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Published online: 20th April, 2018

Paper | Special issue | Prepress
DOI: 10.3987/COM-18-S(T)55
■ Heterogeneous Copper–Catalyzed Synthesis of S–Arylated 2-Aminothiophenols via Ring Opening of Benzothiazoles and C–S Coupling using Aryl Halides

Tomohiro Ichikawa, Tomohiro Matsuo, Takumu Tachikawa, Yoshinari Sawama, Yasunari Monguchi, and Hironao Sajiki*

*Laboratory of Organic Chemistry, Department of Pharmaceutical Sciences, Gifu Pharmaceutical University, 1-25-4 Daigakunishi, Gifu 501-1196, Japan

Abstract

Chelate resins, which are polystyrene-divinylbenezene-based polymers bearing iminodiacetic acids or polyamines as ligands, supported copper catalysts (Cu/CR11 or Cu/CR20) in effectively catalyzing the ring cleaving S-arylation of benzothiazole with aryl iodides or aryl bromides in the presence of lithium tert-butoxide in aqueous 2-propanol.

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Published online: 20th April, 2018

Paper | Regular issue | Prepress
DOI: 10.3987/COM-18-13889
■ Design, Synthesis, and Biological Evaluation of Novel 8-Methoxyquinolones Bearing Fused Pyrrolidinyl Moieties at the C-7 Position with Potent Antibacterial Activity Against Respiratory Pathogens

Takashi Odagiri,* Hiroaki Inagaki, Masatoshi Nagamochi, Takahiro Kitamura, Satoshi Komoriya, and Hisashi Takahashi

*R&D Division, Daiichi Sankyo CO., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan

Abstract

Novel 8-methoxyquinolones bearing fused pyrrolidinyl moieties at the C-7 position were designed, synthesized, and evaluated for their potent antibacterial activity for the treatment of respiratory tract infections. Compound 5, possessing a trans-fused octahydroisoindole ring at the C-7 position of the quinolone scaffold, exhibited potent in vitro antibacterial activity against nosocomial respiratory pathogens including levofloxacin-resistant Escherichia coli and methicillin-resistant Staphylococcus aureus strains. Furthermore, compound 5 showed a favorable pharmacokinetic profile after a single oral administration in rats.

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Published online: 20th April, 2018

Short Paper | Regular issue | Prepress
DOI: 10.3987/COM-18-13891
■ Two New Steroidal Alkaloids from the Bulbs of Fritillaria thunbergii

Won Se Suh, Seung Young Lee, Jong Eel Park, Dong Hyun Kim, Sun Yeou Kim, and Kang Ro Lee*

*Natural Products Laboratory, School of Pharmacy, Sungkyunkwan University, 2066 Seobu-Ro, Jangan-ku, Suwon, Gyeonggi-do, Korea

Abstract

In the quest for biologically active compounds from natural medicinal sources in Korea, the bulbs of Fritillaria thunbergii were investigated. Phytochemical analysis of the MeOH extracts resulted in the isolation and identification of ten steroidal alkaloids (1–10) including two new compounds, named frithunbol A and B (1 and 2). The structures of these new compounds were elucidated based on 1D, 2D NMR analyses and HR-FAB-MS. All the isolated compounds (1–10) were evaluated for their effects on nitric oxide (NO) production in lipopolysaccharide (LPS)-activated BV-2 cells and the neuroprotective effect was determined via induction of nerve growth factor (NGF) in C6 glioma cells. Compounds 2, 3, and 10 significantly inhibited NO levels with IC50 values of 16.35 μM, 11.45 μM and 18.02 μM, respectively. Also, compound 9 was a potent stimulant of NGF release, and enhanced the levels of NGF by 134.81 ± 3.66%.

