Proceedings of the Symposium on Progress in Organic Reactions and Syntheses
31th Synposium on Progress in Organic Reactions and Syntheses
Showing 1-50 articles out of 148 articles from the selected issue
  • Lisa Araki, Shinya Harusawa, Maho Yamaguchi, Mihoyo Fujitake, David M. ...
    Session ID: 1O-01
    Published: 2005
    Released: October 01, 2006
    CONFERENCE PROCEEDINGS FREE ACCESS
    We describe the synthesis of a novel C4-linked imidazole ribonucleoside phosphoramidite (PA). Investigation of protecting groups for the imidazole-N first indicated that pivaloyloxymethyl (POM) was adequate as an N-protecting group for the imidazole nucleoside which could be readily removed under mild basic conditions. The PA was subjected to a TBDMS approach of RNA automatic synthesis to provide an imidazole-substituted VS ribozyme (A756Imz) in an average 99 % coupling yield. The A756Imz catalyzed the almost-complete cleavage of a substrate stem-loop at the correct position. The result powerfully supported a direct role of the nucleobase at position 756 in the chemistry of natural VS ribozyme. Further, in this study, we found that the accurate MW of PAs may be generally determined by using TEOA-NaCl matrix system on LSIMS equipped with a double-focusing mass spectrometer.
  • Midori A. Arai, Hideki Hara, Ryuji Tsutsumi, Tai C. Chen, Toshiyuki S ...
    Session ID: 1O-02
    Published: 2005
    Released: October 01, 2006
    CONFERENCE PROCEEDINGS FREE ACCESS
    Synthesis of 25-hydroxy-19-norvitamin D3 derivatives as prohormone type agents for anti-prostate diseases was accomplished utilizing Julia-type olefination. The compounds showed potent antiproliferative activity on an immortalized normal prostate cell line, PZ-HPV-7. We demonstrated that 25-hydroxy-19-norvitamin D3 was hydroxylated to form 1?,25-dihydroxy-19-norvitamin D3 by human 1?-hydroxylase (CYP27B1) in a cell-free system. Moreover, we have developed a novel rapid analyzing system of ligand induced cofactor recruitment on vitamin D receptor (VDR) using fluorophore labeled coactivator (CoA) and HCHO fixing of the complex. Recruitment of CoA by 19-norvitamin D3 derivatives was analyzed using this system in a high-throughput manner. Efficiency of recruiting of CoA would explain discrepancy between strong biological activity and weak VDR binding affinity of ligands.
  • Satoshi Ueda, Kenji Tomita, Mai Nomura, Akira Otaka, Nobutaka Fujii
    Session ID: 1O-03
    Published: 2005
    Released: October 01, 2006
    CONFERENCE PROCEEDINGS FREE ACCESS
    On the basis of our recent investigation into lipid bilayer-assisted chemical synthesis of 7TM-GPCR, a new method for sequential native chemical ligation (NCL) using a peptide building block with both N-terminal Cys and C-terminal thioester was strongly demanded for the synthesis of multi-topic membrane proteins. Newly developed phenacyl-type protection (Mapoc) for amines provides a facile and efficient synthetic protocol for peptides/proteins, where sequential NCL in the same vessel can be conducted in a purification-free manner. As a practice toward the chemical synthesis of 7TM-GPCR, we applied this protecting group for one-pot synthesis of human brain natriuretic peptide (BNP) using three peptide fragments. Sequence of reaction consisting of 1st NCL, deprotection, 2nd NCL and disulfide formation was conducted in one-pot to give BNP with a high yield and high purity.
  • Yoshio Hayashi, Tomoya Kotake, S. Rajesh, Shigenobu Nishiguchi, To ...
    Session ID: 1O-04
    Published: 2005
    Released: October 01, 2006
    CONFERENCE PROCEEDINGS FREE ACCESS
    Wang resin-supported Evans' chiral auxiliary 1 was designed and synthesized based on a novel polymer-anchoring strategy, which utilizes the 5-position of the oxazolidinone ring. Solid-phase Evans' asymmetric alkylation on 1-derived N-acylimide resin and following lithium hydroperoxide-mediated chemoselective hydrolysis afforded the corresponding a-branched carboxylic acids in desired high stereoselectivities (up to 97% ee) and moderate to good overall yield (up to 70%, for 3 steps), which were comparable to those of the conventional solution-phase methods. Furthermore, recovery and recycling of the polymer-supported chiral auxiliary were successfully achieved without decreasing the stereoselectivity of the product. Therefore, this is the first successful example that the solid-phase Evans' asymmetric alkylation was efficiently performed on the solid-support, and it is concluded that the connection to the solid-support via the 5-position of the oxazolidinone ring is an ideal strategy in the solid-phase Evans' chiral auxiliary.
  • Jun' ichi Uenishi, Yusuke Tanaka, Nobuyuki Kawai
    Session ID: 1O-05
    Published: 2005
    Released: October 01, 2006
    CONFERENCE PROCEEDINGS FREE ACCESS
    The title acetal has been prepared from allyltriisopropylsilane in two steps in 60-75% yield. This acetal can react with 1,2- or 1,3-diols in the presence of acid catalyst to give the corresponding 1,3-dioxolane or 1,3-dioxane in excellent yields. The cyclic acetal is relatively stable under weak acidic conditions. For example, it survives in acetic acid at 80 °C or PPTS in organic solvents. This protecting group can be removed under mild conditions by the treatment of LiBF4 in acetonitrile to give the starting diol efficiently. However, it is hardly deprotected with tetrabutylammonium fluoride. In addition, HF/pyridine can use for the deprotection of 1,3-dioxolane derivatives but not 1,3-dioxane derivatives. Selective protection/deprotection for 1,2- and 1,3-diols can be achieved by the use of triisopropylsilylacetal. Particularly, tolerance of acetal to acids is valuable for organic synthesis.
  • Hiromichi Fujioka, Yoshinari Sawama, Takashi Okitsu, Nobutaka Mu ...
    Session ID: 1O-06
    Published: 2005
    Released: October 01, 2006
    CONFERENCE PROCEEDINGS FREE ACCESS
    Acetal functions are tolerant under neutral and basic conditions. Acidic conditions are usually used for their deprotection, and under these conditions, ketals (acetals from ketone functions) are usually deprotected more easily than the acetals (acetals from aldehyde functions) due to the stability of the cation intermediates. We present a new method1), which can selectively deprotect acetals, not ketals. Thus, the use of combinations of triethyltriflate (TESOTf)-2,6-lutidine or 2,4,6-collidine can selectively deprotect acetals in the presence of ketals. Another advantage of the method is that the compounds with acid-sensitive functional groups can also be well adapted because the reactions proceed under basic condition. Furthermore, we have found that the structures of the intermediates are pyridinium salts.
