HETEROCYCLES

■ Contents

■ A Tribute to Professor Kaoru Fuji on the Occasion of His 80th Birthday

Amos B. Smith III*

*Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia, PA 19104-6323, U.S.A.

■ Preface to Heterocycles Issue Honoring the 80th Birthday of Professor Kaoru Fuji

Takeo Kawabata*

*Institute for Chemical Research, Kyoto University, Gokasho, Uji, Kyoto, 611-0011, Japan

■ Preface to Heterocycles Issue Honoring the 80th Birthday of Professor Kaoru Fuji

Kiyosei Takasu*

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

■ Curriculum Vitae

Kaoru Fuji*

*

■ Publication List by Kaoru Fuji

Kaoru Fuji*

*

■ Recent Advances in the Chemistry of Azaazulenes and Related Compounds

Noritaka Abe*

*Department of Pure and Applied Chemistry, Faculty of Science and Technology, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan

Abstract

In this review, the synthetic methods and about the biological and physical properties of mono- and poly-azaazulenes including some of their dihydro-, tetrahydro-, oxo-derivatives and aromatics- and heterocycles-fused derivatives and related compounds, such as pyrrolobenzazepines, azepinoindole derivatives, and so on, published from end of 2017 to April 2019, are surveyed.

■ An Efficient Enantiospecific Synthesis of Neuroactive Glutamate Analogs

Shuntaro Tsukamoto, Hiyori Itagaki, Kenji Morokuma, Kei Miyako, Yuichi Ishikawa, Ryuichi Sakai, and Masato Oikawa*

*Yokohama City University, Seto 22-2, Kanazawa-ku, Yokohama 236-0027, Japan

Abstract

Herein we report improved enantiospecific synthesis and some structure-activity relationships of our heterotricyclic artificial glutamate analogs bearing seven-membered ring for the C-ring. Starting from readily available oxanorbornene rac-3, optically pure (2R)-TKM-107, (2R)-IKM-154, and the antipodes were synthesized in total nine steps for each. Mice in vivo assay indicated that only the (2R)-enantiomer was active in both cases. Behaviors phenotypes observed in the mice assay suggested that these compounds are similar in mode of action to that of IKM-159 but with discrete potency.

■ A Novel Condensed Heterocyclic Quinone with a Dibenzofuranobisthiadiazole Skeleton

Kazuma Sugawara, Wataru Nojo, Yusuke Ishigaki, Junko Ohkanda, and Takanori Suzuki*

*Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo, Hokkaido 060-0810, Japan

Abstract

Upon oxidation of hydroquinone fused with 1,2,5-thiadiazole by using FeCl3, a novel dibenzofurano[1,2-c:6,7-c']bis[1,2,5]thiadiazole-type quinone was obtained whereas the similar dimerization-condensation process did not occur for the pyrazine-fused hydroquinone under the similar conditions.

■ Synthesis of Novel Fluorous Imidazolium Ionic Liquids

Mitsunori Honda,* Ryu Nakajima, Ko-Ki Kunimoto, and Masahito Segi*

*Division of Material Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma, Kanazawa, Ishikawa 920-1192, Japan

Abstract

The synthesis of a novel class of fluorous ionic liquids was investigated. The 1,3- and 1,2-diperfluoroalkylated imidazolium salts 1 and 2 were successfully prepared. Unfortunately, most of them were solids and had low fluorophilicity. On the other hand, most imidazolium salts 3-8 possessing one or two tris(perfluoroalkyl)silyl groups in cation moiety were liquids at room temperature and had high fluorophilicity independent of the kind of anion moiety. Additionally, dicationic bisimidazolium ionic liquids 10 having two tris(tridecafluorooctyl)silylpropyl groups were also prepared and showed good fluorophilicity.

■ Rapid Exploration of Novel Anthelmintic Agents from Alkyne-Bearing Avermectin Derivatives via Click Chemistry

Tomoyasu Hirose, Akari Ikeda, Ayumi Tsutsui, Satoshi Ōmura, and Toshiaki Sunazuka*

*The Kitasato Institute for Life Sciences and Graduate School of Infection Control Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641

Abstract

We applied copper-catalyzed 1,4-disubstituted-1,2,3-triazole formation, a major connective reaction in “Click Chemistry”, to synthesize novel avermectin derivatives. Among the synthetic triazole-containing avermectins, the 4-hydroxybutyltriazole derivative (3a) was found to demonstrate notable antinematodal activity against ivermectin-resistant Trichinella spiralis in vitro. Furthermore, a new compound (3a) also exhibited strong antinematode properties against ivermectin-resistant Haemonchus contortus in sheep following oral administration.

