'-nonyl)phenyl- propyl phosphate] released AA within 1 h and caused cell death 6 h after treatment. The release of AA was observed in C12 cells [a L929 variant lacking a type a cytosolic phospholipase A2 (cPLA2a)] and L929-cPLAa-siRNA cells (L929 cells treated with small interference RNA for cPLA2a). Treatment with pharmacological inhibitors of secretory and Ca2+-independent PLA2s decreased the DMB-mC11S-induced release of AA. The effect of the S1P analogs tested on the release of AA was comparable to that on cell death in L929 cells, and a high correlation coefficient was observed. Two analogs lacking a butoxycarbonyl moiety [DMAc-mC11S (dimethyl (2S,3R)-2-acetamino-3-hydroxy-3-(3'-undecyl)phenylpropyl phosphate] and DMAm-mC11S [dimethyl (2S,3R)-2-amino-3-hydroxy-3-(3'-undecyl)phenylpropyl phosphate)] had inhibitory effects on the release of AA and cell toxicity induced by DMB-mC11S. Synthetic phosphorylated lipid analogs may be useful for studying PLA2 activity and its toxicity in cells. [Supplementary Fig. 1: available only at http://dx.doi.org /10.1254/jphs.08284FP] © 2009 The Japanese Pharmacological Society.

A novel method for the synthesisof chiral hydroisoquinolines by asymmetricDiels-Alder reaction of nitrogen-containing dienophiles and suitably protected aminosiloxybutadienes has been developed. © 2009 The Chemical Society of Japan.

The γ-aminobutyric acid (GABA) receptor bears important sites of action for insecticides. Alantrypinone is an insecticidal alkaloid that acts as a selective antagonist for housefly (vs rat) GABA receptors, and is considered to be a lead compound for the development of a safer insecticide. In an attempt to obtain compounds with greater activity, a series of racemic alantrypinone derivatives were systematically synthesized using hetero Diels-Alder reactions, and a total of 34 compounds were examined for their ability to inhibit the specific binding of [3H]4′-ethynyl-4-n-propylbicycloorthobenzoate, a high-affinity non-competitive antagonist, to housefly-head membranes. The assay results showed that (1) there is no significant difference between the potencies of natural (+)-alantrypinone and its synthetic racemate; (2) the amide NHs at the 2- and 18-positions are important for high activity; (3) there is a considerable drop in potency for compounds without an aromatic ring at the 16-position; and (4) a large substituent at the 3-position is detrimental to high activity. © 2008 Elsevier Ltd. All rights reserved.

1-Methoxy-3-trimethylsiloxy-1,3-butadiene (Danishefsky-s diene) is recognized as a synthetically useful diene due to its high reactivity in the Diels-Alder reaction with electron-deficient alkenes to give oxygen-functionalyzed cyclohexenes and substituted cyclohexenones, which are important building blocks for the total synthesis of natural products. However, the development of catalytic enantioselective versions of Diels-Alder reactions using Danishefsky type dienes with electron-deficient alkenes has been difficult because of the instability of the dienes under Lewis acidic conditions. Only highly reactive C=O and C=N double bonds are employed in a hetero-Diels-Alder reaction which proceeds under catalysis of chiral Lewis acids. We have developed a new chiral ligand, BINAMIDE, which is easily prepared from 1,1′-binaphtyl-2,2′-diamine by acylation. The highly diastereo- and enantioselective Diels-Alder reaction of Danishefsky type dienes with electron-deficient alkenes in the presence of an Yb(III)-BINAMIDE complex has been developed. The reaction proceeded in an exoselective mode and gave chiral highly functionalized cyclohexene derivatives in good yields. Copyright © 2008 American Chemical Society.

