HETEROCYCLES

■ Contents

■ Preface
In Memorial Issue of the late Professor Kenji Koga

Shiro Ikegami

*Professor, School of Pharmaceutical Sciences, Teikyo University

■ Biographical Data

Kenji Koga*

*Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan

■ Original Papers

Kenji Koga*

*Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan

■ Reviews

Kenji Koga*

*Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan

■ Enantioselective Synthesis of (R)-1-Azaspiro[4.4]nonane-2,6-dione Ethylene Ketal, Key Chiral Intermediate in the Elaboration of (-)-Cephalotaxine

Mathieu Pizzonero, Françoise Dumas,* and Jean d’Angelo*

*Department of Organic Chemistry, BioCIS, UMR 8076 CNRS, School of Pharmacy, Paris XI University, 5, Rue Jean-Baptiste Clément, 92296 Châtenay-Malabry Cedex, France

Abstract

An enantioselective synthesis of (R)-1-azaspiro[4.4]nonane-2,6-dione ethylene ketal (4), chiral relay in the elaboration of (-)-cephalotaxine (1b), starting from (R)-1-(2-methoxycarbonylethyl)-2-oxo-cyclopentanecarboxylic acid methyl ester ((R)-10) (8 chemical operations, 26% overall yield, ee > 95%) is described. The Curtius rearrangement of acyl azide (12) was used as the key strategic element to install with a perfect stereochemical fidelity and a high efficiency an α-nitrogen substituent at the quaternary carbon center in 10.

■ [2+2] and [2+4] Type Cycloadditions of Isocyanates with Ynolates

Mitsuru Shindo,* Akiko Harada, Kenji Matsumoto, and Kozo Shishido

*Kyushu University, 6-1, Kasuga-koen, Kasuga, Fukuoka 816-8580, Japan

Abstract

Ynolates react with isocyanates to give azetidine-2,4-diones via a [2 + 2] type cycloaddition. The [4 + 2] type cycloaddition proceeds in the reactions of vinyl isocyanates with ynolates to provide 2-pyridones.

■ Studies on the Preparation of 1,5-Methanoazocinoindole Based on Indolylborate

Minoru Ishikura,* Norinobu Takahashi, Hidekazu Takahashi, and Kazuo Yanada

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

Abstract

Conversion of piperidine (8), readily available from the palladium catalyzed tandem cyclization-cross-coupling reaction of indolylborate (6) with bromide (7), to 1H-1,5-methanoazocino[4,3-b]indole (15) through piperidine (14) was investigated.

■ Practical Halogenations of Nucleosides Using Tetrabutylammonium Peroxydisulfate

Vasu Sampath, Vidyadhar Jadhav, Hee Yoon Lee,* and Yong Hae Kim*

*Department of Chemistry, Center for Molecular Design and Synthesis, Korea Advanced Institute of Science and Technology, 373-1, Kusong-Dong, Yusung-Gu, Taejon 305-701,Korea

Abstract

Direct halogenation of a wide range of acetylated pyrimidine and purine nucleosides was achieved with high regioselectivity in good yields using tetrabutylammonium peroxydisulfate 1. Treatment of protected nucleosides with HCl/DMF or inorganic salts such as LiCl or NaCl in MeCN/AcOH in the presence of 1 gave the corresponding chlorinated nucleosides and bromination was achieved with N-bromosuccinimide in MeCN in the presence of 1.

■ Direct Access to Heteropolycyclic Spiroketones. 1,3-Dichloroacetone as a Cyclopropanone Equivalent

Leo A. Paquette,* David G. Hilmey, and Peter R. Selvaraj

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

Abstract

A series of hetero spiro cyclobutanones, cyclopentanones, and cyclohexanones has been prepared by taking advantage of the flexibility offered by 1,3-dichloroacetone as a substitute for the elusive cyclopropanone reagent.

■ A New Asymmetric Total Synthesis of Enantiopure (-)-Malyngolide

Hidetoshi Miyamoto, Mitsuhiro Iwamoto, and Masahisa Nakada*

*Department of Chemistry, School of Science and Engineering, Waseda University, 3-4-1 Okubo, Shinjuku-ku, Tokyo 169-8555, Japan

Abstract

A new asymmetric total synthesis of (-)-malyngolide is described. This synthesis is based on the originally developed catalytic asymmetric IMCP reaction; that is, α-diazo-β-keto sulfone (13) was successfully converted to cyclopropane (12) in 92 % yield with excellent enantioselectivity (97% ee), and cyclopropane (12) was successfully converted to (-)-malyngolide.

