HETEROCYCLES

■ Contents

■ Preface to Heterocycles Issue Honoring the 70th Birthday of Professor Dr. Kiyoshi Tomioka

Mitsuru Shindo*

*The Institute of Scientific and Industrial Research (ISIR), Osaka University, Mihogaoka, Ibaraki-shi, Osaka 567-0047, Japan

■ Preface to Heterocycles Issue Honoring the 70th Birthday of Professor Dr. Kiyoshi Tomioka

Motomu Kanai*

*The Institute of Scientific and Industrial Research (ISIR), Osaka University, Mihogaoka, Ibaraki-shi, Osaka 567-0047, Japan

■ Preface to Heterocycles Issue Honoring the 70th Birthday of Professor Dr. Kiyoshi Tomioka

Ken-ichi Yamada*

*The Institute of Scientific and Industrial Research (ISIR), Osaka University, Mihogaoka, Ibaraki-shi, Osaka 567-0047, Japan

■ Curriculum Vitae

Kiyoshi Tomioka*

*

■ Publication List by Kiyoshi Tomioka

Kiyoshi Tomioka*

*

■ Recent Progress of 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

This review describes the synthetic methods and reactions of azaazulenes including some of their dihydro-, tetrahydro-, oxo-derivatives and aromatics- and heterocycles-fused derivatives and related compounds such as pyrrolobenzazepines, and azepinoindole derivatives published during 2010 to 2017. The biological and physical properties of azaazulenes and related compounds are also described.

■ Construction of Cyclic Ether-Fused Tricyclic Naphthoquinone Derivatives by Intramolecular Cyclization Reaction

Tokutaro Ogata* and Tetsutaro Kimachi*

*Faculty of Pharmaceutical Sciences, Hokuriku University, 3-Ho, Kanagawa machi, Kanazawa 920-1181, Japan

Abstract

Cyclic ether-fused tricyclic naphthoquinones are major pharmacophores because they have attractive biological activities represented by antitumor and antibacterial properties. An enormous number of related compounds have been synthesized especially in the last two decades. The methodology for the construction of its skeleton is roughly classified into two types: 1) intermolecular cyclization of naphthoquinones and alkenes, 2) intramolecular cyclization of functionalized naphthoquinones. From the viewpoint of the reagents, a wide range of them from classical Brønsted acids to Lewis acids including fifth period elements have been applied to construct skeletons. The choice of appropriate reagent and reaction conditions against the substrate is the key to accomplishing the regio- and/or stereo-selective synthesis of these compounds, though it seems difficult at first glance to decide how because numerous numbers of actual examples have been presented. Therefore, in this review, we have decided to summarize the methods of constructing the tricyclic naphthoquinones limited by type 2 reactions while systematically classifying the substrates and reagents.

■ Radical Cyclizations of Aryl Bromides for Synthesis of Cyclopenta[b]indoles from Vince Lactam

Takumi Abe,* Tsuyoshi Morita, and Koji Yamada

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

Abstract

Radical cyclizations of aryl bromides, synthesized in two steps from Vince lactam, afforded cyclopenta[b]indoles in good yields. Furthermore, an unprecedented method for constructing cyclopenta[b]indoles utilizing tricyclic intermediate was also explored.

■ Enantioselective Cycloadditions between Aliphatic Nitrile Oxides and 2-Hydroxystyrenes Catalyzed by Chiral Amine-Urea

Yasunori Toda, Masato Koyama, Hiroyoshi Esaki, Kazuaki Fukushima, and Hiroyuki Suga*

*Department of Materials Chemistry, Faculty of Engineering, Shinshu University, 4-17-1 Wakasato, Nagano 380-8553, Japan

Abstract

Chiral amine-urea-catalyzed enantioselective 1,3-dipolar cycloadditions of nitrile oxides with 2-hydroxy-3-methoxystyrene are described. Aliphatic aldehyde-derived hydroximoyl chlorides were used as nitrile oxide precursors, providing optically active isoxazolines with moderate to good enantioselectivities.

■ Fine Chemicals from a Biomass-Derived Dicarboxylic Acid: Chiral Bisoxazolines and Their Application in Enantioselective Diels-Alder Reactions

Sermadurai Selvakumar, Alisa Fairweather, Angel Ugrinov, and Mukund P. Sibi*

*Department of Chemistry, North Dakota State University, Fargo, North Dakota, 58105-5516, U.S.A.