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Published online: 20th April, 2018

Short Paper | Special issue | Prepress
DOI: 10.3987/COM-18-S(F)1
■ A Convenient Synthesis of 2-(Alkyl(or aryl)sulfanyl)-2H-1,4-benzothiazin-3(4H)-one Derivatives

Kazuhiro Kobayashi,* Kazuki Kawano, and Keita Yamashita

*Applied Chemistry Field, Chemistry and Biotechnology Course, Department of Engineering, Graduate School of Sustainability Science, Tottori University, 4-101 Koyama-minami, Tottori 680-8552, Japan

Abstract

A convenient method for the preparation of 2-(alkyl(or aryl)sulfanyl)-2H-1,4-benzothiazin-3(4H)-one derivatives has been developed. Thus, methyl alkyl(2-{[(alkyl(or aryl)sulfanyl)methyl]sulfanyl}phenyl)carbamates, derived from commercially available 2-aminobenzenethiol by an easily operated three-step sequence, are treated with two equivalents of lithium diisopropylamide (LDA) to generate carbanions stabilized by the adjacent two sulfur atoms, which immediately undergo 2H-1,4-benzothiazin-3(4H)-one ring formation by intramolecular attack onto the carbamate carbonyl accompanying elimination of methoxide. In addition, direct or stepwise introductions of alkyl groups to the 2-position are reported

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Published online: 19th April, 2018

Paper | Special issue | Prepress
DOI: 10.3987/COM-18-S(T)67
■ Tandem Oxidation/Cyclization Reaction of 4-(Arylmethyl)oxy-2-diazobutyrate Derivatives

Hideaki Kondo, Shuji Nagano, Hiroyuki Yamakoshi, and Seiichi Nakamura*

*Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan

Abstract

A tandem oxidation/cyclization reaction of γ-(arylmethyl)oxy-α-diazobutyrate derivatives was investigated. While oxidative cleavage of the PMB ether was only observed upon treatment of an α-diazo-β-ketoester with DDQ, oxidation of α-diazo esters with an sp3 carbon at the β-position was accompanied by intramolecular attack of the diazo carbon atom and expulsion of the nitrogen gas to give 2,3-dihydrofurans in modest to good yields when an electron-withdrawing group was substituted at the β-position. Substrates bearing no electron-withdrawing β-substituent were found to give rearranged products, albeit in modest yields. A benzofuran derivative could also be obtained, although a hydroquinone adduct was formed as a byproduct.

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Published online: 19th April, 2018

Review | Regular issue | Prepress
DOI: 10.3987/REV-17-878
■ Rhodanine as a Scaffold: A Short Review on Its Synthesis and Anti-Diabetic Activities

Shaikha S. Alneyadi*

*Department of Chemistry, College of Science, UAE University, Al-Ain, UAE

Abstract

Heterocyclic compounds play an important role in biological processes and synthetic medicinal chemistry, and comprise approximately half of the over 6 million compounds recorded to date in Chemical Abstracts. Owing to their high degree of structural variety, heterocycles have proven to be widely useful therapeutic agents and lead candidates in drug design. In this review, I outline recent studies on the synthesis of the rhodanine core, an important heterocyclic, and the anti-diabetic activities of its derivatives reported between 2007 and 2017.

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Published online: 19th April, 2018

Short Paper | Regular issue | Prepress
DOI: 10.3987/COM-17-13846
■ Preparation of Chiral β-Enamino Esters from Methyl Propiolate: Synthesis of Chiral Methyl-1-Substituted 6-Oxo-1,4,5,6-tetrahydropyridine-3-carboxylates

Hugo Pilotzi, Dino Gnecco,* María L. Orea,* Jorge R. Juárez, David M. Aparicio, and Joel L. Terán

*Centro de Química, Instituto de Ciencias, Benemérita Universidad Autónoma de Puebla, Edif. IC9, Complejo de Ciencias, C. U. 72570 Puebla, Pue., Mexico

Abstract

An efficient procedure to prepare chiral β-enamino esters by reaction of methyl propiolate with chiral amines is described. Aza-annulation of these chiral β-enamino esters with acryloyl chloride afforded the corresponding chiral methyl 1-substituted 6-oxo-1,4,5,6-tetrahydropyridine-3-carboxylates in good yield.

