HETEROCYCLES

■ Contents

■ Preface
In Honor of Professor Pierre Potier on the Occasion of his 70^th Birthday

Shiro Ikegami

*Professor, School of Pharmaceutical Sciences, Teikyo University

■ Pierre Potier
Outstanding Contribution in the Area of Medicinal Chemistry

Yuichi Kanaoka

*Chairman, Toyama International Institution
President, Toyama University of International Studies

■ Pierre Potier at 70.

Guy Ourisson

*,

■ Biographical Data
Titles and Functions
Principal areas of Scientific Interest

Pierre Potier*

*Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-Yvette Cedex, France

■ Selection of Publications

Pierre Potier*

*Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-Yvette Cedex, France

■ Comments on P. Potier‘s Scientific Achievements

Pierre Potier*

*Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-Yvette Cedex, France

■ Homologation of Vicinal Polyketone Networks to Epoxy Ketones with Diazomethane

Ryan E. Hartung and Leo A. Paquette*

*Department of Chemistry, The Ohio State University, 100 West 18th Avenue, Columbus, Ohio 43210, U.S.A.

Abstract

Admixture of vicinal di-, tri-, and tetraketones with ethereal diazomethane results in one-time methylene transfer to the less hindered face of the sterically most accessible and electron-deficient carbonyl group to deliver epoxy ketones in a highly selective manner unless ring strain effects contravene.

■ Synthesis of Bicyclic Heterocycles from Propargyl Esters Using a Palladium Catalyst Bearing a Bidentate Ligand

Masaya Tsubakiyama, Yoshihiro Sato, and Miwako Mori*

*Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12 Nishi 6, Kita-ku, Sapporo, Hokkaido 060-0812, Japan

Abstract

A method for synthesis of bicyclic heterocycles having functional group was developed from phenylpropargyl esters using a palladium catalyst and bidentate ligand. Isoquinoline and benzoazepine derivatives having functional groups could be synthesized using this method in high yields.

■ Access to the Newly Isoindolo[1,3]benzothiazocinones via the Combination of N-Acyliminium Chemistry and Friedel-Crafts Type π-Cyclization

Armelle Cul, Adam Daïch,* Bernard Decroix, Gérard Sanz, and Luc Van Hijfte

*Laboratoire de Chimie, URCOM, Faculté des Sciences et Techniques, Université du Havre, 25 Rue Philippe Lebon, B.P. 540 76058 Le Havre Cedex, France

Abstract

New racemic and chiral [4,2]- and [3,5]benzothiazocines (4) and (5) in the isoindolinone series were synthesized easily in few steps based on the combination of N-acyliminium chemistry and π-cationic cyclization of acylium ions. The chemoselectivity observed during these processes, particularly in the reduction, the thioalkylation and the cyclization stages, were also discussed.

■ Palladium-catalyzed Insertion-Cyclization Reaction of 2,3-Allenols with Aryl Iodides in Water: Synthesis of 1-Arylvinyl-substituted Epoxides

Masahiro Yoshida,* Takayuki Ishii, Takahiro Gotou, and Masataka Ihara*

*Graduate School of Pharmaceutical Sciences, Tohoku University, Aramaki, Aoba-ku, Sendai 980-8578, Japan

Abstract

A methodology for the synthesis of substituted epoxides in water has been described. The reactions of 2,3-dienyl alcohols with aryl iodides in the presence of palladium catalyst in water afford the 1-arylvinyl-substituted epoxides. It is clear that water-soluble ligand TPPDS is suitable for the reaction, and various epoxides are produced in moderate to good yields.

■ Iodine-induced Cyclizations of N-Alkoxyaminoalkenes. A Stereocontrolled Approach to trans-2,6-Disubstituted Piperidine Alkaloids

David R. Williams,* Martin H. Osterhout, and George S. Amato

*Department of Chemistry, Indiana University, 800 E. Kirkwood Avenue, Bloomington, IN 47405-7102, U.S.A.

Abstract

Iodine-induced intramolecular cyclizations of γ-alkenyl-N-alkoxyamines preferentially produce 2,6-trans-disubstituted piperidines. Subsequent iodoetherifications of N-benzyloxypiperidines demonstrate the stereoselective transfer of oxygen to a proximate carbon via formation of bicyclic 1,3-syn-isoxazolidines. The strategy facilitates preparation of nonracemic piperidine diols from acyclic, optically active alcohols.