  • Sho-ichi Takayanagi , Yuji Matsuya, Hideo Nemoto
    Session ID: 1P-01
    Published: 2005
    Released: October 01, 2006
    CONFERENCE PROCEEDINGS FREE ACCESS
    CJ-12,950 and CJ-13,357 are 12-membered salicylic macrolactone compounds, isolated from a zygomycete Mortierella verticillata, but their stereostructures have not been determined. These lactones have been reported to potently induce the LDL receptor gene in vitro, by enhancing LDL receptor expression in human hepatocytes 2-fold at 100 nM. Consequently, they have potential relevance to the treatment of hypercholesterolemia and hyperlipidemia. We planned to develop an efficient synthetic route to the compounds, including elucidation of their stereostructures, using ring-closing metathesis (RCM) and Payne rearrangement as key steps. We have succeeded in constructing the E/Z-12-membered macrolactone structures of the target compounds by means of RCM, which are possible precursors to attempt regioselective epoxidation and subsequent Payne rearrangement.
  • Toshiya Takizawa , Kouichi Narita, Munenori Inoue , Kazuhiro Watanab ...
    Session ID: 1P-02
    Published: 2005
    Released: October 01, 2006
    CONFERENCE PROCEEDINGS FREE ACCESS
    Spirchostatin A (1), isolated from the Pseudomonas sp., is a potent histone deacetylase inhibitor. Therefore, 1 is anticipated to be a promising new agent for cancer chemotherapy. We envisioned that 1 would be elaborated through the twofold macrocyclization of the disulfide 2 possessing the requisite carbon framework, functional groups, and asymmetric carbons. At first, we conducted the synthesis of the segments 3 and 4, which were then subjected to the critical cross coupling reaction. The disulfide bond formation between 3 and 4 proceeded smoothly, and the desired cross coupling product 2 was obtained preferentially. We next investigated the construction of the macrolactam ring. After deprotection of the Boc group and hydrolysis of the methyl ester moiety, the intramoleculer cyclyzation of 10 was carried out using PyBOP, which successfully led to the desired macrolactam 11, a potential key precursor for 1.
  • Masanori Satoh, Tadashi Nakata
    Session ID: 1P-03
    Published: 2005
    Released: October 01, 2006
    CONFERENCE PROCEEDINGS FREE ACCESS
    Maitotoxin, a marine polycyclic ether isolated from the dinoflagellate Gambierdiscus toxicus, is the most toxic and largest natural product known to date except for biopolymers such as protein or polysaccharides. The skeletal novelty, complexity, and biological activity of maitotoxin have attracted the attention of chemists and biologists.We have already developed the SmI2-induced reductive cyclization to synthesize the trans-fused ether ring system stereoselectively. We now report the stereoselective syntheses of the BCDE-ring system of maitotoxin. The key steps involve 6-endo-cyclization of methylepoxide, SmI2-induced cyclization, SmI2-induced double cyclization, and double hydroxylation of TMS enol ether.
  • Masashi Kishida, Hiroyuki Akita
    Session ID: 1P-04
    Published: 2005
    Released: October 01, 2006
    CONFERENCE PROCEEDINGS FREE ACCESS
    Rhodiola rosea (Golden root) is widely distributed at high attitude in Arctic regions, and it is a popular plant for a reputation for stimulating the nervous system, decreasing depression. Cinnamyl b-D-Glucopyranosides, such as Rosin (cinnamyl O-β-D-glucopyranoside; 1) and Rosavin (cinnamyl 6-O-(β-L-arabinopyranosyl)-β-D-glucopyranoside; 6) were isolated from Rhodiola rosea as one of the major active ingredients. We have developed the simple synthesis of cinnamyl β-D-glucopyranoside analogues using palladium(II)-catalyzed Mizoroki-Heck type reaction between allyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (12) and phenylboronic acid congeners. By applying this strategy, we have achieved the synthesis of fourteen Rosin analogues (1-5, 26-34) including five natural products and three natural Rosavin analogues (6-8).
  • Shunta Takeguchi, Takahiro Kawagishi, Hisanaka Ito, Kazuo Iguchi
    Session ID: 1P-05
    Published: 2005
    Released: October 01, 2006
    CONFERENCE PROCEEDINGS FREE ACCESS
    Clavubicyclone, a novel clavulone-related marine prostanoid, was isolated from Okinawan soft coral Clavularia viridis by our group. To determine the absolute stereochemistry of clavubicyclone, development of the total synthetic route was performed. The key step of our synthetic route was construction of bicyclo[3.2.1]octane skeleton by Cope rearrangement of the divinylcyclopropane derivative. The substrate of Cope rearrangement was prepared from cis-2-butene-1,4-diol as a starting material through carbon chain elongation reactions and the rhodium catalyzed intramolecular cyclopropanation reaction. The Cope rearrangement smoothly proceeded by heating the divinylcyclopropane derivative in diphenyl ether (180 °C) to give the desired bicyclo[3.2.1]octane derivative. We are examining to convert the rearrangement product to clavubicyclone.
  • Shigeaki Fujiyoshi, Chizuru Moriyama, Takayuki Sakai, Kazuyuki Miyas ...
    Session ID: 1P-06
    Published: 2005
    Released: October 01, 2006
    CONFERENCE PROCEEDINGS FREE ACCESS
    Spiroxins A-E, isolated from a marine-derived fungus, have a unique octacyclic bisnaphthospiroketal structure. Spiroxin A was reported to show antibacterial and antitumor activities, both of which are thought to be caused by DNA cleavage. We previously reported the first total synthesis of (±)-spiroxin C, which included TBAF-activated Suzuki-Miyaura cross-coupling reaction and an intramolecular bromoetherification reaction as key reactions. Here, we applied the synthetic strategy to that of spiroxin A having additional two functional groups, hydroxyl group and chlorine. Starting from 5, 8-dihydroxy-1-tetralone, we successfully synthesized a key intermediate for spiroxin A by utilizing the above key reactions and regioselective chlorination. Remaining steps to complete the synthesis are under investigation.