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Published online: 18th April, 2018

Paper | Regular issue | Prepress
DOI: 10.3987/COM-18-13887
■ A Novel Tetraphenylethene-Based Fluorescence Probe Based on the Hg2+-Promoted Deprotection of Thioacetal

Jie Ma,* Luliang Yan, Bingkun Chen, and Mengya Sun

*School of Science, University of Shanghai for Science and Technology, Shanghai 200093, China

Abstract

A novel tetraphenylethene-based fluorescence probe compound 1 bearing 1,2-ethanedithiol units linked with tetraphenylethene moiety is synthesized efficiently. Compound 1 exhibit sensitively and selectively to Hg2+ over other metal ions in DMF/H2O solution based on aggregation induced emission (AIE) mechanism. The results show that compound 1 demonstrates an Hg2+-specific bathochromic shift and fluorescent enhancement with a 1:2 reacting stoichiometry. The detection limit of compound 1 for Hg2+ is 2×10-6 mol·L-1.

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Published online: 17th April, 2018

Short Paper | Special issue | Prepress
DOI: 10.3987/COM-18-S(T)70
■ Towards New Sila- or Germa-Derivatives of Motesanib

Thomas Boddaert, Olivier Querolle, Lieven Meerpoel, Patrick Angibaud, Jacques Maddaluno, and Muriel Durandetti*

*COBRA UMR CNRS 6014, Normandie Univ, UNIROUEN, INSA Rouen, CNRS, 76000 Rouen, France

Abstract

Developing new access to original silylated heterocycles is an emerging challenge in medicinal chemistry. In this paper, we describe a synthesis of silylated and germylated Motesanib analogues relying on a peptide coupling between a nicotinic acid derivative and silylated or germylated heterocycles, prepared according to our previous reports.

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Published online: 17th April, 2018

Short Paper | Special issue | Prepress
DOI: 10.3987/COM-18-S(T)32
■ A New Method of Deuterium Incorporation to TMS-Epoxyalcohol using Sodium Methylsulfinylmethylide-d5 (Nadmso-d5)

Yutaro Nanba 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

A reaction of 1-TMS-1,2-epoxyoctan-3-ol with NaDMSO-d5 (Na+ CD3S(O)CD2–), prepared in situ from DMSO-d6 and NaH, afforded non-1-ene-1,1-d2-3,4-diol. Both the anti and syn isomers showed similar reactivity and the stereochemistry was preserved. α-Ethoxyethyl ether of the epoxy alcohol was converted to the corresponding mono-ethoxyethyl ether of the 1-ene-3,4-diol. Hydroboration and hydrogenation of the corresponding TBS ethers afforded compounds with the "CH2CD2OH" and "CH2CD2H" groups, respectively.

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Published online: 17th April, 2018

Short Paper | Special issue | Prepress
DOI: 10.3987/COM-18-S(T)49
■ Concise and Scalable Synthesis of (±)-Aurantioclavine

Hideo Ikota, Chihiro Tsukano,* and Yoshiji Takemoto*

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

Abstract

A synthetic route to (±)-aurantioclavine has been established using a six-step transformation without toxic metal reagents. This synthetic route is useful because it is not only a short-step synthesis but is applicable to gram-scale synthesis of a protected (±)-aurantioclavine.

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Published online: 16th April, 2018

Paper | Special issue | Prepress
DOI: 10.3987/COM-18-S(T)61
■ Unexpected Emergence of Luciferase-Inhibitory Activity During Structural Development Study of Phenyloxadiazole-Based Ppar Ligands

Ryuta Shioi, Yosuke Toyota, Tomomi Noguchi-Yachide, Minoru Ishikawa, Takao Yamaguchi, Makoto Makishima, Yuichi Hashimoto, and Kenji Ohgane*

*Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan

Abstract

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that regulate transcription of genes involved in lipid, glucose, and cholesterol homeostasis in a ligand-dependent manner. PPARs have long been a target of drug development, and evaluation of PPARs activity frequently involves reporter-gene assay, in which luciferase activity is utilized to visualize transcriptional activation by the receptors. Here, we report our experience of the unexpected emergence of luciferase-inhibitory activity during our search for PPAR antagonists. We believe information about negative experiences like this will help to make medicinal chemists more aware of potential pitfalls in SAR studies with luciferase-based assays.