■ Planar Chiral Phosphino[2.2]paracyclophanol-Catalyzed Highly Regio- and Stereoselective [3+2] Annulation Reaction of Morita–Baylis–Hillman Carbonates with Dicyanomethylideneoxindoles

Shinji Kitagaki,* Mayuka Tsuji, Hideki Teramoto, Naoko Takenaga, and Keisuke Yoshida

*Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya 468-8503, Japan

Abstract

To demonstrate the utility of [2.2]paracyclophane as a chiral organocatalyst backbone, we examined a planar chiral pseudo-ortho-diarylphosphino[2.2]paracyclophanol, phosphino-PCP-ol, which has a spacer aryl group between the pseudo-ortho-substituted PCP-ol backbone and the diarylphosphino group. We tested this catalyst in the [3+2] annulation reaction of Morita–Baylis–Hillman carbonates, derived from aromatic aldehydes and methyl acrylate, with 3-(dicyanomethylidene)-2-oxindole. The catalyst produced the desired 3-spirocyclopentene-2-oxindoles in high yields, and high regio-, diastereo-, and enantioselectivities.

■ Synthesis of 1,3,4-Oxadiazoles as Selective T-Type Calcium Channel Inhibitors

Man Zhang, Bende Zou, Medha J. Gunaratna, Sahani Weerasekara, Zongbo Tong, Thi D. T. Nguyen, Serkan Koldas, William S. Cao, Conrado Pascual, Xinmin Simon Xie,* and Duy H. Hua*

*Department of Chemistry, Kansas State University, 1212 Mid Campus Drive, Manhattan, KS 66506, U.S.A.

Abstract

Neuropathic pain, epilepsy, insomnia, and tremor disorder may arrive from an increase of intracellular Ca2+ concentration through a dysfunction of T-type Ca2+ channels. Thus, T-type calcium channels could be a target in drug discovery for the treatments of neuropathic pain and epilepsy. From rational drug design approach, a group of 2,5-disubstituted 1,3,4-oxadiazole molecules was synthesized and their selective T-type channel inhibitions were evaluated. The synthetic strategy consists of a short sequence of three reactions: (i) condensation of thiosemicarbazide with acid chlorides; (ii) ring closing by 1,3-dibromo-5,5-dimethylhydantoin; and (iii) coupling with various acid chlorides. 5-Chloro-N-(5-phenyl-1,3,4-oxadiazol-2-yl)thiophene-2-carboxamide (11) was found to selectively inhibit T-type Ca2+ channel over Na+ and K+ channels in mouse dorsal root ganglion neurons and/or human embryonic kidney (HEK)-293 cells and to suppress seizure-induced death in mouse model. Consequently, compound 11 is a useful probe for investigation of physiologic and pathophysiologic roles of the T-channel, and provides a basis to develop a novel therapeutic to treat chronic neuropathic and inflammatory pains.

■ Synthesis of Optically Active (R)- and (S)-β-Arginine from Pyroglutamic Acid

Yoko Yasuno, Akira Sawai, Ai Sekihara, and Tetsuro Shinada*

*Graduate School of Science, Osaka City University, 3-3-138, Sugimoto, Sumiyoshi, Osaka 558-8585, Japan

Abstract

The first synthesis of optically active β-arginine was achieved starting from commercially available pyroglutamic acid. The new synthetic protocol is characterized by the use of nitrile as a carboxylic acid surrogate which could be transformed to the corresponding 2-acyl-1,3-bis(1,1-dimethylethyl)imidodi-carbonic acid ester (active amide) via Pt-catalyzed hydration under the mild conditions. The active amide was converted to β-arginine and Boc-β-Arg-Val-OMe in good yield.

■ Synthesis of Indolines via a Photocatalytic Intramolecular Reductive Cyclization Reaction

Eiji Yamaguchi,* Yumiko Goto, and Akichika Itoh*

*Laboratory of Pharmaceutical Synthetic Chemistry, Gifu Pharmaceutical University, 1-25-4, Daigaku-nishi, Gifu 501-1196, Japan

Abstract

Herein, we synthesized a series of indolines using a photocatalytic intramolecular reductive cyclization reaction. This reaction uses several N-allyl-2-iodoanilines in the presence of 10-phenylphenothiazine (Ph-PTZ) as an organic photocatalyst. Further, the corresponding aryl radical is generated through the reductive cleavage of the C–I bond, generating 5-exo cyclization products.