  • Masataka Fujino, Hironori Fukumoto, Masashi Tashiro, Keisuke Takah ...
    Session ID: 1P-07
    Published: 2005
    Released: October 01, 2006
    CONFERENCE PROCEEDINGS FREE ACCESS
    Phospholine is a member of the phoslactomycin family of phosphate ester antibiotics that display potent antitumor activity against a broad range of cancerous cell lines in vitro. Such antitumor activity is attributed to highly potent and selective inhibition of protein phosphatase 2A and 4. Their interesting molecular architectures and the potential as a lead for developing antitumor drugs make these phosphate ester antibiotics attractive targets for synthetic studies. We describe our study toward the enantiocontrolled synthsis of phospholine based on the strategy involving Brown's asymmetric allylation for the introduction of C4 and C5 chiral centers, ring closing metathesis for the construction of the g-lactone moiety, Sharpless dihydroxylation for the assembly of C8 and C9 hydroxy groups, and Suzuki-Miyaura coupling for the attachment of the characteristic C8 aminoethyl substituent.
  • Hiroaki Miyaoka, Makiko Muroi, Kie Arai, Hidemichi Mitome
    Session ID: 1P-08
    Published: 2005
    Released: October 01, 2006
    CONFERENCE PROCEEDINGS FREE ACCESS
    7,20-Diisocyanoadociane, isolated from the marine sponge Adocia sp. by Wells et al. in 1976, is a diterpenoid containing all-trans-hexadecahydropyrene ring with two isocyano and four methyl groups. 7,20-Diisocyanoadociane has been shown to exhibit antimalarial activity. Its unique structural features and biological activity prompted the authors to undertake the synthesis of 7,20-diisocyanoadociane. The authors investigated the construction of all-trans-hexadecahydropyrene ring system, which is the fundamental skeleton in 7,20-diisocyanoadociane. The construction of all-trans-hexadecahydropyrene ring system was involved the continual reaction of isomerization and intramolecular Diels-Alder reaction as the key step.
  • Masayuki Utsugi, Mitsuhiro Iwamoto, Hatsuo Kawada, Masayuki Miyano ...
    Session ID: 1P-09
    Published: 2005
    Released: October 01, 2006
    CONFERENCE PROCEEDINGS FREE ACCESS
    We started to synthesize antitumor agent Taxol via a convergent and efficient route. We planned to prepare A-ring and C-ring fragments with perfect stereoselectivity, followed by their coupling and construction of the eight-membered ring for the total synthesis of Taxol. During these studies we found the unprecedented construction of the eight-membered ring via the intramolecular B-alkyl Suzuki-Miyaura coupling and the stereoselective construction of the A-ring via the intramolecular silicon-tethered nucleophilic addition. Although the remaining problem to be solved was to construct the trans-fused B,C-ring, we have succeeded to construct it by 1,4-addition of a cyanide ion and SN2' reduction of the allylic phosphonium salt. These studies will be reported.
  • Hideto Miyabe, Kazumasa Yoshida, Yoshiji Takemoto
    Session ID: 1P-10
    Published: 2005
    Released: October 01, 2006
    CONFERENCE PROCEEDINGS FREE ACCESS
    Our laboratory is interested in developing the effective oxygen and nitrogen nucleophiles for allylic substitution. Recently, we have been found that the nitrogen atoms of hydroxylamines having an N-electron-withdrawing substituent act as reactive nucleophiles, and the selective formation of the branched products was observed in the iridium-catalyzed allylic substitution. The iridium complex of pybox having phenyl group catalyzed the reaction with high activity to form the branched products with good enantioselectivities. Based on these results, we investigated the enantioselective iridium-catalyzed allylic substitution with guanidines having N-electron-withdrawing substituents. The stability of conjugate base of guanidines was important for the nucleophilic property of a nitrogen atom of guanidines. Excellent enantioselectivities were also observed in the reaction with guanidines.
  • Kuzuishi Makino, Yasuhiro Hiroki, Masamichi Iwasaki , Yasumasa Ha ...
    Session ID: 1P-11
    Published: 2005
    Released: October 01, 2006
    CONFERENCE PROCEEDINGS FREE ACCESS
    Catalytic asymmetric hydrogenation of α-amino-β-keto esters through dynamic kinetic resolution (DKR) is a powerful methodology for the synthesis of chiral β-hydroxy-α-amino acids, which are an important class of amino acids broadly found in nature as components of complex natural products. We have reported the direct anti-selective hydrogenation reactions of α-amino-β-ketoesters using Ru-BINAP catalyst via DKR, which was highly effective for the substrate with an alkyl carbon at the C4 position. In the case of aromatic substrates at C4 position, however, Ru-BINAP catalyst was ineffective for direct anti-selective hydrogenation concerning enantiomeric excess. In this symposium, we describe a novel iridium catalyzed anti-selective asymmetric hydrogenation of α-amino-β-keto esters through dynamic kinetic resolution and the additive effect of sodium iodide in enantiomeric selectivities.
  • Masahiro Noji, Yousuke Konno, Noriko Futaba, Keitaro Ishii
    Session ID: 1P-12
    Published: 2005
    Released: October 01, 2006
    CONFERENCE PROCEEDINGS FREE ACCESS
    We have developed a highly effective secondary benzylation system for aromatic nucleophiles using benzyl alcohols catalyzed by rare-earth metal and hafnium triflate in nitromethane. The benzylation proceeds smoothly even in the presence of water. In this presentation, we will report a convenient method for α-secondary benzylation of enolacetates as a nucleophile. Various enol acetates prepared from methyl or cyclic ketone underwent sec-benzylation with sec-bezyl alcohols in the presence of 0.5-1 mol% of La, Yb, Sc, and Hf triflates. Addition of Mg(ClO4)2 increased the yield of the benzylation. Various 1-phenylethanols bearing a functional group (e.g, hydroxy, acetoxy, benzyloxy, tert-butyldimethylsilyloxy) were able to be used for the benzylation.