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Published online: 13th April, 2018

Paper | Special issue | Prepress
DOI: 10.3987/COM-18-S(T)34
■ Computational Study for the Selective Aromatic Nucleophilic Substitution on 4-Dimethylamino- 2-Methoxy-3-Trifluoroacetylquinoline

Norio Ota, Shota Sasakawa, Yasuhiro Kamitori, and Etsuji Okada*

*Department of Chemical Science and Engineering, Graduate School of Engineering, Kobe University, 1-1 Rokkodai-cho, Nada-ku, Kobe 657-8501, Japan

Abstract

The selective nucleophilic substitution on aromatic ring occurs at the 4-position of 4-dimethylamino-2-methoxy-3-trifluoroacetylquinoline 1 by the reaction with various amines to afford the N-N exchanged products solely, and any O-N exchange reactions at the 2-position are not performed. Our DFT calculation study led to a rational explanation of this unique selectivity based on the frontier electron densities (LUMO) of 1 and energies of the Meisenheimer complexes which were assumed to be formed as the intermediates on such substitution course. It was also investigated about the reaction of related 4-dimethylamino-2-methoxyquinolines bearing various electron-withdrawing groups at the 3-position.

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Published online: 13th April, 2018

Paper | Special issue | Prepress
DOI: 10.3987/COM-18-S(T)68
■ Synthesis of 4,5-Disubstituted Pyrano[3,4-b]Pyrrol-7(1H)- Ones via Sonogashira–Hagihara Cross-Coupling of N-Benzenesulfonyl-3-bromo-1H-pyrrole-2-carboxylate and Subsequent Iodine-mediated Cyclization

Tsutomu Fukuda,* Minoru Komure, Gen Onodera, Masanari Kimura, and Masatomo Iwao

*Division of Chemistry and Materials Science, Graduate School of Engineering, Nagasaki University, 1-14, Bunkyo-machi, Nagasaki 852-8521, Japan

Abstract

A method for the synthesis of 4,5-disubstituted pyrano[3,4-b]pyrrol-7-(1H)-ones has been developed in this study. The key reactions involved are the Sonogashira–Hagihara cross-coupling of methyl N-benzenesulfonyl-3-bromo-1H-pyrrole-2-carboxylate with terminal alkynes, followed by the iodine-mediated cyclization of 3-alkynylated N-benzenesulfonyl-1H-pyrrole-2-carboxylates. The thus-obtained 5-substituted 4-iodopyrano[3,4-b]pyrrol-7(1H)-ones could be converted to 4,5-disubstituted pyrano[3,4-b]pyrrol-7(1H)-ones via the Suzuki–Miyaura or Sonogashira–Hagihara cross-coupling reactions.

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Published online: 12th April, 2018

Paper | Special issue | Prepress
DOI: 10.3987/COM-18-S(T)84
■ Total Synthesis of Lissoclinolide by Acid-Induced Lactonization of An (E)-a-Bromo-γ,δ-Epoxy Acrylate Derivative

Kenichi Kobayashi,* Keisuke Kuwahara, Kosaku Tanaka III, Risako Kunimura, and Hiroshi Kogen*

*Graduate School of Pharmaceutical Sciences, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan

Abstract

The stereoselective total synthesis of lissoclinolide, a naturally occurring antibiotic and cytotoxic butenolide, was achieved in 10 steps including a highly E-selective Still–Gennari-type olefination and an acid-induced lactonization of an (E)-α-bromo-γ,δ-epoxy acrylate derivative. The key regioselective 5-exo lactonization could be regulated by using AcOH under kinetically controlled conditions.