■ Iridoid Glucosides from Linociera sangda

Yukiko Takenaka, Naoaki Okazaki, Toyoyuki Nishi, Naotaka Nagakura, and Takao Tanahashi*

*Kobe Pharmaceutical University, 4-19-1 Motoyamakita-machi, Higashinada-ku, Kobe 658-8558, Japan

Abstract

A phytochemical investigation of the aerial parts of Linociera sangda led to the isolation of three new iridoid glucosides (1–3), together with nine known iridoid glucosides and a flavonoid glycoside, nicotiflorin. The structures of the new compounds were elucidated spectroscopically. Compounds 1–3 are members of a rare group of iridoids with a spirolactone ring, and compound 3 is the first instance of an adduct of iridoid glucoside and flavonoid glycoside.

■ Gold(I)-Catalyzed 10-endo-dig-Selective Cycloisomerization of N-(2-Anilinobenzyl)propargylamines

Mamoru Ito,* Daisuke Inoue, Asahi Takaki, Kyalo Stephen Kanyiva, and Takanori Shibata*

*Chemistry and Biochemistry, Advanced Research Center of Science and Engineering, Waseda University, 3-4-1 Okubo, Shinjuku-ku, Tokyo 169-8555, Japan

Abstract

The cationic gold(I)-catalyzed 10-endo-dig-selective cycloisomerization of N-(2-anilinobenzyl)propargylamine derivatives was developed. The reaction proceeded smoothly under mild conditions to give dibenzodiazecines. The catalytic construction of an entropically and enthalpically disfavored ten-membered ring was achieved by using a highly nucleophilic 3,5-dimethoxyanilino group as a reaction site.

■ Extraction Properties of 4-Tetra(hydroxyphenyl)BTPhen in Liquid-Liquid Extraction Systems with Cyclohexanone/Octanol or in a Solid-Phase Extraction System

Ashfaq Afsar, Jasraj S. Babra, Petr Distler, Laurence M. Harwood,* Iain Hopkins, Jan John,* James Westwood, and Zoe Y. Selfe

*Department of Nuclear Chemistry, Faculty of Nuclear Sciences and Physical Engineering, Czech Technical University in Prague, Břehová 7, 11519 Prague 1, Czech Republic

Abstract

The extraction properties of tetra(4-hydroxyphenyl)BTPhen have been investigated. Liquid-liquid extraction studies in proposed SANEX diluents, cyclohexanone and 1-octanol, indicate that actinide-lanthanide separation is superior in cyclohexanone; whereas actinide-actinide separation is more efficient in 1-octanol. Immobilization of the ligand onto a silica support results in the separation factor becoming dependent upon the concentration of nitrate anions in the aqueous phase. The immobilized ligand was also applied to the extraction of transition metals, resulting in >70% uptake of all transition metals examined, in the presence of alkali and alkaline earth metals.

■ Pyridine-Directed Rh-Catalyzed C6-Selective C–H Acetoxylation of 2-Pyridones

Sunit Hazra, Koji Hirano,* and Masahiro Miura*

*Department of Applied Chemistry, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan

Abstract

A Rh(III)-catalyzed C-H acetoxylation of 2-pyridones with phenyliodine(III) diacetate (PIDA) in a DCE/AcOH mixed solvent system has been developed using N-2-pyridyl function as directing group. The reaction occurs under mild conditions, typically in air at 40 oC, to selectively produce the corresponding C6-acetoxylated 2-pyridones in moderate to good yields.

■ A Mild Bischler–Napieralski-Type Cyclization of Trichloromethyl Carbamates for the Synthesis of β-Carbolinones

Seiya Hirao, Mayumi Kitamori, Tomoki Itoh, Yuusuke Chiba, and Takumi Abe*

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

Abstract

A straightforward synthesis of β-carbolinones by the Bischler–Napieralski-type cyclization of the corresponding trichloromethyl carbamates, which does not require acids, bases, oxidants, or transition-metals to promote the cyclization, has been achieved.