  • Masatoshi Koizumi, Xiang-Min Sun, Kei Manabe , Shu Kobayashi
    Session ID: 1P-13
    Published: 2005
    Released: October 01, 2006
    CONFERENCE PROCEEDINGS FREE ACCESS
    New types of P,N-ligands containing a tetrahydroisoquinoline skeleton as an N-donors were synthesized from P-stereogenic phenyl-P-proline, which we have designed and established an efficient synthetic route. The cis isomer was found to act as an excellent ligand in Pd-catalyzed asymmetric allylic substitution reactions. The reactions of 1,3-diphenyl-2-propenyl acetate with several nucleophiles in the presence of [Pd(π-allyl)Cl]2, cis-P,N-ligand (Pd:ligand = 1:2), and a base afforded the desired products in high yields with high enantioselectivity. It was suggested that these ligands did not serve as a P,N-bidentate ligand but as a P-monodantate ligand in these reactions.
  • Shunsuke Kotani, Shunichi Hashimoto, Makoto Nakajima
    Session ID: 1P-14
    Published: 2005
    Released: October 01, 2006
    CONFERENCE PROCEEDINGS FREE ACCESS
    Although phosphine oxides possess a notable electron-pair donor property to form complexes with a variety of compounds, less attention has been paid to chiral phosphine oxides in the field of asymmetric synthesis except for their utility as synthetic intermediates in the preparation of chiral phosphine ligands. Recently we reported on the enantioselective allylation of aldehydes with trichlorosilyl compounds catalyzed by a chiral phosphine oxide. As part of our ongoing program directed at the development of asymmetric organocatalysis, we herein report the enantioselective aldol reaction with trichlorosilyl enol ethers catalyzed by BINAPO to afford the corresponding aldol adducts in high diastereo- and enantioselectivities (~92% de, ~96% ee).
  • Hirofumi Matsunagai, Tadao Ishizuka, Makoto Nakajima, Takehisa Kun ...
    Session ID: 1P-15
    Published: 2005
    Released: October 01, 2006
    CONFERENCE PROCEEDINGS FREE ACCESS
    We previously developed chiral "roofed" 2-imidazolidinones (DHAIm), which are conformationally rigid and sterically bulky, from the thermal [4+2] cycloaddition of a simple 5-membered heterocycle, 1,3-dihydro-2-imidazolone, with anthracene followed by optical resolution and showed to be excellent chiral auxiliaries for asymmetric C-C bond formations. Prompting these results, we applied "roofed" cis-diamine, ring-opened form of DHAIm, to catalytic asymmetric reactions as chiral ligands. Thus, a chiral Ru (II) complex, prepared from "roofed" cis-diamine and [RuCl2(benzene)]2, proved to be an efficient catalyst for the asymmetric transfer hydrogenation of a wide variety of aryl ketones, including sterically bulky ketones. The Ru(II) complex showed both a high catalytic activity and enantioselectivity (up to 99% ee) when the reaction was conducted in the presence of 5HCO2H.2NEt3.
  • Norihito Tokunaga, Yusuke Otomaru, Ryo Shintani, Tamio Hayashi
    Session ID: 1P-16
    Published: 2005
    Released: October 01, 2006
    CONFERENCE PROCEEDINGS FREE ACCESS
    The asymmetric synthesis of diarylmethylamines by the catalytic asymmetric arylation has attracted growing attention due to their importance in biological activity. We have developed new methods of furnishing optically active diarylmethylamines with high yields (>94%) and enantioselectivity (95-99% ee) by use of C2-symmetric chiral diene ligands (Ph-bod* and Ph-bnd*) for the rhodium-catalyzed asymmetric arylation of of N-sulfonylarylimines with arylboroxines in aqueous solvent conditions. These chiral diene ligands showed much higher enantioselectivity and catalytic activity in these arylation reactions than chiral bisphoshine ligands. Under the present reaction conditions, arylboroxines can be used as arylating reagents, which are stable, less toxic, and easily prepared from commercially available arylboronic acids.
  • Kiyoto Suzuki, Kazuhiro Kondo, Toyohiko Aoyamo
    Session ID: 1P-17
    Published: 2005
    Released: October 01, 2006
    CONFERENCE PROCEEDINGS FREE ACCESS
    Asymmetric arylation of aromatic aldehydes with Rh-our hemilabile-type chiral ligand, (R,R)-4-[bis(3',5'-dimethyl-4'-methoxyphenyl)phosphanomethyl]-5-[bis(3',5'-dimethyl-4'-methoxyphenyl)phosphinomethyl]-2,2-dimethyl-1,3-dioxolane, catalyst is disclosed. Our hemilabile-type ligand was found to display a peculiar catalytic behavior due to the presence of two donors of diverse donating properties. This arylation of various aromatic aldehydes with 2 mol equiv of phenylboronic acid and NaOt-Bu, and a catalytic amount of Rh complex and our hemilabile-type ligand in DME/H2O (5:1) at 100 °C was performed, obtaining enatioselectivity of up to 84%. This is, to the best of our knowledge, the best enantioselectivity in the reported literature for Rh-catalyzed arylation of aromatic aldehydes.
  • Yasuko Tomizawa, Kimiko Kuwahara, Takumichi Sugihara
    Session ID: 1P-18
    Published: 2005
    Released: October 01, 2006
    CONFERENCE PROCEEDINGS FREE ACCESS
    Low-valent molybdenum complexes showed similar reactivity typically in the Pauson-Khand-type reactions with their cobalt complexes. However, these two categories of metal complexes showed completely different feature in the catalytic reaction. While dicobalt octacarbonyl with certain activator catalyzed the intramolecular Pauson-Khand reaction, one of the low-valent molybdenum complexes, π-allylmolybdenum, did not catalyzed the desired reaction but produced cyclohexadiene derivatives as a major component even under pressured CO atmosphere. This trend in cyclization clearly appeared when 1,7-diphenyl-1,6-heptadiynes were used as substrate. Cyclopentadienone derivatives were produced when dicobalt octacarbonyl was used as a catalyst, whereas substituted benzene derivatives were produced when π-allylmolybdenum was used in the presence of excess allyl bromide.
  • Ichiro Suzuki, Kei Takeda
    Session ID: 1P-19
    Published: 2005
    Released: October 01, 2006
    CONFERENCE PROCEEDINGS FREE ACCESS
    Biginelli reactions are simple one-pot but low-yielding condensations of dicarbonyl compounds with aldehydes and urea or thiourea in the presence of catalytic amount of acid to produce 3,4-dihydropyrimidin-2- (1H)-ones. Recently, to improve the efficiency of this reaction, modifications using Lewis acids have been reported. However, some of these procedures involve difficulties such as the use of stoichiometric amounts of catalysts, high temperatures and so on. Here we report efficient Biginelli type condensation reactions using Ni(NTf2)2 and Cu(NTf2)2 as a Lewis acid catalyst. This study demonstrates that these Lewis acid can catalyze the Biginelli type reactions efficiently in protic solvents such as MeOH and water. It is noteworthy that the efficiency of the catalysts M(NTf2)2 was considerably improved by adding HNTf2.