Abstract

2,5-Furandicarboxylic acid (FDCA) is a feedstock chemical readily available from cellulosic biomass. Six chiral bisoxazolines varying in the steric size of the blocking group have been synthesized from FDCA in modest to good overall yields. The effectiveness of the new chiral bisoxazolines has been evaluated in enantioselective Diels-Alder reactions.

■ Synthesis of 6/6/6-Tricyclic Ether System via Achmatowicz and Intramolecular Oxa-Michael Reactions

Hiroki Yamamoto, Kohei Torikai, Makoto Ebine, and Tohru Oishi*

*Department of Chemistry, Faculty and Graduate School of Science, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan

Abstract

Synthesis of 6/6/6-tricyclic ethers possessing 1,3-diaxial methyl groups was examined via Achmatowicz reaction and intramolecular oxa-Michael reaction. A key precursor was prepared via coupling of an aldehyde with a furyllithium derivative followed by radical deoxygenation of the resulting secondary alcohol. The intramolecular oxa-Michael reaction proceeded in a stereoselective manner to afford cis-fused product as a single isomer.

■ 2-Iodoimidazolinium Salt-Catalyzed Friedel–Crafts Reaction: Synthesis of Bis(indolyl)methane Alkaloids

Satoru Kuwano, Takumi Suzuki, and Takayoshi Arai*

*Department of Chemistry, Graduate School of Science, Chiba University, , Japan

Abstract

2-Iodoimidazolinium salt-catalyzed Friedel–Crafts reactions of indoles with aldehydes were developed. Under mild reaction conditions, various bis(indolyl)methane derivatives, an important class of indole alkaloids, were obtained in good to high yields.

■ A Synthetic Approach to Derive exo-Glucal Derivatives Through the Reaction of a1-C-Vinylated Glucopyranose Derivative with Phenols

Takashi Yamanoi,* Sho Matsuda, Junki Nakgawa, Mikio Watanabe, Yoshiki Oda, and Akihiro Yoshida

*Faculty of Pharmacy and Pharmaceutical Sciences, Josai University, 1-1 Keyakidai, Sakado, Saitama 350-0295, Japan

Abstract

In this study, a synthetic approach to prepare exo-glucal derivatives through the reaction of a 1-C-vinylated glucopyranose derivative with phenols in the presence of an appropriate promoter has been investigated. The reaction between 2,3,4,6-tetra-O-benzyl-1-C-vinyl-α-D-glucopyranose and different phenols using 5 mol% Bi(OTf)3 produced the corresponding exo-glucal derivatives as major products along with spiro O-glucoside derivatives as minor products.

■ Asymmetric Total Synthesis and Structure Confirmation of (+)-(3E)-Isolaurefucin Methyl Ether

Te-ik Sohn, Byungsook Kim, Deukjoon Kim,* and Robert S. Paton

*The Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Shillim-Dong, San 56-1, Kwanak-Gu, Seoul 151-742, Korea

Abstract

An asymmetric total synthesis and structure confirmation of (+)-(3E)-isolaurefucin methyl ether (2a) was accomplished. Our synthesis features two complementary routes to construct the α,α’-trans-2,8- dioxabicyclo[5.2.1]decane skeleton of the natural product from α,α’-trans-γ,δ-unsaturated oxocene alcohol 7, namely, an intramolecular epoxide opening route and a novel methoxyetherification route based on organoselenium- mediated oxonium ion formation/fragmentation. A computational analysis was performed to model the observed different fragmentation behaviors of the respective oxonium ions 8 and 8’ derived from α,α’-trans- and α,α’-cis-γ,δ-unsaturated oxocene alcohols 7 and 7’ during the organoselenium-mediated oxonium ion formation/fragmentation. Regarding the possibility of the natural product being an artifact, the reactivity of chlorofucin surrogate 16 and neoprelaurefucin surrogate 16’ during methanolysis was compared, the results were in good agreement with calculations.