(Chemical Equation Presented) A new and facile access to cinnolines, dihydrocinnolines, and 1-aminoindolines was established by use of diazo functionalities. The hydrazines and hydrazones as cyclization precursors derived from 3-haloaryl-3-hydroxy-2-diazopropanoates, which are prepared by one-pot procedure utilizing phase-transfer catalysis, are successfully converted to the corresponding nitrogen heterocycle by Cu-catalyzed N-arylation. Furthermore, analysis of UV spectra proved that 4-oxo-3-carboxylates predominantly exist not as 4-hydroxycinnoline (enol form) but as cinnolone (keto form). © 2008 American Chemical Society.

Chelated tethering ligands were confined on a Au(111) substrate, and the confinement of the ligands was confirmed by X-ray photoelectron spectroscopy (XPS). Palladium was anchored to the ligands to construct heterogeneous (Pd)-L-Au(111) catalysts (L = ligand). A (Pd)-Au(111) catalyst was also prepared by adsorbing the Pd complex directly on the Au(111) substrate without a tethering ligand. Both types of catalysts were used in the Mizoroki-Heck reaction to evaluate their catalytic activities. The tether-ligated Pd catalyst (Pd)-L-Au(111) activity decreased with recycling, whereas the (Pd)-Au(111) catalyst was quite stable upon reuse. The surfaces of both catalyst types were evaluated using XPS to determine the presence of tethering ligands and/or Pd on the Au(111). The ligands of the tether-ligated Pd catalysts could not be detected on the Au(111) surface after the Mizoroki-Heck reaction, which suggests weak bonding of the S-Au by which the ligand is bound to the Au(111) substrate. © 2008 The Chemical Society of Japan.

Tricyclic core of manzamine B was successfully synthesized through asymmetric Diels-Alder reaction and RCM strategy. Cr-salen-F complex was found to be the most effective catalyst in DA reaction of aminodienes with heterocyclic dienophiles to give up to 97% ee. In the construction of 11-membered ring by RCM, first-Grubbs cat. gave better stereoselectivity. © 2006 Elsevier Ltd. All rights reserved.

Sphingosine 1-phosphate (S1P) receptors are G-protein-coupled receptors. Among the five identified subtypes S1P1-5, the SIP3 receptor expressed on vascular endothelial cells has been shown to play an important role in cell proliferation, migration, and inflammation. A pharmacophore-based database search was used to identify a potent scaffold for an S1P3 receptor antagonist by common feature-based alignment and further validated using the Güner-Henry (GH) scoring method. Assumed excluded volumes were merged into this model to evaluate the steric effect with the S1P3 receptor. Three commercially available compounds were identified as S1P3 receptor antagonists, with IC50 values <5 μM. The synthesis of further derivatives revealed that the 3,4-dialkoxybenzophenone scaffold is a potent component of an S1P3 receptor antagonist. Our results indicate that pharmacophore-based design of S1P3 receptor antagonists can be used to expand the possibility of structural modification through scaffold-hopping based on a database search. © 2007 American Chemical Society.

Our synthetic study of nitrogen-containing heterocycles using ring-closing metathesis (RCM), such as chiral bicyclic lactams, azacycloundecenes, axially chiral macrolactams, 1,2-dihydroquinolines, 2-quinolinone and indoles, including a development of silyl-enol ether ene metathesis and isomerization of terminal olefins, are described. Their applications to natural product synthesis are also reported. © 2006 Elsevier B.V. All rights reserved.

A new type of furan-iminium cation cyclization was developed and successfully applied to the synthesis of 25, a central core of ircinal A. Compound 25 was efficiently converted to racemic ircinal A, a biogenetic and synthetic precursor of manzamine A. An asymmetric synthesis of ircinal A will also be discussed.

We have developed a method for preparing a recyclable and environmentally benign organopalladium catalyst for the Heck reaction supported on sulfur-terminated gallium arsenide(001). This three-component catalyst, {Pd}-S-GaAs(001), exhibited high stability and activity, furthermore, it tolerated reuse in 10 runs of the Heck reaction (average yield, 97%) under aerobic conditions. The sulfur layer was very important to stabilize this catalyst. Only trace amounts of Pd were leached from this catalyst to the reaction mixture, as measured by ICP-mass. The valence of immobilized Pd was zero by XPS spectrometry. © 2006 Wiley-VCH Verlag GmbH & Co. KGaA.