■ Enantioselective Syntheses of Heliannuols G and H

Sachie Morimoto, Mitsuru Shindo, and Kozo Shishido*

*Graduate of School of Pharmaceutical Sciences, University of Tokushima, 1-78-1 Sho-machi, Tokushima 770-8505, Japan

Abstract

Enantioselective total syntheses of the proposed structures for heliannuols G and H have been accomplished. However, their spectral properties were not identical with those of the natural products.

■ A Cation-Exchange Resin Promoted Imino Aldol Reaction of Chiral Alkoxyketene Silyl Acetals with α,β-Unsaturated Imines, Leading to a Facile Synthesis of β-Lactams

Makoto Shimizu,* Masanori Tachi, Shiho Fukukshima, and Iwao Hachiya

*Department of Chemistry for Materials, Faculty of Engineering, Mie University, 1515 Uehama-cho, Tsu, Mie 514-5807, Japan

Abstract

Imino aldol reaction of chiral ketene silyl acetals derived from 3-hydroxybutanoates with α,β-unsaturated imines proceeds smoothly to give β-amino esters in good yields with high syn-selectivity under the influence of a cation-exchange resin. Subsequent treatment with tert-butylmagnesium chloride gave β-lactams in a highly stereoselective manner.

■ Asymmetric Introduction of Nucleophiles to the 2-Position of Pyrrolidine Ring through N-Acylpyrrolidinium Ion

Osamu Onomura, Takashi Ikeda, and Yoshihiro Matsumura*

*Department of Pharmaceutical Sciences, Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan

Abstract

Asymmetric carbon-carbon bond-forming reaction at the 2-position of a pyrrolidine ring was achieved. The reaction involved a chiral Ti(IV) catalyzed coupling between 1-methoxycarboyl-2-methoxypyrrolidine and silyl enol ethers to afford 2-substituted pyrrolidines with up to 53 % ee.

■ A Highly Efficient Synthesis of Trispheridine through a Construction of Tetrahydrophenanthridine Based on a Microwave-assisted Thermal Electrocyclic Reaction of an Aza 6π-Electron System

Teppei Kumemura, Tominari Choshi, Junko Yukawa, Aya Hirose, Junko Nobuhiro, and Satoshi Hibino*

*Graduate School of Pharmacy and Pharmaceutical Sciences, Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Fukuyama, Hiroshima 729-0292, Japan

Abstract

A highly efficient synthesis of a phenanthridine alkaloid, trispheridine (1) has been achieved in a 74% overall yield in a four-step sequence. The key step is the construction of a tetrahydrophenanthridine based on a microwave -assisted thermal electrocyclic reaction of an aza 6¿-electron system including the benzene double bond.

■ The Synthesis of Heteroarylazulene

Taku Shoji, Shigeru Kikuchi, Shunji Ito, and Noboru Morita*

*Department of Chemistry, Graduate School of Science, Tohoku University, Aoba-ku, Sendai 980-8578, Japan

Abstract

Palladium-catalyzed cross-coupling reaction of 2- and 6-haloazulenes with lithium tri(heteroaryl)magnesates gave corresponding heteroarylazulenes in excellent yields which were independent of binding position.

■ Kinetic Resolution via the [2,3] Stevens Rearrangement of Epimeric Six-membered Ammonium Ylides: A New Entry to Enantio-enriched α-Amino Acid Derivatives

Eiji Tayama,* Hiroyuki Tanaka, and Takeshi Nakai

*Graduate School of Science and Technology, Niigata University, 8050, 2 no-cho, Ikarashi, Nigata 950-2181, Japan

Abstract

The asymmetric [2,3] Stevens rearrangement of epimeric mixtures of N-allylic ammonium salts derived from (5R)-5-phenyl-1,4-oxazin-2-one is shown to proceed with efficient kinetic resolution to afford the unnatural α-amino acid derivatives in high enantio-purities.

■ New Utilizations of Optically Active Homoallylamines: Highly Stereoselective Synthesis of Cyclic Guanidine and Thiourea

Reiko Yanada, Akira Kaieda, Kazuo Yanada, and Yoshiji Takemoto*

*Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-shimoadachi-machi, Sakyo-ku, Kyoto 606-8501, Japan

Abstract

Halocyclizations of optically active homoallylguanidine and homoallylthiourea were examined. These reactions proceeded stereoselectively to give six membered cyclic guanidines and thiourea. High 1,3-asymmetric induction by the homoallylic substituents is observed in these halocyclizations.

