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Published online: 13th August, 2019

Communication | Special issue | Prepress
DOI: 10.3987/COM-19-S(F)39
Synthesis of Dibenzoxazonines by Domino [2+2] Cycloaddition—4π Electrocyclic Ring Opening Reaction of Cyclic Imines with Ynamides

Kiyosei Takasu,* Masaki Tsutsumi, Tomohiro Ito, Hiroshi Takikawa, and Yousuke Yamaoka

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

Abstract

Dibenzo[b,h][1,4]oxazonines and the thiazonine congener were synthesized from cyclic imines with ynamides by acid-mediated domino (2+2) cycloaddition—4π electrocyclic ring opening reaction. The reaction enables two carbon-enlargement of the cyclic imine substrates. The X-Ray crystallography made clear that the oxazonine skeleton has a unique bent-conformation.

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Published online: 8th August, 2019

Paper | Special issue | Prepress
DOI: 10.3987/COM-19-S(F)24
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.

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Published online: 7th August, 2019

Paper | Special issue | Prepress
DOI: 10.3987/COM-19-S(F)19
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.

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Published online: 7th August, 2019

Short Paper | Special issue | Prepress
DOI: 10.3987/COM-19-S(F)26
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.

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Published online: 7th August, 2019

Review | Special issue | Prepress
DOI: 10.3987/REV-19-SR(F)2
Mini-Review: The Chemistry of Vorapaxar – Is There Any Room for Improvement Left?

Piotr P. Graczyk* and Sven Nerdinger

*Selvita Services Sp. z o. o., Bobrzynskiego 14, 30-348 Krakow, Poland

Abstract

Based on the case of Vorapaxar, this review describes the key role of an early chemistry effort to enable rapid discovery of an optimal synthetic route to a commercially important product. The intramolecular Diels-Alder (IMDA) reaction developed by scientists from Schering to make natural product Himbacine in mid-‘90s allowed formation of the Vorapaxar’s backbone almost 10 years later. Since then this strategy has been followed by all companies. Additional improvements by Schering to the synthesis of Vorapaxar greatly limited the opportunities for generic manufacturers to secure new intellectual property. Most of the chemistry presented in this review comes from the patent applications and as such has not been subjected to rigorous peer review, but in our opinion this paper may serve as helpful information for readers in the area of drug discovery.

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Published online: 6th August, 2019

Review | Special issue | Prepress
DOI: 10.3987/REV-19-SR(F)1
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.

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Published online: 5th August, 2019

Paper | Special issue | Prepress
DOI: 10.3987/COM-19-S(F)16
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.

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Published online: 1st August, 2019

Paper | Special issue | Prepress
DOI: 10.3987/COM-19-S(F)23
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.

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Published online: 31st July, 2019

Paper | Special issue | Prepress
DOI: 10.3987/COM-19-S(F)13
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.

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Published online: 30th July, 2019

Short Paper | Special issue | Prepress
DOI: 10.3987/COM-19-S(F)15
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.

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Published online: 26th July, 2019

Communication | Special issue | Prepress
DOI: 10.3987/COM-19-S(F)17
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.

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Published online: 24th July, 2019

Communication | Special issue | Prepress
DOI: 10.3987/COM-19-S(F)22
One-Pot Synthesis of 9-Spirofluorenes via Tandem Copper-Catalyzed Arylative Cyclization and Spirocyclization of Biaryl-Substituted Alkynyl Alcohols

Noriko Okamoto, Takuya Sueda, and Reiko Yanada*

*Faculty of Pharmaceutical Sciences, Hiroshima International University, 5-1-1, Hirokoshingai, Kure, Hiroshima, 737-0112, Japan

Abstract

A tandem copper-catalyzed arylative cyclization and spirocyclization strategy to access spiro cyclic compounds is described. This method enables the one-pot construction of 9-spirofluorenes from readily available alkynyl alcohols with biaryl-substituents via the copper-catalyzed arylative ring-closing reaction and the Friedel–Crafts reaction.

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Published online: 24th July, 2019

Paper | Special issue | Prepress
DOI: 10.3987/COM-19-S(F)10
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 (13), together with nine known iridoid glucosides and a flavonoid glycoside, nicotiflorin. The structures of the new compounds were elucidated spectroscopically. Compounds 13 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.

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Published online: 22nd July, 2019

Short Paper | Special issue | Prepress
DOI: 10.3987/COM-19-S(F)12
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.

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Published online: 19th July, 2019

Communication | Special issue | Prepress
DOI: 10.3987/COM-19-S(F)18
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.

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Published online: 17th July, 2019

Paper | Special issue | Prepress
DOI: 10.3987/COM-19-S(F)8
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.

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Published online: 20th June, 2019

Paper | Special issue | Prepress
DOI: 10.3987/COM-19-S(F)6
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.

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Published online: 20th June, 2019

Paper | Special issue | Prepress
DOI: 10.3987/COM-19-S(F)5
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.

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Published online: 3rd June, 2019

Communication | Special issue | Prepress
DOI: 10.3987/COM-19-S(F)7
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.

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Published online: 3rd June, 2019

Short Paper | Special issue | Prepress
DOI: 10.3987/COM-19-S(F)11
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.

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Published online: 10th April, 2019

Communication | Special issue | Prepress
DOI: 10.3987/COM-19-S(F)2
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.

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Published online: 10th April, 2019

Paper | Special issue | Prepress
DOI: 10.3987/COM-19-S(F)3
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 MoritaBaylisHillman 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.

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Published online: 12th March, 2019

Short Paper | Regular issue | Prepress
DOI: 10.3987/COM-19-14033
Synthesis of 1,2-Benzothiazole-3(2H)-thione 1,1-Dioxides by DBU-Promoted Cyclization of 2-(Aminosulfonyl)-N-methylbenzothioamide Derivatives

Kazuhiro Kobayashi* and Daiki Fujiwara

*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

An efficient method for the preparation of 2-alkyl-1,2-benzothiazole-3(2H)-thione 1,1-dioxides has been developed. Thus, the reaction of 2,N-dilithio derivatives of N-alkylbenzenesulfonamides with methyl isothiocyanate affords 2-[(alkylamino)sulfonyl]-N-methylbenzothioamides, which are treated with a catalytic amount of DBU in refluxing toluene to provide the desired products in moderate to good yields.

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83 data found. 61 - 83 listedFirst Previous