A pure ruthenium hydride complex with N-heterocyclic carbene (NHC) ligand was efficiently generated from the reaction of a second-generation Grubbs ruthenium catalyst with vinyloxytrimethylsilane and unambiguously characterized. This ruthenium hydride complex showed high catalytic activity for the selective isomerization of terminal olefin and for the cycloisomerization of 1,6-dienes. These reactions of N-allyl-o-vinylaniline lead to novel synthetic methods for heterocycles such as indoles and 3-methylene-2,3-dihydroindoles, which are useful synthons for bioactive natural products. These procedures address an important issue in diversity-oriented synthesis. © 2006 American Chemical Society.

Highly reactive organopalladium catalysts have been successfully developed on a sulfur-terminated (S-terminated) GaAs(001) substrate, which has a highly uniform (2 × 6) reconstructed surface formed by molecular-beam epitaxy. This new material catalyzed the coupling reaction of iodobenzene and methyl acrylate and could be used repeatedly at least ten times to give good to excellent yields in the Heck reaction. The immobilization of organopalladium in acetonitrile at 100°C followed by treatment at elevated temperature in acetonitrile is essential for producing an active and stable catalyst on S-terminated GaAs(001). Moreover, we have shown that the amount of S-Ga bonds is responsible for stabilizing the activity of the catalyst. In addition, we examined the physical character of organopalladium on a surface before and after the Heck reaction by X-ray photoelectron spectroscopy (XPS). © 2006 The Japan Society of Applied Physics.

The one-pot synthesis of α-diazo-β-hydroxyesters from sodium azide under phase-transfer-catalyzed conditions has been achieved. This protocol includes three different chemical transformations promoted by a single catalyst in each step to give products in good to excellent yields. The reaction was applied to a catalytic asymmetric aldol-type reaction using α-diazoesters with aldehydes in the presence of a chiral quaternary ammonium salt and gave products with up to 81% ee. The diastereoselective transformation of the products to chiral α-amino-β-hydroxyester derivatives is also described. © 2005 Elsevier Ltd. All rights reserved.

Fistulosin 1, which was isolated from the root of the Welsh onion, is a novel indole alkaloid that has antifungal activity. The first total synthesis of the reported structure of fistulosin using our cycloisomerization of diene is described. © 2006 American Chemical Society.

A catalytic asymmetric Michael reaction using Schiff bases promoted by D2-symmetrical ammonium salts as phase-transfer catalysts is described. The reaction of glycine Schiff base (1a) gave the Michael adduct with up to 91% ee and tetrasubstituted carbons was also constructed using alanine Schiff base (3a) with up to 63% ee. © 2006 The Japan Institute of Heterocyclic Chemistry.

A simple and facile method for the cleavage of carbon-oxygen bonds promoted by niobium pentachloride(V) is described. Excellent yields and regioselectivities were observed with various alkyl aryl ethers to give the phenols. NMR studies revealed the formation of monoaryloxy niobium salt(V), and a neighboring-group effect may play a significant role in the regioselectivity. © Wiley-VCH Verlag GmbH & Co. KGaA, 2006.

(Chemical Equation Presented) A new type of furan-iminium cation cyclization was developed and used to construct the ABC ring of manzamine A. The cyclization proceeded at the 2-position with complete regio- and stereoselectivity to give a spiro-center. The product was efficiently converted to the highly substituted core structure of manzamine A. © 2006 American Chemical Society.

Facile access to optically active pyrroloindoles by Fischer-type pyrroloindole synthesis is investigated. The reaction using chiral hydrazines prepared from commercially available chiral amines proceeded with diastereoselective cyclization (up to 70% de), and a short-step conversion of the cycloadducts to (-)-desoxyeseroline and pyrroloindole alkaloids was achieved. © 2005 The Japan Institute of Heterocyclic Chemistry.