  • Daisuke Sano, Kazuhiro Nagata, Takashi Itoh
    Session ID: 1P-20
    Published: 2005
    Released: October 01, 2006
    CONFERENCE PROCEEDINGS FREE ACCESS
    α-Cyanoacetic acid esters are useful precursors for the synthesis of α- and β-amino acids, and α,α-disubstituted α-cyanoacetates can be valuable synthons for the synthesis of natural products which have a chiral quaternary carbon center. We have investigated asymmetric alkylation of α-cyanoacetates using chiral phase-transfer catalyst, and found that enantioselectivity was dependent on the type of ester group of substrate, solvent, and base. When the alkylation of α-substituted α-cyanoacetic acid t-butyl esters was carried out in ether solution using 1 mol% of phase-transfer catalyst(1), chiral α,α-dialkylated α-cyanoacetates were obtained in high yields with high enantioselectivities up to 94%. Application of the present reaction to the synthesis of a variety of β-amino acids and naturally occurring products, which have a chiral quaternary carbon center, is under investigation.
  • Kazuhiro Yoshizawa, Takayuki Shioiri
    Session ID: 1P-21
    Published: 2005
    Released: October 01, 2006
    CONFERENCE PROCEEDINGS FREE ACCESS
    We have developed the unprecedented reaction of 1-phenyl-2-(trimethylsilyl)acetylene with aromatic aldehydes to produce the highly Z-selective β-branched Morita-Baylis-Hillman-type adducts catalyzed by the quaternary ammonium fluoride derived from cinchonine, and revealed the unusual reactivity of this ammonium fluoride compared with TBAF. In the course of study about the mechanism, it was found that (1,3-diaryl-2-propynyl) trimethylsilyl ethers, which is postulated as intermediates in this reaction, were easy to isomerize to corresponding silyl allenolates by catalytic KOt-Bu under very mild conditions. The allenolates in situ react with various aldehydes to afford Z-selective β-branched Morita-Baylis-Hillman-type adducts in one-pot reaction.
  • Yoshimi Kouchi, Kanako Ogura, Osamu Onomura , Yoshihiro Matsumura
    Session ID: 1P-22
    Published: 2005
    Released: October 01, 2006
    CONFERENCE PROCEEDINGS FREE ACCESS
    Enantioselelctive reduction of ketones and imines has been one of major topics in asymmetric synthesis. One of recent interesting reducing reagents is trichlorosilane (Cl3SiH), which is a liquid material easily available from silicon industry. However, some activator is necessary for Cl3SiH to efficiently reduce ketones and imines. We already reported some chiral N-formylpyrrolidine derivatives as organic activators in enantioselective reduction of ketones and imines by Cl3SiH, although the enantioselectivity was low to moderate. In our continuing effort to exploit new chiral organic activators, we found new highly effective pyrrolidine derivatives to reduce aromatic ketones and aromatic imines (up to 97%ee for ketones and up to 80%ee for imines).
  • Hiroaki Sawamoto, Hiroyuki Ishihara, Naoyoshi Maezaki, Tetsuaki Tana ...
    Session ID: 1P-23
    Published: 2005
    Released: October 01, 2006
    CONFERENCE PROCEEDINGS FREE ACCESS
    Vinylic sulfoxides are a well-known chiral controller and applied to many asymmetric reactions. However, applications to transition metal-catalyzed reactions are limited. We have developed a novel Ni(0)-catalyzed asymmetric carbocyclization of enone to vinylic sulfoxide, in which carbon-carbon bond formation between these functional groups proceeded smoothly upon treatment with Et2Zn in the presence of Ni(0)-catalyst to give disubstituted cyclopentane compound. In contrast that the (E)-vinylic sulfoxide afforded cis-isomer, the (Z)-vinylic sulfoxide produced trans-isomer predominately. Diastereoselectivity of the reaction was influenced by solvent and additive. Both the yield and selectivity were improved when tolune was used as a solvent in the presence of three equivalents of MeCN. Addition of zinc bromide also afforded good results in the reaction of the (E)-vinylic sulfoxide.
  • Andrei Gavryushin, Shuji Yasuike, Paul Knochel
    Session ID: 1P-24
    Published: 2005
    Released: October 01, 2006
    CONFERENCE PROCEEDINGS FREE ACCESS
    We found very interesting to design a route for the substitution of a phenolic hydroxyl for a halogen. The key step of this transformation is a novel cross-coupling reaction between zinc-silicon reagent and aryl triflates. We have chosen dimethylphenylsilyllithium as a source of silicon due to its ease of preparation from relatively cheap starting materials. An addition of ZnBr2(0.5 equiv.) in THF gave silicon-zinc species. Screening of transition metal catalyst showed that Ni(dppp)Cl2 affords fast and complete conversion of Aryl triflates into corresponding silicon derivate in excellent yield. The aryl dimethylphenylsilanes, obtained via new Ni-catalyzed cross-coupling reaction, can be easily transformed into the corresponding aryl iodides in high yields by treatment with 2 equiv. of iodine monochloride in dichloromethane at 0 °C. Furthermore, the obtained arylsilanes can be converted in good yields into the corresponding boronic esters.
  • Koji Ishida, Toshihide Maki
    Session ID: 1P-25
    Published: 2005
    Released: October 01, 2006
    CONFERENCE PROCEEDINGS FREE ACCESS
    A new type of photocleavable molecular devices has been developed for laser ionization TOF-Mass spectrometry. The presented molecules contain an ether bond which is photo cleavable. Highly selective photo cleavage of the ether bond was observed under standard laser ionization condition by negative mode TOF-Mass spectrometry. The observed result indicates that chemically robust ether bond can be used as photocleavable devices for direct Mass detection from solid support.
  • Koji Matsumoto, Takayoshi Suzuki, Hidehiko Nakagawa , Kohfuku Kohda, ...