■ Novel Trifluoromethylated Spiro-1,3,4-thiadiazoles via [3+2]-Cycloadditions of 2,3-Diphenylcyclopropenethione with Selected in situ-Generated Nitrile Imines Derived from Trifluoroacetonitrile

Greta Utecht-Jarzyńska, Marcin Jasiński,* Kamil Świątek, Grzegorz Mlostoń, and Heinz Heimgartner*

*Department of Chemistry, University of Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland

Abstract

The in situ-generated N-aryl nitrile imines derived from trifluoroacetonitrile react efficiently with 2,3-diphenylcyclopropenethione to give spirocyclic 1,3,4-thiadiazole derivatives as products of a regio- and chemoselective (3+2)-cycloaddition in good to excellent yields. A stepwise mechanism via initial nucleophilic attack of the S-atom onto the electrophilic C-atom of the electron-deficient 1,3-dipole leading to a zwitterionic intermediate is postulated to explain these formal (3+2)-cycloaddition reactions. The presence of the CF3 group is necessary to activate the nitrile imine for the efficient trapping of the cyclopropenethione. These are the first examples of a successful reaction of this C=S dipolarophile affording 1,3,4-thiadiazoles as formal (3+2)-cycloadducts.

■ Synthesis of Oxygen-Heterocycles Having Linker Components for Trapping Cysteine Derivatives

Eito Yoshioka, Ikko Minato, Hideki Takashima, and Hideto Miyabe*

*Laboratory for Medicinal Chemistry, School of Pharmacy, Hyogo University of Health Sciences, 1-3-6 Minatojima, Chuo-ku, Kobe City, 650-8530, Japan

Abstract

Tricyclic oxygen-heterocycles 10, 13a, 13b and 18 having a linker component were synthesized for the site-specific modification of proteins and peptides. The linker components were initially introduced by Sonogashira-Hagihara cross coupling of 5-bromo-2-hydroxybenzaldehyde 5 and a variety of alkynes. Next, the desired oxygen-heterocycles 10, 13a, 13b and 18 were synthesized by the condensation reaction of coupling products with cyclohexane-1,3-dione in the presence of N,N-diisopropylethylamine. Finally, the trapping ability of these oxygen-heterocycles was demonstrated by the representative reaction of oxygen-heterocycle 10 with glutathione 19 as a nucleophile having a thiol group.

■ Conformational Properties and M1 Antimuscarinic Activity of 4-Substituted Pirenzepine/Telenzepine Analogues

Yuki Kanase, Kosho Makino, Takashi Yoshinaga, Hidetsugu Tabata, Tetsuta Oshitari, Hideaki Natsugari, and Hideyo Takahashi*

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

Abstract

The atropisomeric and conformational properties of the 4-Cl/Me-substituted pirenzepine/telenzepine analogues were examined. Although the 4-substitution is not effective in reducing the rotational barrier of the N5–(C1'=O) bond, the butterfly motion of the tricyclic ring system was frozen. The atropisomers showed little racemization after heating at 80 °C for 5 days. While these analogues showed less affinity to the M1 receptor compared with pirenzepine, a ca. 4.4-fold difference in potency between the atropisomers was observed for 1b.

■ Synthesis and Hybridizing Property of Oligonucleotides Including 2′-C,4′-C-Ethyleneoxy-Bridged 2′-Deoxyadenosine with an Exocyclic Methylene Unit

Takashi Osawa, Yoshinori Onishi, Sawako Wakita, Yuta Ito, and Yoshiyuki Hari*

*Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima 770-8514, Japan

Abstract

2′,4′-Bridged nucleic acids (2′,4′-BNAs) are of interest because oligonucleotides that include them have excellent duplex-forming capability and high nuclease resistance compared to natural oligonucleotides. We have recently developed 2′-C,4′-C-ethyleneoxy-bridged thymidine with an exocyclic methylene unit (methylene-EoDNA-T) as a novel 2′,4′-BNA analog. Oligonucleotides that include methylene-EoDNA-T have marked hybridizing capability, nuclease resistance, and in vitro gene-silencing potency. In the present study, we designed and synthesized a 2′-deoxyadenosine analog of methylene-EoDNA (methylene-EoDNA-A), and incorporated it into oligonucleotides. The results of melting temperature (Tm) analysis of duplexes formed from methylene-EoDNA-A-modified oligonucleotides indicated that the hybridizing capability with regard to complementary DNA was almost the same or slightly higher than that of natural DNA. Moreover, methylene-EoDNA-A:methylene-EoDNA-T base pairs increased the thermal stability of DNA duplexes compared to that of DNA duplexes containing methylene-EoDNA-A- or methylene-EoDNA-T-modification in one strand.

■ Stereoselective Synthesis of β-Amino Acids by Aldol-Type Addition

David Benito-Garagorri, Wolfgang Felzmann, Sven Nerdinger, and Kathrin Höferl-Prantz*

*Global Portfolio, Sandoz GmbH, Biochemiestrasse 10, 6250 Kundl, Austria

Abstract

A synthesis of α-oxygenated β-amino acid derivatives using an aldol-type addition is described. Depending on the enol equivalent different oxidation states of the oxygen substituent are accessible, while choosing a chiral imine allows to generate the aldol product in a stereoselective manner. This methodology has been applied to the synthesis of the biologically active compound Telaprevir, used in the traetment of Hepatitis C.