An efficient method for the preparation of N-sulfonyl-2-quinolinone using ring-closing metathesis (RCM) is described. © 2005 The Japan Institute of Heterocyclic Chemistry.

An efficient homocoupling of imines to give vicinal diamines promoted by low-valent niobium, generated by treatment of NbCl5 with zinc powder, is described. The desired products were obtained in good to excellent yields. Dihydroisoquinoline derivatives also gave the coupling products with good diastereoselectivities (D,L/meso). Optical resolution of the racemic octahydrobiisoquinolines was achieved and their complexes with Cu1 used in the catalytic asymmetric oxidative coupling of β-naphthols. © Wiley-VCH Verlag GmbH & Co. KGaA, 2005.

The reaction of N-allyl-ortho-vinylaniline with ruthenium carbene catalyst at 50 °C gives substituted 1,2-dihydroquinoline through ring-closing metathesis (RCM), which is easily converted to the corresponding quinoline after deprotection. In sharp contrast, when vinyloxytrimethylsilane is added to this reaction mixture, 1,2-dihydroquinoline is not formed and selective isomerization of N-allyl-ortho-vinylaniline is observed at 50 °C to give corresponding enamide, which is successfully converted to indole derivative by RCM. The same catalyst system provide indoline derivative at 160 °C by cycloisomerization. Based on a detailed mechanistic study, it becomes clear that a ruthenium carbene catalyst, which is highly effective for RCM, reacts with an electron-rich terminal olefin selectively, and another ruthenium species, which effectively catalyzes the isomerization of terminal olefin and cycloisomerization of alpha, omega-diene, is generated. © 2005 Elsevier B.V. All rights reserved.

d-erythro-Sphingosine-1-phosphate (S1P), a sphingolipid metabolite, affects various neuronal functions including cell fate. S1P appears to have contradictory effects in PC12 cells, a neuronal model cell line; neurite retraction and cell survival/differentiation. In the present study, we examined whether S1P induces cell death in undifferentiated PC12 cells. Culture with S1P at 20 μM for 4 h caused lactate dehydrogenase leakage 24 h later. The response was reduced by an inhibitor of caspases and accompanied by the release of cytochrome c and DNA fragmentation. S1P caused the phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK) within 10 min. An inhibitor of p38 MAPK (10 μM SB203580) inhibited both the release of cytochrome c and DNA fragmentation induced by S1P. Treatment with nerve growth factor or pertussis toxin (PTX) decreased S1P-induced phosphorylation of p38 MAPK and cell death. These findings suggest that S1P-activated p38 MAPK acts as a death signal upstream of the release of cytochrome c. N-Monomethyl-S1P (MM-S1P), a weak agonist in cells expressing S1P1 receptors, had marked effects (phosphorylation of p38 MAPK, release of cytochrome c and DNA fragmentation) at lower concentrations than S1P and in a PTX-sensitive manner. These findings show that the activation of S1P receptors by S1P and MM-S1P causes cell death accompanied by DNA fragmentation via the p38 MAPK pathway-mediated release of cytochrome c in PC12 cells. The potential of S1P and MM-S1P to act as agonists of S1P receptors and as intracellular messengers is discussed. © 2005 Elsevier Inc. All rights reserved.

Friedel-Crafts acylation catalyzed by niobium pentachloride with silver salt is described. Aromatic compounds with Ac2O or Bz2O were smoothly converted into the corresponding ketones in good to excellent yields. This system was also applied to the Sakurai-Hosomi reaction using acetals. The reaction proceeded quite rapidly to give the desired products in excellent yields. © 2005 Elsevier Ltd. All rights reserved.

Angustureine, isolated from the bark of Galipea officinalis Hancock, is a novel quinoline alkaloid with a n-pentyl side chain at the 2-position. The total synthesis of (+)-(S)-angustureine and a determination of the absolute configuration of the natural product angustureine were achieved using ring-closing metathesis (RCM) and the Mitsunobu reaction as key steps. © 2005 Elsevier Ltd. All rights reserved.