    Session ID: 1P-26
    Published: 2005
    Released: October 01, 2006
    CONFERENCE PROCEEDINGS FREE ACCESS
    To investigate the magnetic anisotropy effect of C60, thirteen N-acyl fulleropyrrolidines and two N-acyl fulleroazilidines were synthesized and their 1H-NMR analyses were carried out. The protons of fulleropyrrolidine derivatives appeared at low magnetic field compared with those of the corresponding pyrrolidine derivatives. In addition, the downfield shifts correlated strongly with the distances between the protons and the fullerene skeleton. The greater downfield shifts were observed with fulleroazilidine derivatives in which the distances between the protons and the fullerene skeleton are shorter. Comparison of the downfield shifts of fulleropyrrolidine derivatives with those of the corresponding isoindoline derivatives suggested that the magnetic anisotropy effect of C60 is approximately four times greater than that of benzene. These results indicated the possibility of C60 as a tool for structural analysis using NMR.
  • Hiroki Tsumoto, Katsumasa Takahashi, Kohfuku Kohda, Takayoshi Suzuki ...
    Session ID: 1P-27
    Published: 2005
    Released: October 01, 2006
    CONFERENCE PROCEEDINGS FREE ACCESS
    Our strategy is to use a physico-chemical property of C60 for MALDI-TOF MS analysis of biomolecules. There are two advantages in the C60 derivatization of biomolecules. First, as a result of improved ionization efficiency by C60 moiety, signal intensities could be increased. Second, after derivatization by C60 moiety, a mass of small molecules (m/z < 500 Da) shifts away from the matrix range toward higher mass range. Here we report synthesis of labeling reagents containing C60 moiety to couple C60 to amino group of biomolecules. A series of [60]fullerene carboxylic acid was activated by esterification with N-hydroxysuccinimide of pentafluorophenol and the active esters were used as labeling reagents. The derivatization reaction of amino acids and peptides were demonstrated and the MALDI-TOF MS analysis indicated the potential utilities of the reagents for MALDI analysis of small molecules.
  • Katsumasa Takahashi, Hiroki Tsumoto, Kohfuku Kohda, Takayoshi Suzuki ...
    Session ID: 1P-28
    Published: 2005
    Released: October 01, 2006
    CONFERENCE PROCEEDINGS FREE ACCESS
    MALDI-TOF MS is useful for the analysis of biomolecules. However, it is generally difficult to use MALDI-TOF MS for the analysis of small molecules (m/z <500 Da). This is in part due to the poor ionization efficiency for lack of high-proton-affinity functional groups and the presence of matrix-related ions in the low-mass range. We developed new labeling reagents containing C60 moiety to improve the ionization efficiency and to shift a mass of small molecules. We demonstrated the derivatization of amino acids and peptides by C60 derivatives and analyzed the derivatized by MALDI-TOF MS. As expected, the ionization efficiency of peptides was improved by coupled with C60 moiety. And by using the isotope-coded light (d0) and heavy (d5) reagents, relative quantification of amino acid was achieved. Our derivatization method is found to be useful for the qualitative and quantitative MALDI analysis of small molecules.
  • Toshikatsu Takanami, Wakaba Inoue, Shigeru Kobayashi, Mikiko Hayash ...
    Session ID: 1P-29
    Published: 2005
    Released: October 01, 2006
    CONFERENCE PROCEEDINGS FREE ACCESS
    Construction of a novel achiral host molecule system utilizing meso-carbon bridged zinc porphyrin dimers, bis(zinc porphyrin), is presented. These dimers that adopt a pseudocofacial conformation in the absence of a guest molecule can effectively bind not only strong amino-containing ligands but also relatively weak ligans such as alcohols and ethers over room temperatures. The direct determination of the absolute configuration of monoalcohols at low concentrations and room temperature based on the CD exciton chirality method can now be realized utilizing the bis(zinc porphyrin).
  • Tomoya Fujiwara, Hidehito Fujisawa, Taiki Murai, Yoshio Takeuchi, ...
    Session ID: 1P-30
    Published: 2005
    Released: October 01, 2006
    CONFERENCE PROCEEDINGS FREE ACCESS
    We previously showed that the CFTA method is very useful for 1H NMR determination of the absolute configurations of chiral molecules. We here report the application of CFTA for determination of absolute configuration by 19F NMR spectroscopy. We first examined a series of CFTA amides of α-amino esters to obtain 19F chemical shift differences (Δ&deltaF) between the diastereomers. A consistent relationship between the sign of Δ&deltaF and their absolute configuration was observed without exception. This result indicates that the absolute configurations of α-amino esters can be determined by the use of CFTA. The ab initio calculations suggested that the Δ&deltaF could be attributed to the different biases of conformational equilibrium between two diastereomers, which are induced by attractive interactions. We also report the application for determination of the absolute configuration of other primary amines and secondary alcohols.
  • Kazushige Sasaki, Yuji Matsuya, Hiroshi Ochiai, Hideo Nemoto
    Session ID: 1P-31
    Published: 2005
    Released: October 01, 2006
    CONFERENCE PROCEEDINGS FREE ACCESS
    We have accomplished a synthesis of various furan-fused compounds using tandem electrocyclic reaction of benzocyclobutene derivatives, including o-quinodimethane formation and inverse electron demand Diels-Alder reaction. This synthetic method has several advantageous features such as high generality, short-step sequence, and high stereoselectivity. These furan-fused compounds exhibited antiviral activity against influenza A virus, and favorably showed low cytotoxicity. Moreover, these compounds exhibited the activity against influenza B virus, which is different property from amantadine.
  • Yoshiaki Imamura, Yuji Matsuya, Hideo Nemoto
    Session ID: 1P-32
    Published: 2005
    Released: October 01, 2006
    CONFERENCE PROCEEDINGS FREE ACCESS
    Wortmannin, furan-fused steroidal natural product, has been known to possess various bioactivities, and recently, has been reported to exhibit a specific PI3-kinase inhibitory activity. In this study, we undertook the development of a new short-step approach for the construction of the A, B, E ring-system, which is thought to be a pharmacophore structure of wortmannin. The benzocyclobutene derivative containing furanyl side chain was prepared from readily available 1-cyano-5-methoxybenzocyclobutene in 3 steps. This compound was subjected to thermal ring-opening to form o-quinodimethane, which successively underwent intramolecular cycloaddition to afford the furan-fused tetracyclic compound as a mixture of two diastereomers. After desilylation, these isomers could be separated and were oxidized in a three-step sequence to afford the E-aromatized compound. Subsequent chemical transformations are now in progress.