■ Isolation of Inohanalactone, a γ-Butyrolactone, from Nocardia inohanensis IFM0092T

Natsumi Kobayashi, Yasumasa Hara, Midori A. Arai, Shoko Hara, Tohru Gonoi, Takashi Yaguchi, and Masami Ishibashi*

*Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan

Abstract

Because research on the genus Nocardia has not progressed as compared to the extensively studied genus Streptomyces, Nocardia is considered as a useful undeveloped resource for exploring natural products. In this study, a new γ-butyrolactone derivative, named inohanalactone (1), was isolated from Nocardia inohanensis IFM0092T. Inohanalactone possesses an aliphatic side chain containing 8 carbons, a vicinal diol, and a cis double bond. Inohanalactone was produced by N. inohanensis IFM0092T in the modified Czapek–Dox medium, whereas it was not produced in other media such as Nutrient broth, Waksman, and Yeast-Malt-Glucose media.

■ Synthesis and Physical Properties of π-Extended Molecules Having p-Methylenequinone Unit

Rui Umeda,* Masamichi Nakatsukasa, and Yutaka Nishiyama*

*Faculty of Chemistry, Materials and Bioengineering, Kansai University, Suita, Osaka 564-8680, Japan

Abstract

In this paper, we reported the facile synthesis of the π-extended molecules having p-methylenequinone unit from the aromatic ketones, such as fluorenone, xanthone, thioxanthone, dibenzosuberenone, and acridone, in few steps and the results of their physical properties.

■ Synthesis of Axially Chiral Binaphthothiophene δ-Amino Acid Derivatives Bearing Chalcogen Bonds

Shohei Hamada, Shuo Wang, Takuya Murai, Yongning Xing, Takumi Inoue, Yoshihiro Ueda, Takahiro Sasamori, Takeo Kawabata, and Takumi Furuta*

*Department of Pharmaceutical Chemistry, Kyoto Pharmaceutical University, 1 Misasagi-Shichonocho, Yamashina, Kyoto 607-8412, Japan

Abstract

Axially chiral binaphthothiophene amino acid was synthesized as a stable artificial δ-amino acid. N- and C-protected derivatives of this unnatural amino acid were also prepared and applied for derivatization to the dipeptide. The crystal structure of the dipeptide revealed that the carbonyl groups of both the amide and the ester moieties were fixed with naphthothiophene rings in coplanar geometry via intramolecular chalcogen bonds.

■ Intramolecular Oxa-Michael Reactions of Aldols Generated from Enones and Isatins to Afford Spirooxindole Tetrahydropyrans

Maira Pasha, Muhammad Sohail, and Fujie Tanaka*

*Chemistry and Chemical Bioengineering Unit, Okinawa Institute of Science and Technology Graduate University, 1919-1 Tancha, Onna, Okinawa 904-0495, Japan

Abstract

Spirooxindole derivatives are found in bioactive natural products and are used in drug discovery and related research. Here, acid-catalyzed diastereoselective intramolecular oxa-Michael cyclization reactions of β-hydroxyenones generated from enones and isatin derivatives that afford spirooxindole tetrahydropyrans are reported. The major diastereomers of the products of these reactions were previously difficult to access by the amine-catalyzed hetero-Diels-Alder reactions of enones with isatins. With the use of enantiomerically enriched forms of the starting materials in the reactions, enantiomerically enriched spirooxindole tetrahydropyrans that retained the enantiopurities of the starting materials were obtained.

■ Synthesis of Three Stereoisomers of Erythrochelin, a Hydroxamate-Type Tetrapeptide Siderophore from Saccharopolyspora erythraea

Michiyasu Nakao, Ayumu Adachi, Syuji Kitaike, and Shigeki Sano*

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

Abstract

Details of the synthesis of three stereoisomers of erythrochelin, a hydroxamate-type tetrapeptide siderophore produced by Saccharopolyspora erythraea, were described. Both enantiomers of protected δ-N-hydroxyornithine were used as key intermediates in the synthesis of stereoisomers of erythrochelin containing a (3S,6S)-3,6-disubstituted-2,5-diketopiperazine ring. From comparisons of 1H and 13C NMR spectra, neither of stereoisomers provided a match for the erythrochelin spectral data, and the absolute configuration of erythrochelin was unambiguously reconfirmed to be (R,R,S,S).