■ Synthesis of Affinity Nanoparticles Coupled to FR901464 Derivatives

Yoshimasa Imamura, Yoshihiro Ohtsu, Hiroshi Tanaka, Mamoru Hatakeyama, Takashi Manabe, Haruma Kawaguchi, Hiroshi Handa,* and Takashi Takahashi*

*Department of Applied Chemistry, Graduate School of Science and Technology, Tokyo Instituteof Technology, Meguro-ku, Tokyo 152-8552, Japan

Abstract

The synthesis of two latex nano-particles coupled to FR901464 derivatives is described. Two FR901464 derivatives attached with an amino-alkyl group at a different position were prepared from natural occurring FR 901464. Biological activities of the two ligands were significantly different. The acylation of two amino ligands with the activated esters on latex particles smoothly proceeded to provide the corresponding latex nano-particles coupled to FR 901464 at a different position.

■ Mode Switching during the Cycloaddition of 5-Fluoro-1,3-dimethyluracil with Naphthalene from 1,4- to 1,2-Addition

Kazue Ohkura,* Tatsuyuki Sugaoi, Tetsuya Ishikara, and Koh-ichi Seki*

*Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido 061-0293, Japan

Abstract

UV-irradiation of a solution of 5-fluoro-1,3-dimethyluracil (5-FDMU) and naphthalene (1) in acetonitrile effected both 1,2- and 1,4-cycloaddition. The 1,2-cycloaddition proceeds more smoothly than the alternative 1,4-cycloaddition. The 1,2-cycloadduct (2), however, is labile to the UV-light used for the reaction, and is rapidly converted to 5-FDMU and naphthalene, while the 1,4-adduct (3) is insensitive to UV-light. Thus, 2 is obtained as the major product by short-period irradiation, while 3 is produced predominantly when the irradiation duration is prolonged. Mode-selective 1,2-cycloaddition is achieved when UV-irradiation is performed in the presence of piperylene.

■ Synthesis of N-Trifluoroacetyl-2-hydroxynoraporphine by Radical Reaction of p-Quinol Acetate of N-Trifluoroacetyl-1-(2-iodoveratryl)methyl-1,2,3,4-tetrahydro-7-methoxyisoquinolin-6-ol

Akiko Moriya and Osamu Hoshino*

*Faculty of Pharmaceutical Sciences, Science University of Tokyo, 2641 Yamazaki, Noda, Chiba 278-8510, Japan

Abstract

Radical reaction of p-quinol acetate (8b) of N-trifluroroacetyl-1- (2-iodoveratryl)methyl-1, 2, 3, 4-tetrahydro-7-methoxyisoquinolin-6-ol (7b) using tributyltin hydride gave the corresponding noraporphine (9)(45 %), while that of the bromo congener (8a) failed. Similar reaction of 8b using tris(trimethylsilyl)silane improved the yield (75 %) of 9.

■ Polyhydroxyazepanes Mimicking Monosaccharides: Synthesis of an α-D-Galacto-like Iminoheptitol

Hongqing Li, Yves Blériot,* Jean-Maurice Mallet, Yongmin Zhang, Eliazar Rodriguez-Garcia, Pierre Vogel, Silvia Mari, Jesús Jiménez-Barbero, and Pierre Sinaÿ*

*Chemistry Department, UMR 8642, Ecole Normale Supérieure, 24 rue Lhomond, 75231 Paris Cedex 05, France

Abstract

The synthesis of three new examples of seven-membered ring iminoalditols, displaying an extra hydroxymethyl group on the ring compared to the previously reported polyhydroxylated azepanes, has been achieved from D-lyxonolactone. None of them, including the α-D-galacto-like azepane (7), showed significant glycosidase inhibition on green coffee bean α-galactosidase and other commercially available hydrolases.

■ Synthetic Study of Hydrophilic Analogue of Scyphostatin via π-Facial Selective Diels-Alder Reaction

Wataru Miyanaga, Ryukichi Takagi, and Katsuo Ohkata*

*Department of Chemistry, Faculty of Science, Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima, Hiroshima 739-8526, Japan

Abstract

An analogue of the hydrophilic moiety of scyphostatin was synthesized via π-facial selective Diels-Alder reaction of a 2,5-cyclohexadien-1-one bearing a spirolactone with cyclopentadiene.

■ Synthesis of 3-Alkylidene-isoindolinones via Sulphide Contraction

Xiaoxiang Zhu, Nigel H. Greig,* Qian-sheng Yu, Tada Utsuki, Harold W. Hollowya, Debomoy K. Lahiri, and Arnold Brossi

*Drug Design & Development, National Institute on Aging Intramural Program, National Institutes of Health, 5600 Nathan Shock Dr., Baltimore, MD 21224-6825, U.S.A.

Abstract

Isoindolinones are essential moieties in numerous natural products, chemical research tools and therapeutics. Syntheses of such isoindoline containing agents may occur through precursors, particularly via 3-alkylidene-isoindolinones. An alternate approach be can achieved via sulphide contraction, described herein. As an example, phthalimide was thionated with Lawesson’s reagent to give monothiophthalimide (4), which on stirring with α-bromoketones in the presence of base led to the Eschenmoser coupling reaction. In this manner, compounds (5, 6a and 6b) were formed by alkylation of monothiophthalimide with various α-bromoketones, followed by elimination of sulfur. For the compounds (6a and 6b), (Z)-3-alkylidene-isoindolinones were generated as a single product and no (E)-isomer was separated from the reaction mixture.