  • Yoshitomo Suhara, Aya Murakami, Yuka Shimomura, Kimie Nakagawa, Tos ...
    Session ID: 1P-33
    Published: 2005
    Released: October 01, 2006
    CONFERENCE PROCEEDINGS FREE ACCESS
    It is generally accepted that availability of vitamin K in vivo depends on the homologues and their biological activities would be different from organ to organ. To evaluate this hypothesis, we examined the uptake, metabolism and utilization of menaquinone-4 (MK-4) and phylloquinone (PK) using their 18O-labeled compounds in two kinds of human cultured cell lines (Hep G2 and MG-63). The 18O-labeled vitamin K analogues were synthesized from naphthoquinone derivative and isoprenol. The detection of the vitamin K analogues (18O-, 16O-quinone and epoxide forms) was carried out with LC-APCI-MS/MS method. In this method, the molecular oxygen of 18O-labeled vitamin K was exchanged by atmospheric 16O2 during the formation of vitamin K epoxide with carboxylative catalytic reaction. As the results, significant difference was observed between MK-4 and PK in the amounts uptaken into the cells.
  • Shinobu Honzawa, Naoyuki Takahashi, Atsushi Yamashita, Takayuki Sugi ...
    Session ID: 1P-34
    Published: 2005
    Released: October 01, 2006
    CONFERENCE PROCEEDINGS FREE ACCESS
    1α,25-Dihydroxyvitamin D3(1) has a wide range of biological activities, for example, calcium and phosphorus homeostasis, cell growth and differentiation. The actions of 1 are mediated by a specific nuclear receptor, vitamin D receptor (VDR). Hydrogen bonds between three hydroxyl groups of 1 and hydrophilic amino acids in the ligand-binding domain (LBD) of VDR are essential for its actions. Arginine 274 is known to form hydrogen bond with 1α-OH of 1, and its mutation lead to loss of the affinity and its actions. For the mutant VDR we designed the analogs having a CH3 or HOCH2 group on its 1α-position to effect hydrophobic interaction. A coupling reaction of CD ring bromoolefin and A ring enyne was carried out by the method developed by Trost. A ring enynes for 1α-CH3 and 1α-HOCH2 analogs were prepared from D-galactose and D-glucose, respectively.
  • Masaaki Kurihara, Wataru Hakamata, Shiho Shigenaga, Yukiko Sato, Ha ...
    Session ID: 1P-35
    Published: 2005
    Released: October 01, 2006
    CONFERENCE PROCEEDINGS FREE ACCESS
    The active form of vitamin D3, 1α,25-dihydroxyvitamin D3 1, is not only a regulator of calcium homeostasis and bone development and remodeling but also a potent differentiator of leukemic cells. LG190178 is a novel non-secostreroidal ligand for vitamin D receptor (VDR), which may have potential as therapeutics for cancer, leukemia and psoriasis with less calcium mobilization side effects than are associated with secosteroidal 1α,25-(OH)2D3 analogs. But LG190178 includes 4 stereoisomers. We calculated to make ducking model of 4 isomers and VDR, respectively. (S,S)-Isomer model is most stable one. There are hydrogen bonds between 2-OH and Arg-274, Ser-237 and between 2'-OH and His-305, His-397. (2S)-Isomers ((S,S) and (S,R)) are more important than (2R)-isomers. We synthesized (2S)- and (2R)-LG190178.
  • Ayumu Niida, Kenji Tomita, Hiroaki Tanigaki, Nobutaka Fujii, Hiroka ...
    Session ID: 1P-36
    Published: 2005
    Released: October 01, 2006
    CONFERENCE PROCEEDINGS FREE ACCESS
    We described new synthetic routes for (Z)-alkene or (E)-fluoroalkene dipeptide isosteres as cis-amide equivalents and application of the synthetic dipeptide isosteres to probe structural requirement of peptide transporter (PEPT1). We evaluated affinities of synthetic Phe-Gly derivatives for human di/tripeptide transporter, PEPT1. In this experiment, trans-amide isosteres exhibited superior affinities for PEPT1 compared to cis-amide equivalents. This result suggested that PEPT1 predominantly recognizes trans-amide conformations of dipeptides.
  • Hirokazu Tamamura, Kenichi Hiramatsu, Satoshi Ueda, Zixuan Wang, John ...
    Session ID: 1P-37
    Published: 2005
    Released: October 01, 2006
    CONFERENCE PROCEEDINGS FREE ACCESS
    L,L- And L,D-type (E)-alkene dipeptide isosteres (EADIs), which have unnatural side chains at the α-position, were synthesized by the combination of stereoselective aziridinyl ring-opening reactions and organozinc-copper-mediated anti-SN2'reactions to a single substrate of γ,δ-cis-γ,δ-epimino (E)-α,β-enoate. The utility of this procedure was demonstrated by the stereo-controlled synthesis of a couple of diastereomeric EADIs of Arg-L/D-3-(2-naphthyl)alanine (Nal) that is contained in a low molecular weight CXCR4 antagonist FC131 [cyclo(-D-Tyr-Arg-Arg-Nal-Gly-)]. Several FC131 analogs, in which these EADIs were inserted for reduction of their peptide character, were synthesized for the development of nonpeptide CXCR4 antagonists with anti-HIV and anti-cancer-metastasis activity.
  • Yosuke Demizu, Masakazu Tanaka, Mitsunobu Doi, Masaaki Kurihara, Tok ...
    Session ID: 1P-38
    Published: 2005
    Released: October 01, 2006
    CONFERENCE PROCEEDINGS FREE ACCESS
    We have developed a practical synthetic route of optically active cyclic α,α-disubstituted α-amino acids; (3S,4S)- and (3R,4R)-1-amino-3,4-di(methoxy)cyclopentanecarboxylic acids (Ac5cdiOM) starting from dimethyl L-(+)- and D-(-)-tartrate, respectively. These amino acids (S,S)- and (3R,4R)-Ac5cdiOM were introduced into L-leucine sequences by the solution-phase methods using EDC as a coupling reagent, and the conformations of their heteropeptides have been studied by using X-ray crystallographic analysis, FT-IR, and CD spectra. It has become clear that the propensity of cyclic α,α-disubstituted α-amino acid (3R,4R)-Ac5cdiOM is to form a right-handed (P) alpha-helix, whereas that of Aib is to form both right-handed (P) and left-handed (M) 310-helices.