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Published online: 12th April, 2018

Paper | Special issue | Prepress
DOI: 10.3987/COM-18-S(T)72
■ Arylation Reactions of Monocarba-Closo-Dodecaborate at the Boron Vertices

Mai Otsuka, Gaku Akimoto, Atsuya Muranaka, Ryo Takita,* and Masanobu Uchiyama*

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

Abstract

We have developed two methods for aryl group introduction at the boron vertices of monocarba-closo-dodecaborate under palladium catalysis. Details of reaction development, as well as mechanistic insights, are described.

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Published online: 12th April, 2018

Short Paper | Special issue | Prepress
DOI: 10.3987/COM-18-S(T)52
■ Metal-free Oxidative Cross-Coupling of Pyrroles with Electron-Rich Arenes Using Recyclable Hypervalent Iodine(III) Reagent

Koji Morimoto, Toru Kamitanaka, Toshifumi Dohi, and Yasuyuki Kita*

*Research Organization of Science and Technology, Ritsumeikan University, 1-1-1 Nojihigashi, Kusatsu, Shiga, 525-8577, Japan

Abstract

The facile and clean oxidative cross-coupling reaction of pyrroles has been developed using the recyclable hypervalent iodine(III) reagents having an adamantane core. The recyclable iodine(III) reagent could be recovered from the reaction mixtures as the corresponding reduced forms, i.e., the tetraiodide 2, by a simple solid-liquid separation. By re-oxidizing the recovered 2 to the initial reagent 1a using m-chloroperbenzoic acid (mCPBA), the reagent 1a can be reused.

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Published online: 12th April, 2018

Short Paper | Regular issue | Prepress
DOI: 10.3987/COM-18-13882
■ One-Pot Synthesis of 2-Substituted 1H-Isoindole-1,3(2H)-dithiones from Secondary Benzothioamides and Isothiocyanates

Kazuhiro Kobayashi,* Daiki Fujiwara, and Miyuki Tanmatsu

*Applied Chemistry Field, Chemistry and Biotechnology Course, Department of Engineering, Graduate School of Sustainability Science, Tottori University, 4-101 Koyama-minami, Tottori 680-8552, Japan

Abstract

The reaction of 2,N-dilithiobenzothioamides, generated from readily available secondary benzothioamides and two equivalents of butyllithium, with isothiocyanates, followed by aqueous workup, gives the corresponding N1,N2-disubstituted benzene-1,2-dicarbothioamides, which undergo intramolecular attack of one of the thioamide nitrogen on the adjacent thiocarbonyl moiety with loss of primary amines to provide 2-substituted 1H-isoindole-1,3(2H)-dithiones.

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Published online: 12th April, 2018

Short Paper | Regular issue | Prepress
DOI: 10.3987/COM-18-13888
■ Synthesis of 3-Aroylindoles as Intermediates of Cannabimimetics and Elucidation of Their Physicochemical Properties

Koji Araki, Kosho Makino, Hidetsugu Tabata, Hiroshi Nakayama, Kei Zaitsu, Tetsuta Oshitari, Hideaki Natsugari, and Hideyo Takahashi*

*Faculty of Pharmaceutical Sciences, Teikyo University, 2-11-1 Kaga, Itabashi-ku, Tokyo, 173-8605, Japan

Abstract

In order to synthesize the intermediates of cannabimimetics, the benzoylation of indoles with 2'/3'/4'-substituted benzoyl chloride in the presence of Et2AlCl was examined. Among the products, we found that the 1H NMR spectra of 3-(2'-substituted)-benzoyl-2-methylindoles had interesting features. We investigated their physicochemical properties based on VT-NMR, and it was revealed that conformer A (s-trans) is present in preference to conformer B in these compounds.