Sphingolipid metabolites such as sphingosine regulate cell functions including cell death and arachidonic acid (AA) metabolism. d-erythro-C18- Sphingosine-1-phosphate (d-e-S1P), a sphingolipid metabolite, acts as an intracellular messenger in addition to being an endogenous ligand of some cell surface receptors. The development of S1P analogs may be useful for studying and/or regulating S1P-mediated cellular responses. In the present study, we found that several synthetic S1P analogs at pharmacological concentrations stimulated AA metabolism and cell death in PC12 cells. d-erythro-N,O,O- Trimethyl-C18-S1P (d-e-TM-S1P), l-threo-O,O-dimethyl-C18-S1P (l-t-DM-S1P) and l-threo-O,O-dimethyl-3O-benzyl-C18-S1P (l-t-DMBn-S1P) at 100 μM stimulated [ 3H]AA release from the prelabeled PC12 cells. l-t-DMBn-S1P at 20 μM increased prostanoid formation in PC12 cells. l-t-DMBn-S1P-induced AA release was inhibited by d-e-sphingosine, but not by the tested PLA 2 inhibitors. l-t-DMBn-S1P did not stimulate the activity of cytosolic phospholipase A 2α (cPLA 2α) in vitro and the translocation of cPLA 2α in the cells, and caused AA release from the cells lacking cPLA 2α. These findings suggest that l-t-DMBn-S1P stimulated AA release in a cPLA 2α-independent manner. In contrast, d-e-S1P and d-erythro-N-monomethyl-C18-S1P caused cell death without AA release in PC12 cells, and the effects of d-e-TM-S1P, l-t-DM-S1P and l-t-DMBn-S1P on cell death were limited. Synthetic S1P analogs may be useful tools for studying AA metabolism and cell death in cells. © 2004 Elsevier Inc. All rights reserved.

We have recently completed the total synthesis of nakadomarin A utilizing furan-iminium cation cyclization, that is, intramolecular vinylogous Mannich reaction of furan. In this time, further application of this reaction to the synthesis of manzamine A was investigated. We expected that 6/6/5 tricyclic core of manzamine A would be constructed by furan-iminium cation cyclization between spiro iminium cations 1 and 2-furyl group connected to A ring with 1 or 2 carbon unit. Firstly, two cyclization precursors, 12 and 19, were prepared. From spirolactam 5, C1 unit and 2-furyl group were introduced to give furyl ketone 7 by carbonylative Stille coupling. Then deprotection and 1,2-reduction of enone gave secondary alcohol 10. Following protection of alcohol and reduction of lactam gave hemiaminal 12. On the other hand, C2 unit and 2-furyl group were introduced to 5 stepwisely. Wittig reaction of 5 gave exo olefin 13 which was diastereoselectively hydrogenated after deprotection of PMB to give 15. Then the ester 15 was converted to 2-furyl ketone 16 via Weinreb amide. After the protection of carbonyl group of ketone, hemiaminal 19 was obtained in similar protocol as above. Then, furan-iminium cation cyclization was examined. Both 12 and 19 cyclized regioselectively at 2-position of furan under mild acidic conditions. Furthermore, the stereochemistry of spiro center was completely controlled to give the ABC ring system of manzamine A with correct stereocenters. In conclusion, we have developed the new strategy of furan-iminium cation cyclization. This methodology would be effective in construction of carbon flameworks. Total synthesis of manzamine A using this strategy is now under investigating.

A more reactive palladium catalyst than homogeneous Pd(PPh 3)4 catalyst for the Heck reaction supported on a sulfur-terminated GaAs(001) plate was developed. Sulfur termination using (NH4)2Sx at 60°C and Pd absorption in acetonitrile at 100°C is essential for the preparation of an active and stable catalyst. The catalyst could be reused in this reaction up to ten times.