  • Yusuke Ohta, Saori Itoh, Nobutaka Fujii, Akira Otaka
    Session ID: 1P-39
    Published: 2005
    Released: October 01, 2006
    CONFERENCE PROCEEDINGS FREE ACCESS
    In naturally occurring protein splicing, cystein thiol-assisted cleavage of the peptide bond adjacent to the Cys residue is the initial step of the reaction affording peptide thioester via N-S acyl transfer, where loss of planarity of the amide bond has been reported to be responsible for the activation of the peptide bond. On the basis of protein splicing mechanism, we attempted to develop the biomimetic methodology for the preparation of peptide thioesters which have shown their great potential in the peptide/protein synthesis utilizing native chemical ligation (NCL) protocols. We evaluated the system utilizing an S-protected cysteine-derived N-acyloxazolidinone to activate amide bond resulting in the formation of peptide thioesters. In this system, removal of S-protection can trigger the acyl transfer from the activated amide bond to the deprotected thiol group. And this newly developed biomimetic protocol for thioesters was successfully applied to the synthesis of 32-mer peptide (hBNP derivative) using NCL.
  • Youhei Sohma, Atsuhiko Taniguchi, Maiko Kimura, Yoshio Hayashi, Shu ...
    Session ID: 1P-40
    Published: 2005
    Released: October 01, 2006
    CONFERENCE PROCEEDINGS FREE ACCESS
    Understanding of the dynamic events of Aβ1-42, such as the folding, self-assembly, and aggregation processes, is of great significance in Alzheimer' s disease (AD) research. Based on the O-acyl isopeptide method, we have developed a novel "click peptide" of Aβ1-42, "26-O-acyl isoAβ1-42 (26-AIA-42)". This click peptide suppresses the agglutinative nature of Aβ1-42 with only one insertion of an isopeptide structure during SPPS, and could migrate to the original Aβ1-42 quickly via a pH-dependent O-N intramolecular acyl migration reaction (by pH-triggered "click"). In addition, we have synthesized a photo-triggered "click peptide" of Aβ1-42, i.e., 26-N-Nvoc-26-O-acyl isoAβ1-42 to provide a novel biological evaluation system with high spatial and temporal resolution in AD-related research.
  • Youhei Sohma, Yousuke Chiyomori, Atsuhiko Taniguchi, Maiko Kimura, ...
    Session ID: 1P-41
    Published: 2005
    Released: October 01, 2006
    CONFERENCE PROCEEDINGS FREE ACCESS
    The highly agglutinative feature of Aβ1-42 is a significant obstacle for establishing a reliable in vitro biological experiment system to investigate the major causative agents of Alzheimer's disease (AD) and its related diseases. To solve this problem, based on the O-acyl isopeptide method, we have developed novel pH-triggered "click peptides" of wild- and mutant-type Aβ1-42s, "26-O-acyl isoAβ1-42s (26-AIAβ42s)". These isopeptides suppressed the agglutinative nature of each Aβ1-42 with only one insertion of the isopeptide structure, and could migrate to the corresponding Aβ1-42 quickly via pH-dependent O-N intramolecular acyl migration reaction (by pH-triggered "click"). The method would provide a novel biological evaluation system in AD-related research, in which 26-AIAβ42 can be stored in a solubilized form and rapidly produces intact Aβ1-42 in situ during biological experiments.
  • Akira Iida, Tomohito Okabayashi, Atsushi Horii, Kenta Takai, Yoo ...
    Session ID: 1P-42
    Published: 2005
    Released: October 01, 2006
    CONFERENCE PROCEEDINGS FREE ACCESS
    The Claisen condensation is recognized as a fundamental and useful C-C bond forming reaction to obtain β-keto esters in organic syntheses. However, α,α-dialkylated esters could not undergo this type of the condensation, because these esters lack the ability to force the formation of a stable enolate. Now, we developed a new practical, efficient and powerful crossed Claisen condensation of α,α-dialkylated esters between ketene silyl acetals and various electrophiles (acid chlorides, carboxylic acids, esters). Taking into account the fact that the Claisen condensation ofα,α-dialkylated esters is very difficult, the present method will provide a new avenue for the preparation of inaccessible β-ketoesters. The present method could be successfully applied to a facile synthesis of pyrazolone derivatives.
  • Shimpei Sugiyama, Tsuyoshi Satoh
    Session ID: 1P-43
    Published: 2005
    Released: October 01, 2006
    CONFERENCE PROCEEDINGS FREE ACCESS
    Treatment of optically active 1-chlorovinyl p-tolyl sulfoxides having two different substituents at the 2-position, which were synthesized from aldehydes or unsymmetrical ketones and (R)-(-)-chloromethyl p-tolyl sulfoxide in two or three steps, with the lithium enolate of tert-butyl acetate gave optically active adducts with 99% chiral induction from the sulfur chiral center. The adducts were converted to optically active β-substituted carboxylic acid derivatives. In the same way, treatment of optically active 1-chlorovinyl p-tolyl sulfoxides, which were synthesized from symmetrical ketones and (R)-(-)-chloromethyl p-tolyl sulfoxide in three steps, with lithium enolate of carboxylic acid tert-butyl esters gave optically active adducts having a substituent at the α-position with high 1,4-chiral induction from the sulfur chiral center in high yield.
  • Takeo Kawabata, Daiki Monguchi, Simpei Kawakami , Katsuhiko Moriyam ...
    Session ID: 1P-44
    Published: 2005
    Released: October 01, 2006
    CONFERENCE PROCEEDINGS FREE ACCESS
    We have developed asymmetric induction based on memory of chirality. This enables highly enantioselective synthesis of unusual amino acids with a tetra-substituted carbon center, new cyclic amino acids, and multi-substituted nitrogen heterocycles. These reactions proceed via enolate intermediates with dynamic axial chirality. Due to dynamic nature of the chiral enolate intermediates, racemization of them gradually takes place. A typical chiral enolate intermediate undergoes racemization with a barrier of 16.0 kcal/mol and the corresponding half-life of 22 h at -78 °C . The chiral enolate is expected to undergo racemization very quickly at 20 °C with a half life of 0.05 sec. These backgrounds prompt us to avoid asymmetric reactions at room temperature. However, we report here that several reactions proceed in up to 99% ee based on memory of chirality even at room temperature.
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