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Published online: 10th April, 2018

Paper | Special issue | Prepress
DOI: 10.3987/COM-18-S(T)74
■ The First Synthesis of 3-O-Methylcyanidin and the Effect of 3-O-Substitution on Stability Under Acidic Conditions

Asmaa B. El-Meligy, Takehiro Ishihara, Kin-ichi Oyama, Ahmed M. El-Nahas, and Kumi Yoshida*

*Graduate School of Informatics, Nagoya University, Chikusa, Nagoya 464-8601, Japan

Abstract

The simplest and most common anthocyanin in nature is 3-O-glucosylcyanidin (1), and 3-O-glucosylation is believed to stabilize the chromophore. To clarify the effect of the glucose residue we compared the stability of 1 with its aglycone, cyanidin (2), and newly synthesized 3-O-methylcyanidin (3). In an aqueous solution at pH 1, 1 and 3 showed similar stabilities, and 2 was less stable than 1 and 3, indicating that 3-O-substituion does enhance stability. We also analyzed the co-pigmentation effect of flavocommelin (4) and rutin (5), on the color and stability of 3-O-substituted cyanidins and cyanidin. The bathochromic shift of λvismax and stability of the color by addition of 4 was greater than that of rutin (5). 4 might stack closer and stronger to the anthocyanidin chromophore than 5.

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Published online: 9th April, 2018

Short Paper | Special issue | Prepress
DOI: 10.3987/COM-18-S(T)59
■ Synthesis of Oroxylin a Starting from Naturally Abundant Baicalin

Rie Fujita, Kengo Hanaya, Shuhei Higashibayashi, and Takeshi Sugai*

*Department of Pharmaceutical Science, Keio University, 1-5-30, Shibakoen, Minato-ku, Tokyo 105-8512, Japan

Abstract

A new approach to oroxylin A, a monomethylated trihydroxyflavone, is described. The starting material was baicalin, a representative naturally abundant flavonoid glucuronide. First, conditions for the cleavage of the glycosidic bond were established, using a mixture of water and conc. sulfuric acid (5:2) at 121 °C for 40 min. The hydrolysis was performed in a high-pressure steam sterilizer so that the temperature and reaction time were precisely controlled. Subsequent acetylation of the crude material furnished baicalein 6,7-diacetate on a preparative scale and in a reproducible manner. Next, the C-7 position was protected site-selectively with a methoxymethyl (MOM) group, taking advantage of an unexpected sequential migration of the two acetyl groups among the C-5, C-6, and C-7 positions under basic conditions. The removal of the two remaining acetyl groups followed by site-selective methylation of the C-6 position furnished 5-hydroxy-6-methoxy-7-methoxymethoxyflavone (oroxylin A C-7 MOM ether). Finally, by the deprotection of the MOM ether, oroxylin A was obtained in 6 total steps and 62% overall yield from baicalin.

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Published online: 6th April, 2018

Paper | Special issue | Prepress
DOI: 10.3987/COM-18-S(T)77
■ Lithiation of 1-Alkoxyindole Derivatives

Kyoko Nakagawa-Goto, Tetsuya Kobayashi, Toshiya Kawasaki, and Masanori Somei*

*Noto Marine Laboratory, Institute of Nature and Environmental Technology, Faculty of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University, 56-7 Matsuhidai, Matsudo-shi, Chiba 270-2214, Japan

Abstract

Lithiation of 1-alkoxyindoles, 3-dimethylaminomethyl- and 3-dimethylaminoethyl-1-methoxyindole occurred regioselectively at the 2-position. The introduction of a sterically bulky group into the 2-position of 3-dimethylaminomethyl-1-methoxyindoles directed the lithiation to the 4-position.