■ Asymmetric Synthesis of Heterocyclic β-Aminosulfones via Nucleophilic 1,2-Addition of 2-Lithiobenzo[b]thiophene to Aldehyde-SAMP-hydrazones

Dieter Enders* and Giuseppe Del Signore

*Institut für Organische Chemie, Rheinisch-Westfälische, Technische Hochsch, Aachen University, Professor-Pirlet-Straße 1, D-52074 Aachen, Germany

Abstract

An efficient asymmetric synthesis of α-(1,1-dioxo-2,3-dihydro-1H-1λ⁶-benzo[b]thiophen-2-yl)-substituted amines is described. Key steps of the synthesis are the nucleophilic 1,2-addition of 2-lithio-benzo[b]thiophene to aldehyde-SAMP-hydrazones, a benzo[b]thiophene oxidation using dimethyldioxirane and a highly diastereoselective conjugate reduction with L-Selectride.^® The heterocyclic β-aminosulfones are obtained in five steps and good overall yields (23-49%) and very high diastereo-and enantiomeric excesses (de > 96%, ee = 88-99%).

■ A Flexible Approach to (S)-3-Amino-2-pyrrolidinone Derivatives

Tian Tang, Chen Zhu, and Pei-Qiang Huang*

*Department of Chemistry, Xiamen University, 422 Siming Nanlu, Xiamen, Fujian 361005, China

Abstract

Starting from (S)-aspartic acid, a flexible chemoselective approach to (S)-3-amino-2-pyrrolidinone derivatives was reported. The (S)-3-amino-2-pyrrolidinone derivatives thus synthesized are useful templates for designing medicinal interesting compounds.

■ Influence of Polymerization Degree of Poly-L-leucine Catalyst and Substituent Effect on the Juliá-Colonna Asymmetric Epoxidation of Benzalacetophenones

Ryukichi Takagi, Shahnaz Begum, Akiko Siraki, Arata Yoneshige, Kin-ichirou Koyama, and Katsuo Ohkata*

*Department of Chemistry, Faculty of Science, Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima, Hiroshima 739-8526, Japan

Abstract

The Juliá-Colonna asymmetric epoxidation reaction of substituted benzalacetophenone afforded the corresponding epoxide with high yield and high enantioselectivity, catalyzed by the specified length of poly-L-leucine (chain length n > 15). Poly-L-leucine catalysts have been prepared by the polymerization reaction of L-leucine-NCA with initiators (BnONa, n-BuNH₂, H₂O) and characterized by the MALDI-TOF Mass and IR analysis.

■ Hexafluoroactone as Protecting and Activating Reagent: A New Approach to O-Glycosides

Klaus Burger,* Michael Kluge, Beate Koksch, Susanna Fehn, Christoph Böttcher, Lothar Henning, and Gerhared Müller

*Institute of Analytical Chemistry, University of Leipzig, Johannisallee 29, D-04103 Leipzig, Germany

Abstract

O-Glycosylated hexafluoroacetone-protected amino acid derivatives have been synthesized starting from serine, threonine, 4-hydroxyproline and tyrosine. They represent a new class of building blocks suitable for a divergent approach to O-glycopeptides.

■ Chemistry of Indoles Carrying a Basic Function. Part IX. Unexpected Cyclizations of Diketones Derived from Uhle’s Ketone

István Moldvai,* Eszter Gács-Baitz, Eszter Temesvári-Major, Mária Incze, László Poppe, and Csaba Szántay*

*Institute of Chemistry, Chemical Research Center, Hungarian Academy of Sciences, H-1025 Budpest II, Pusztaszeri ut 59-67, P.O. Box 17, Hungary

Abstract

Starting from a tricyclic diketone (14) obtained by Bowman’s method, a tetracyclic oxonaphthalene derivative (17) has been prepared through intramolecular aldol condensation followed by indole → naphthalene isomerization. An unexpected formation of a lactol ether (16) was observed as a result of acidic treatment of 14. Two modified reaction sequences starting from N-methyl derivatives have also been presented. The keto ketal (26) gave a macrocyclic lactol (27) with unexpected structure as a result of deketalization with trimethylsilyl iodide. The formation of a tetracyclic lactam (37) was observed while applying the modified Reformatsky reaction to ketone (33).