■ Synthesis of Substituted t-Butyl 3-Alkyloxindole-3-carboxylates from Di-t-butyl (2-Nitrophenyl)malonates

Yu-suke Yamai, Akio Tanaka, Tatsuo Yajima, Kyoji Ishida, Itaru Natsutani, Shinichi Uesato, Yasuo Nagaoka, and Takaaki Sumiyoshi*

*Faculty of Chemistry, Materials and Bioengineering, Kansai University, 3-3-35 Yamate-cho, Suita, Osaka 564-8680, Japan

Abstract

Using a novel tandem reduction-cyclization, we synthesized t-butyl 3-alkyloxindole-3-carboxylates from the di-t-butyl 2-alkyl-2-(2-nitrophenyl)malonate. Introduction of an α-substituent to the di-t-butyl 2-(2-nitrophenyl)malonates and addition of acid promoted reactivity. This methodology was successfully applied to gram-scale-synthesis of the t-butyl 3-methyloxindole-3-carboxylate 1 and 3-hydroxymethyl-3-methyloxindole 2 without silica gel column chromatography.

■ Polymeric Silver(I) Complexes Based on Bidentate Imidazoline-2-thiones. Synthesis and Crystal Structures

Barbara Rietzler, Gerhard Laus, Klaus Wurst, Thomas Gelbrich, Sven Nerdinger,* Erwin Schreiner, and Herwig Schottenberger

*Sandoz GmbH, Biochemiestrasse 10, 6250 Kundl, Austria

Abstract

The bidentate ligand 1,6-bis(1-methylimidazol-2-ylthio)hexane or its hexafluoride salt reacted with silver(I) triflate, nitrate or oxide, respectively, to give the corresponding polymeric silver(I) complexes. Three crystal structures have been determined and showed linear and cyclic motifs.

■ Palladium-Catalyzed Selective Formation of Substituted Pyrroles from Alkene-tethered Cyclic Oxime Esters

Kazuhiro Okamoto,* Tomohiro Oda, Gaku Matsushita, Takuya Shimbayashi, Kohei Sasakura, and Kouichi Ohe*

*Deparment of Energy and Hydrocarbon Chemistry, Graduate School of Engineering, Kyoto University, Kyoudai-katsura, Nishikyo, Kyoto 615-8510, Japan

Abstract

Isoxazol-5(4H)-ones were used as nitrene precursors for the selective formation of trisubstituted pyrroles by applying a palladium-catalyzed decarboxylative ring-reconstruction method. The use of bulky biaryl-type monophosphine ligands was effective for improving the selectivity. Deuterium-labeling experiments suggested a mechanism involving -hydride elimination followed by reductive elimination from an aza--allyl intermediate.

■ Research on Unique Masked ortho-Benzoquinone Monohemiaminal: Synthesis and Reactions

Yuri Matsumoto, Akihiko Nakamura, Emi Saito, and Masahisa Nakada*

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

Abstract

Synthesis of ortho-benzoquinone monohemiaminals via the oxidative dearomatization/O-cyclization cascades of phenols bearing an ortho substituent derived from an amino alcohol with PIDA is described. The cascade reactions of substrates bearing a chiral substituent were found to proceed in a stereoselective manner. The Diels-Alder reactions of the ortho-benzoquinone monohemiaminals proceed in a highly stereoselective manner. The oxidative dearomatization/O-cyclization cascade affording the ortho-benzoquinone monohemiaminal had never been reported; hence, there is still ample scope for further investigation.

■ Activation of 1-Methyl-5-nitro-2-pyrimidinone by Dearomatization Using a Secondary Amine

Haruyasu Asahara, Azusa Yasuoka, and Nagatoshi Nishiwaki*

*School of Environmental Science and Engineering, Kochi University of Technology, Tosayamada-cho, Kami, Kochi, 782-8502, Japan

Abstract

Electron-deficient 1-methyl-5-nitro-2-pyrimidinone is easily attacked by methanol or pyrrolidine to afford the corresponding adducts, respectively, by which aromaticity of nitropyrimidinone is lost. Indeed, the amine-adduct exhibited higher reactivity than that of original structure to facilitate the reaction with 1,3-dicarbonyl compound leading to diazabicyclic compound at room temperature. The amine-adduct also underwent the ring opening reaction to furnish nitroenamines with (Z)-configuration.