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Published online: 5th April, 2018

Paper | Special issue | Prepress
DOI: 10.3987/COM-18-S(T)37
■ Synthesis and Biological Activities of Acetal Analogs at Position 3 of 10-Methyl-Aplog-1, A Potential Anti-Cancer Lead Derived from Debromoaplysiatoxin

Koutaro Hayakawa, Yusuke Hanaki, Harukuni Tokuda, Ryo C. Yanagita, Yu Nakagawa, Mutsumi Okamura, Shingo Dan, and Kazuhiro Irie*

*Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Oiwakecho, Kitasirakawa, Sakyo-Ku, Kyoto City, Kyoto 606-8502, Japan

Abstract

10-Methyl-Aplog-1 (1), a simplified analog of tumor-promoting debromoaplysiatoxin (DAT), is a potential anti-cancer lead because, unlike DAT, 1 is not tumor-promoting or proinflammatory. However, its synthesis required 23 linear steps with an overall yield of 1.1%. To develop a more synthetically accessible compound, we designed a new analog (2) whose carbon atom at position 4 was replaced with an oxygen atom. Simultaneous construction of the spiroketal at position 7, the acetal at position 3, and the macrolactone ring enabled us to reduce the synthetic steps to produce 2 and its 3-epimer (16) in 18 linear steps with overall yields of 0.30 and 0.67% respectively. Although both analogs retained anti-proliferative activity, it was weaker than that of 1.

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Published online: 3rd April, 2018

Short Paper | Special issue | Prepress
DOI: 10.3987/COM-18-S(T)62
■ Intramolecular Heck Insertion of A Diene-Allylic Amination Cascade to Synthesize A 2-Alkenyl-3,4-fused Indole Structure

Takahito Kuribara, Jun Ueda, Yuito Tanaka, Masaya Nakajima, Shingo Harada, and Tetsuhiro Nemoto*

*Pharmaceutical Chemistry, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo, Chiba, Japan

Abstract

Iodoanilines bearing a diene side-chain at the 3-position were converted to tricyclic fused indole derivatives under palladium catalysis. This cascade reaction proceeds through an intramolecular Heck insertion of the diene, followed by an allylic amination reaction sequence. Experimental and computational studies indicated that 3--allyl palladium complex-mediated substitution was operative for the latter cyclization.

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Published online: 3rd April, 2018

Communication | Special issue | Prepress
DOI: 10.3987/COM-18-S(T)46
■ Ruthenium-Catalyzed [2 + 2] Cyclization of 1,7-Allenynes in Ionic Liquid and Catalyst Recycling

Nozomi Saito,* Momoko Koyama, and Yoshihiro Sato

*Faculty of Pharmaceutical Sciences, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan

Abstract

Ruthenium-catalyzed [2 + 2] cyclization of 1,7-allenynes in ionic liquid ([BDMI]PF6) as a reaction medium proceeded to give the corresponding bicyclo[4.2.0]octa-1(8),5-diene derivative in high yield. Furthermore, the recovered catalyst immobilized in the ionic liquid could be recycled up to 10 times.

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Published online: 2nd April, 2018

Communication | Special issue | Prepress
DOI: 10.3987/COM-18-S(T)40
■ Synthesis of Novel 1,3-Dioxa-5-thiazatriquinane and 1-Oxa-3,5-dithiazatriquinane Derivatives and their Pharmacologies

Ryuichiro Ohshita, Noriki Kutsumura, Yasuyuki Nagumo, Naoshi Yamamoto, Tsuyoshi Saitoh, Shigeto Hirayama, Hideaki Fujii, and Hiroshi Nagase*

*International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan

Abstract

Novel triplet compounds with the 1,3-dioxa-5-thiazatriquinane and 1-oxa-3,5-dithiazatriquinane skeletons have been synthesized via the enantiomerically pure oxazoline intermediates. Their assay results showed that the substitution of sulfur atoms for the oxygen atoms increased the affinities for the opioid receptors and affected to the expression of the agonistic/antagonistic activities.