■ A Concise Enantioselective Synthesis of (+)-α-Conhydrine

Kazuhiro Nagata, Yosuke Toriizuka, and Takashi Itoh*

*School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan

Abstract

A short step synthesis of (+)-α-conhydrine was achieved employing a kinetic resolution of 2-(1-hydroxypropyl)pyridine with lipase PS and a chelation-controlled diastereoselective reduction of pyridine ring as key reactions.

■ Cu(II)-mediated Stereoselective Michael Addition of a Methyl Group to an α,β-Unsaturated Ester as the C2-Side Chain in 3-(t-Butyldimethylsilyloxy)tetrahydropyrans

Keisuke Suzuki, Ulrike Jannsen, Hiroko Matsukura, and Tadashi Nakata*

*Department of Chemistry, Faculty of Science, Tokyo University of Science, Kagurazaka 1-3, Shinjuku-ku, Tokyo 162-8601, Japan

Abstract

Stereoselective Michael addition of a methyl group to an α,β-unsaturated ester as the C2-side chain in 3-(t-butyldimethylsilyloxy)tetrahydropyrans was accomplished under the conditions using MeMgBr and TMSCl in the presence of a catalytic amount of Cu(N-i-Pr-Sal)₂.

■ Anion-induced Fluorescence Quenching and Excimer Formation of Anthracene-Imidazolium Receptor

Kiyoshi Sato,* Yuichi Sadamitsu, Sadao Arai, Tetsuya Shimada, Haruo Inoue, and Takamichi Yamagishi

*Department of Applied Chemistry, Faculty of Engineering, Tokyo Metropolitan University, Hachioji, Tokyo 192-0397, Japan

Abstract

New anthracene based fluorescent anion receptor bearing two imidazolium units linked by methylene spacers at 9,10-positions has been synthesized. Complexation behavior and fluorescent properties of the receptor with inorganic anions (Cl^-, Br^-, I^-, NO₃^-, HSO₄^-, and H₂PO₄^-) in acetonitrile were investigated by ¹H NMR spectrometric and fluorimetric titrations, and fluorescence lifetime measurement. At low receptor concentration level (0.1 μM), fluorescence of the receptor was quenched by formation of 1:1 host-guest complex with the anions. At relatively higher receptor concentrations (above 1.0 μM), H₂PO₄^- anion quenched the monomer emission mainly by the excimer formation due to anion-induced ground state aggregation. Fluorescence lifetime measurements revealed that quenching mechanisms are different between halide ions and oxoanions.

■ Synthetic Studies of Liposidomycin Degradation Product: Attempt for Introduction of an Uracil Group

Shouhei Fukunishi, Makoto Ubukata, and Noriyuki Nakajima*

*Biotechnology Research Center, Toyama Prefectural University, 5180 Kurokawa, Kosugi, Toyama 939-0398

Abstract

Toward the synthesis of liposidomycin degradation product, the introduction of a uracil group was studied. In the presence of an N-methyl group on the diazepanone ring, the introduction of a uracil group failed. The O-nitrobenzenesulfonyl (Ns) protecting group played an important role for the introduction of a uracil group.

■ Sterically Congested “Roofed” 2-Iminothioethers as New Chiral Ligands for Palladium-catalyzed Asymmetric Allylic Alkylation

Ryoh Tokuda, Hirofumi Matsunaga,* Tadao Ishizuka, Makoto Nakajima, and Takehisa Kunieda*

*Faculty of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-hon-machi, Kumamoto 862-0973, Japan

Abstract

The preparation of a new class of “roofed” aminothiol derivatives, from sterically congested, conformationally rigid chiral 2-thiazolidinones is described. The compounds function as efficient chiral ligands for the palladium-catalyzed asymmetric allylic alkylation of 1,3-diphenyl-2-propenyl acetate with dimethyl malonate in the presence of cesium carbonate as a base.