■ Solvent-free Synthesis of Quinolones Derivatives

Petra Cernuchová, Giang Vo-Thanh, Viktor Milata*, and André Loupy*

*Laboratoire des Réactions Sélectives sur Supports, ICMMO, CNRS UMR 8615, Bât. 410, Université Paris-Sud, Orsay 91405, Orsay Cedex, France

Abstract

Quinolones can be prepared in a three step procedure from triethylorthoformate and activated methylene derivatives leading to alkoxymethylenemalonates followed by reaction with aromatic amines and finally a cyclization. All the reactions were carried out under solvent-free conditions possibly under microwave activation with benefits for the first step.

■ Novel Synthesis of Benzoxazoles from o-Nitrophenols and Amines

Hiromi Nishioka,* Yukiko Ohmori, Yumiko Iba, Eri Tsuda, Takashi Hrayama*

*Faculty of Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushima-naka, Okayama 700-8530, Japan

Abstract

o-Nitrophenols and o-nitroaniline were reacted with amines at 210-215°C to produce the corresponding benzoxazoles and benzimidazoles, respectively, in moderate yields. The reactions between o-nitrophenols containing a CO₂Me or OMe group on their benzene rings and N,N-diethylaniline were examined to investigate the effects of the position and electronic character of these substituents on the formation of the oxazole ring.

■ Diels-Alder Reaction and Double Phenylation in Reaction of Thiophenes with Diphenyliodonium Triflate

Bian-Xiang Zhang, Takato Nuka, Yuzo Fujiwara, Teizo Yamaji, Zhaomin Hou, and Tsugio Kitamura*

*Faculty of Science and Engineering, Saga University, Honjo 1, Saga, Saga 840-8502, Japan

Abstract

The reaction of 2,5-dimethylthiophene with diphenyliodonium triflate in the presence of N-phenylmaleimide and a catalytic amount of Cu(OAc)₂ gave 1:1 and 1:2 cycloadducts with N-phenylmaleimide. The similar reactions of 2,5-bis(trimethylsilyl)thiophene, 3-phenylthiophene, and thiophene afforded 2,5-diphenylthiophene, 2,3,5-triphenylthiophene, and 2,5-diphenylthiophene, respectively. The cycloadducts and 2,5-diphenylated thiophenes are considered to be formed via S-phenylation of thiophenes affording 1-phenylthiophenium triflates.

■ Stereoselective Synthesis of 4-Aminomethyl-3-hydroxyprolinols and Ring Expansion into Enantiopure Polyfunctionalized Piperidines

Abdallah Deyine, Jean-Marc Delcroix, and Nicole Langlois*

*Institut de Chimie des Substances Naturelles, C.N.R.S., 1 avenue de la Terrasse, Bat. 27, 91198 Gif sur Yvette, France

Abstract

A stereoselective route was developed to synthesize enantiopure 3,4,5-trisubstituted piperidines in few steps. The functionalities were introduced starting from (S)-pyroglutaminol as chiral material. The method is based on the 1,3-dipolar cycloaddition of N-benzylnitrone to a derived bicyclic α,β-ethylenic lactam, followed by a ring enlargement of five to six membered nitrogen heterocycles through aziridinium ions.

■ Antileishmanial Activities of Rhodacyanine Dyes

Kiyosei Takasu,* Hiroki Terauchi, Hiroshi Inoue, Marii Takahashi, Setsuko Sekita, and Masataka Ihara*

*Graduate School of Pharmaceutical Sciences, Tohoku University, Aramaki, Aoba-ku, Sendai 980-8578, Japan

Abstract

Rhodacyanine dyes, potent antimalarial agents, was found to possess strong antileishmanial activity against Leishmania major in vitro. The efficacies of several compounds are comparable to one of clinically used amphotericin B.

■ Electrochemical Polymerization of Tetramethylene-crosslinked Bis(2,5-di-2-thienyl-1H-pyrrole)

Katsuhiko Ono,* Hiroaki Totani, Masakazu Ohkita, Katsuhiro Saito,* and Masaki Kato

*Department of Life and Material Engineering, Graduate School of Engineering, Nagoya Institute of Technology, Gokiso-cho, Showa-ku, Nagoya 466-8555, Japan

Abstract

Electrochemical polymerization of 1,1’-(1,4-butanediyl)bis(2,5-di-2-thienyl-1H-pyrrole) (7) afforded a thin film with a smooth surface on an ITO (indium-tin-oxide) electrode due to the network structure. The potentiostatic electrolysis was finished within 15 min, indicating an effective film formation technology for organic devices.

■ Cycloaddition Reactions of Neutral 2-Azadienes with Acetylenic Esters

Francisco Palacios,* Concepción Alonso, Cristina Tobillas, and Gloria Rubiales

*Department of Organic Chemistry I, Basque Country University, P.O. Box 450, 01080 Vitoria, Spain

Abstract

A method for the preparation of functionalized polysubstituted dihydropyridine and pyridine derivatives is described, based on cycloaddition reactions of 2-aza-1,3-dienes with dimethyl acetylenedicarboxylate and ethyl propiolate.