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Published online: 2nd April, 2018

Paper | Special issue | Prepress
DOI: 10.3987/COM-18-S(T)47
■ Synthesis of Iodinated Thiazolo[2,3-a]Isoquinolinium Salts and their Crystal Strucutres with/without Halogen Bond

Shoji Matsumoto,* Ryuta Sumida, Sia Er Tan, and Motohiro Akazome

*Department of Applied Chemistry and Biotechnology, Graduate School and Faculty of Engineering, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan

Abstract

We investigated the cyclization reaction of 2-(2-(phenylethynyl)- phenyl)thiazoles with I2. A six-membered ring was formed to produce the corresponding thiazolo[2,3-a]isoquinolin-7-ium salts. The counter anions (I− and I3−) varied based on the structure of the thiazole moiety. We also revealed the single-crystal X-ray structures of those thiazolo[2,3-a]isoquinolin-7- ium salts. We discovered that various structures with and without halogen bonds existed, although they were the prospective structures to make “charge-assisted halogen bonds”.

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Published online: 2nd April, 2018

Short Paper | Special issue | Prepress
DOI: 10.3987/COM-18-S(T)48
■ Synthesis of Alkynyl C-Nucleotide Triphosphates Toward Enzymatic Elongation of Artificial DNA

Yutaro Oda, Junya Chiba,* and Masahiko Inouye

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

Abstract

Four types of alkynyl C-nucleotide triphosphates were synthesized, in which heterocyclic compounds as a non-natural nucleobase were tethered to deoxyribose through acetylene bonds. The non-natural nucleobases are D*, T*, G*, and C*, corresponding to natural A, T, G, and C, respectively, from a hydrogen-bonding pattern of view. All the non-natural triphosphates were found to be a good substrate for terminal deoxynucleotidyl transferase (TdT), a natural nucleic acid-relevant enzyme.

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Published online: 30th March, 2018

Paper | Special issue | Prepress
DOI: 10.3987/COM-18-S(T)58
■ Substituent Effects in Regio- and Stereoselective Ring-Opening Reaction of Aziridines with Et3N·3HF for β-Fluoroamine Synthesis

Shigeru Sasaki,* Satono Watanabe, Kaori Shiino, Yuko Yanaka, Shiho Kaneko, Kana Miyamoto, Ayano Yasui, Hina Sakaino, Hiroyoshi Teramoto, Takayasu Yamauchi, and Kimio Higashiyama

*Synthetic Organic Chemistry, Institute of Medicinal Chemistry, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan

Abstract

This paper discusses the reactivity of various 2-substituted aziridine derivatives. The reaction of chiral 2-aryl-substituted aziridines with triethylamine trihydrofluoride (Et3N·3HF) afforded chiral β-fluoroamines with high stereoselectivity. In contrast, the reaction of chiral 2-aliphatic-substituted aziridines with benzyl bromide, followed by treatment with Et3N·3HF, gave chiral β-fluoroamines with high stereoselectivity.

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Published online: 29th March, 2018

Short Paper | Special issue | Prepress
DOI: 10.3987/COM-18-S(T)73
■ Isolation of Aaptic Acid from the Marine Sponge Aaptos Lobata and Inhibitory Effect of Aaptamines on Rankl-Induced Formation of Multinuclear Osteoclasts

Arina Fukumoto, Yuki Hitora, Aika Kai, Hikaru Kato, Esther D. Angkouw, Remy E. P. Mangindaan, Nicole J. de Voogd, and Sachiko Tsukamoto*

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

Abstract

A new aaptamine congener, aaptic acid (1), was isolated from the marine sponge Aaptos lobata collected in Indonesia, together with aaptamine (2), demethyl(oxy)aaptamine (3), and isoaaptamine (4). The chemical structure of 1 was assigned on the basis of NMR data. The isolated compounds were tested for inhibitory activities against osteoclastogenesis in RAW264 cells. At 5 μM concentration, 2-4 inhibited RANKL-induced multinuclear osteoclast formation by 25%, 54%, and 17%, respectively. In contrast, 1 did not inhibit osteoclastogenesis even at 50 μM.

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