■ Direct C-C Bond Formation between Thymine Derivatives and Naphthalene through [2+2]-Photocycloaddition

Kazue Ohkura,* Tetsuya Ishihara, Hajime Takahashi, Haruko Takechi, and Koh-ichi Seki*

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

Abstract

In contrast to our previous findings that UV-irradiation of 1,3-dimethylthymine (1a) with naphthalene (2) underwent 1,4-cycloaddition to give an ethenobenzoquinazoline derivative, UV-irradiation of a mixture of 1a and 2 in the presence of piperylene preferentially underwent 1,2-cycloaddition to give cis-tetrahydronaphthocyclobutapyrimidine in high stereoselectivity. Similar irradiation of 1,3-dimethyluracil and its derivatives (1) with substituents at C-5 gave the corresponding cis-1,2-adducts (3) in fair yields.

■ Novel Protocol for the Asymmetric Synthesis of 3-Hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one via Bakers’ Yeast Reduction

Takuzo Komiyama, Yutaka Takaguchi, and Sadao Tsuboi*

*Department of Environmental Chemistry and Materials, Faculty of Environmental Science and Technology, Okayama University, 2-1-1 Tsushima-naka, Okayama 700-8530, Japan

Abstract

A novel protocol for the asymmetric synthesis of 3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one is reported. Darzens condensation reactions of anisaldehyde with dichloroacetates, followed substitution reaction of sodium o-nitrophenylthiolate and bakers’ yeast reduction furnished 2-hydroxy-3-(4-methoxyphenyl)-3-(2-nitrophenylsulfanyl)propionates. Further reduction of a nitro group and cyclization gave the title compound.

■ Sc(OTf)₃-catalyzed C-Glycosylation of β-Diketones. A Facile Access to Useful Precursors of Heteroaromatic C-Glycosides

Takahito Yamauchi, Masayuki Shigeta, Takashi Matsumoto,* and Keisuke Suzuki*

*Department of Chemistry, Faculty of Science, Tokyo Instituteof Technology, 2-12-1, Ookayama, Meguro-ku, Tokyo 152-8551, Japan

Abstract

Scandium tris(triflate) efficiently catalyzes C-glycosylation of β-diketones with glycosyl acetate. Elaboration of the β-diketo moiety in the resulting C-glycosides to heterocycles provides a flexible route to the C-nucleoside analogs.

■ Syntheses and Biological Activities of Structurally Stiff Rhodacyanines as Novel Antimalarial Candidates

Kiyosei Takasu,* Daiki Morisaki, Marcel Kaiser, Reto Brun, and Masataka Ihara*

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

Abstract

New classes of rhodacyanine as structurally stiff derivatives were designed and synthesized. The synthetic compounds were evaluated the antimalarial activity and cytotoxicity in vitro.

■ An Enantio- and Diastereocontrolled Synthesis of (+)-7-Deoxy-trans-dihydronarciclasine

Takashi Fujimura, Masatoshi Shibuya , Kunio Ogasawara,* and Yoshiharu Iwabuchi*

*Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Aobayama, Sendai 980-8578, Japan

Abstract

An enantio- and diastereocontrolled synthesis of (+)-7-deoxy-trans-dihydronarciclasine, a potent antineoplastic phenanthridone alkaloid from the bulbs of Hymenocallis carbaea and H. littoralis, has been developed starting with the chiral cyclohexanoid building block.

■ 1,3-Dipolar Cycloaddition of Ethyl 2,3-Pentadienoate with Pyridinium Dicyanomethylides: Regiospecific Formation of Ethyl 3-Cyano2-ethylindolizine-1-carboxylates and a Novel Formation of Tricyclic Compounds

Naoto Hayashi, Naoto Kawajiri, Takane Uchida, and Kiyoshi Matsumoto*

*Faculty of Pharmaceutical Sciences, Chiba Institute of Science, 3 Shiomi-cho, Choshi, Chiba 288-0025, Japan

Abstract

Pyridinium dicyanomethylides underwent site- and regioslective 1,3-dipolar cycloaddition with ethyl 2,3-pentadienoate to give ethyl 3-cyano-2-ethylindolizine-1-carboxylates in moderate yields. In two cases, a novel type of the tricyclc compounds, in addition to indolizines, were obtained whose structure was established by a single crystal X-Ray analysis. A plausible mechanism for its formation is also presented.

■ Diastereoselective Fischer-Type Pyrroloindole Synthesis and Its Application to the Synthesis of Chiral Pyrroloindole Alkaloids

Atsushi Nishida,* Satoru Ushigome, Ayako Sugimoto, and Shigeru Arai

*Graduate School of Pharmaceutical Science, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan

Abstract

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.