■ Synthesis and Biology of Dimeric, Trimeric and Tetrameric Analogues of Duocarmycin SA

Ravi Gandamala, Steven Hoekman, Mehrnoush Kangani, John E. Nidhiry, Kamala Penchalaiah, Dushyant Singh Raghuvanshi, and Lutz F. Tietze*

*Institute of Organic and Biomolecular Chemistry, University of Göttingen, Tammannstr. 2, D-37077 Göttingen, Germany

Abstract

Novel dimeric, trimeric and tetrameric analogues of Durocarmycin SA have been prepared by the reaction of seco-CBI with di-, tri- and tetracarboxylic acid chlorides in the presence of a base in good yields. The highest bioactivity against cancer cells was observed for the compound obtained from the dicarboxylic acid.

■ Derivatization of Secondary Aliphatic Alcohols to Picolinates – A New Option for HPLC Analysis with Chiral Stationary Phase

Keita Nishimura, Shuhei Tanabe, Riku Shinohara, and Yuichi Kobayashi*

*Department of Biomolecular Engineering, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Box B52, 4259 Nagatsuta-cho, Midori-ku, Yokohama 226-8501, Japan

Abstract

Derivatization of secondary alcohols (R1R2CHOH) to benzoates has frequently employed to determine enantiomer ratios using HPLC with chiral stationary phase (CSP). However, a small difference in substituents (R1, R2) often results in insufficient separation. To find an alternative derivatization that detects such a small difference, picolinates (2-pyridyl-CO2CHR1R2) possessing Me/Et, Me/vinyl, Me/acetylenic, Et/n-Pr, and n-Pr/allyl substituents were prepared and separation efficiency was compared with that of benzoates (PhCO2CHR1R2). Eight commercially available CSPs containing carbamates or benzoates of cellulose and amylose were examined to find that retention factors (k'1 and k'2) and resolution (Rs) of picolinates were greater than those of the corresponding benzoates and that good to excellent Rs values (≥1.25) were recorded over a wide range of CSPs.

■ Stereoselective Synthesis of a Pivotal Chiral Intermediate for Natural Salicylic Macrolides

Yoshihito Oguma, Nozomi Yamamoto, Kenji Sugimoto, and Yuji Matsuya*

*Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, Sugitani 2630, Toyama, 930-0194, Japan

Abstract

As a part of our ongoing research projects on the synthesis of natural salicylic macrolides, the optically active protected salicylate bearing the chiral diene substituent was required as a pivotal synthetic intermediate. The synthesis of the compound was achieved with a high optical purity starting from D-mannitol through Heck coupling reaction and terminal methylenation as key C–C bond forming reactions.

■ Total Synthesis of Phenanthroquinolizidine Alkaloid Cryptopleurine and Phenanthroindolizidine Alkaloid Tylophorine

Yousuke Yamaoka,* Marie Taniguchi, Ken-ichi Yamada, and Kiyosei Takasu*

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

Abstract

Total synthesis of phenanthroquinolizidine alkaloid cryptopleurine was achieved in 11 steps from commercially available 6-bromoveratraldehyde. The crucial step of phenanthrene construction is a formal [2 + 2] cycloaddition of 2-acyl-2’-vinyl-1,1'-biaryl, followed by an acid promoted ring-contraction/ring-opening sequence. The key point to complete the total synthesis of cryptopleurine is use of nosyl amide as a nucleophile for cyclization of piperidine ring. The synthesis of tylophorine was also achieved in the similar manner.

■ Synthesis and Properties of Oligonucleotides Containing 3′-O,4′-C-Ethyleneoxy-Bridged 5-Methyluridines

Takashi Osawa, Yuka Hitomi, Sawako Wakita, Han Kim, Masakazu Dohi, Masahiko Horiba, Yuta Ito, Satoshi Obika, and Yoshiyuki Hari*

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

Abstract

A phosphoramidite of 3ʹ-O,4ʹ-C-ethyleneoxy-bridged 5-methyluridine (3ʹ,4ʹ-EoNA-T) was successfully incorporated into oligonucleotides, and their abilities to form duplexes with RNA and DNA as well as triplexes with double-stranded DNA were evaluated. The stabilities of the duplexes formed between RNA and 3ʹ,4ʹ-EoNA-modified oligonucleotides were only slightly lower than those of the natural DNA–RNA duplex, while the duplexes formed between 3ʹ,4ʹ-EoNA-modified oligonucleotides and DNA were drastically less stable than the natural DNA–DNA duplex. Moreover, under the same conditions as the UV-melting experiments of the duplexes, 3ʹ,4ʹ-EoNA-modified oligonucleotides were unable to form triplexes with dsDNA. These results showed that oligonucleotides containing 3ʹ,4ʹ-EoNA-T had excellent RNA selectivity.

■ Synthesis of Salacinol-d4 as an Internal Standard for Mass-Spectrometric Quantitation of Salacinol, a Potent α-Glucosidase Inhibitor Found in a Traditional Ayurvedic Medicine “Salacia”

Genzoh Tanabe,* Sanami Teramae, Yousuke Kunikata, Shinsuke Marumoto, Shuhei Okugawa, Fumihiro Ishikawa, Weija Xie, Toshio Morikawa, and Osamu Muraoka

*Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashi-Osaka, Osaka 577-8502, Japan

Abstract

Accurate quantitative analysis of trace principles in extracts of biologically active natural medicines relies on the use of reliable internal standards (ISs), which, in the case of liquid chromatography–mass spectrometry (LC-MS) analysis, commonly correspond to isotope-labeled stable analogues of the analytes. Herein, we describe the synthesis of salacinol-1,1,5,5-C-d4 (7), an isotope-labeled stable analogue of salacinol (1), which, in turn, is a potent α-glycosidase inhibitor isolated from Salacia (a traditional Ayurvedic medicine), and show that the isotopic purity of the labeled standard is satisfactory for LC-MS analysis.

■ Synthesis of Tripeptides Containing Heterocyclic α-Amino Acids by Using Heterospirocyclic 3-Amino-2H-azirines

Christoph Strässler, Anthony Linden, and Heinz Heimgartner*

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

Abstract

By using the ‘azirine/oxazolone method’, di- and tripeptides containing six-membered heterocyclic 4-amino-4-carboxylic acids with a piperidine, tetrahydropyran or tetrahydrothiopyran ring have been synthesized. It has been shown that the corresponding heterospirocyclic 3-(N-methyl-N-phenylamino)-2H-azirines are suitable synthons for these heterocyclic α-amino acids. As expected, the presence of these α,α-disubstituted α-amino acids stabilizes β-turn conformations in the prepared tripeptides of type Z-Phe-Xaa-Val-OR.

■ Phenylphosphinic Acid-Promoted Addition of Isocyanide to 1-Methoxyisochroman Derivatives

Takahiro Soeta,* Syunsuke Matsuzaki, and Yutaka Ukaji*

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

Abstract

A synthetic method for preparation of isochroman-1-carboxylamides in good to high yields by addition of isocyanides to 1-methoxyisochroman derivatives in the presence of phosphinic acid was developed. A wide range of 1-methoxyisochroman derivatives and isocyanides were suitable for this reaction.

■ Formal Total Synthesis of (±)-Strictamine

Keigo Sato, Noriyuki Takanashi, Noriyuki Kogure, Mariko Kitajima, and Hiromitsu Takayama*

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

Abstract

A formal total synthesis of an akuammiline-type indole alkaloid, (±)-strictamine, which features ozonolysis, the Staudinger reaction, and the aza-Wittig reaction to construct its D-ring, is reported.

■ Concise Synthesis of Azafluorenone and Its Application to Indeno[1,2-c]isoquinolone

Takashi Nishiyama, Takaya Fujiwaki, Noriyuki Hatae, Emiko Uchiyama, Nao Takeuchi, Kazuhide Minami, Chika Yokoyama, Tomoya Kinoshita, Minoru Ishikura, Satoshi Hibino, and Tominari Choshi*

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

Abstract

The total synthesis of azafluorenone alkaloid, an onychine isolated from Onychopetalum amazonicum, was newly achieved by constructing an azafluorene framework using thermal electrocyclization of the aza 6π-electron system. This methodology was applied for the synthesis of indeno[1,2-c]isoquinolones as an attractive scaffold for developing anticancer agents.