HETEROCYCLES

Published online: 6th December, 2019

■ Synthesis and Evaluation for Biological Activities of 2-Thio-Acylated Thiazoles Containing Pyrazole Moiety

Eiichi Masumoto, Nobuhiro Kashige, Hayate Nagabuchi, Fumi Okabe-Nakahara, and Hiroshi Maruoka*

*Faculty of Pharmaceutical Sciences, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan

Abstract

An approach to the synthesis of novel 2-thio-acylated thiazoles containing pyrazole moiety is described. The pyrazole-thiazolethione derivative as the key building block for bis-heterocycles was formed via a Knoevenagel-type condensation of rhodanine with pyrazol-3-one. Thermal treatment of the pyrazole-thiazolethione derivative with acid anhydride and/or chloride in refluxing toluene caused diacylation reaction to give the corresponding 2-thio-acylated thiazoles containing pyrazole moiety. All the synthesized compounds were characterized by spectroscopic analysis and were tested for their DNA cleavage activity in vitro. Furthermore, they were evaluated for their antifungal activity against Candida albicans and Saccharomyces cerevisiae.

Published online: 26th November, 2019

■ Some Hybrid Linker Mode C2-Symmetrical 1,3,5-Triazine Derivatives and Their Biological Evaluation

Nobuko Mibu, Makoto Furutachi, Yusuke Inoue, Yuka Fujita, Yumemi Matsumoto, Yuki Kawano, Syoko Tomonaga, Junko Matsuyama, Kanae Yamada, Ryo Sato, Kazumi Yokomizo, Jian-Rong Zhou, Shunsuke Shimomura, Kaori Ota, and Kunihiro Sumoto*

*Faculty of Pharmaceutical Sciences, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan

Abstract

We report the preparation of some new C2-symmetrical multivalent hybrid-type molecules having a methylene linker group and 1,3,5-triazine (TAZ) recognition moieties in the molecule and we also report the results of biological evaluation of their anti-herpes simplex virus type 1 (anti-HSV-1) activity and cytotoxic activity against Vero cells. All mid-size C2-symmetrical multivalent hybrid-type molecules (3a-2, 3a-4, 3b-2, 3b-3, 3b-4) showed considerably high levels of anti-HSV-1 activity (EC50 = 7.6 ~ 95.6 μM) with low levels of cytotoxicity (CC50 > 200 μM) against Vero cells. Among the tested compounds, the hybrid-type C2-symmetrical multivalent molecule (3a-4) seems to be an interesting new lead in the search for new hybrid-type multivalent mid-size antiviral compounds.

Published online: 25th November, 2019

■ One-Pot Synthesis of 3-(Guaiazulen-3-yl)dihydro-1H- indol-4(5H)-ones via Domino Reaction

Lu Zhang, Dao-Lin Wang,* Jin-Juan Xing, and Lin Liu

*College of Chemistry and Chemical Engineering, Bohai University, 19, Keji Rd., New Songshan District, Jinzhou City, Liaoning Province 121001, China

Abstract

A facile and efficient one-pot procedure for the preparation of 3-(guaiazulen-1-yl)dihydro-1H-indol-4(5H)-ones by a catalyst-free, three- component reaction of guaiazulene, methylglyoxal and enaminones under mild conditions in good yield is reported.

Published online: 25th November, 2019

■ Sugar Based γ-Amino Alcohol Organocatalyst for Asymmetric Michael Addition of β-Keto Esters with Nitroolefins

Divakar Ganesan, Madhu Chennapuram, Zubeda Begum, Chigusa Seki, Yuko Okuyama, Eunsang Kwon, Koji Uwai, Michio Tokiwa, Suguru Tokiwa, Mitsuhiro Takeshita, and Hiroto Nakano*

*Division of Sustainable and Environmental Engineering, Graduate School of Engineering, Muroran Institute of Technology, 27-1 Mizumoto, Muroran, Hokkaido 050-8585, Japan

Abstract

Sugar based γ-amino alcohol was used in asymmetric Michael addition of β-keto esters with nitroolefins for the first time affording the corresponding several chiral Michael adducts bearing quaternary chiral carbon center in moderate to good chemical yields and stereoselectivities (up to 98%, up to dr. 95:5, up to 84% ee).

Published online: 21st November, 2019

■ Recent Advances in Synthetic Hetaryne Chemistry

Yu Nakamura, Suguru Yoshida,* and Takamitsu Hosoya*

*Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10, Surugadai, Kanda, Chiyoda-ku 101-0062, Japan

Abstract

Recent advances in synthetic hetaryne chemistry are reviewed. Various methods for the generation of hetaryne intermediates from several types of precursors enabled facile syntheses of a broad range of heteroaromatic compounds including natural products.

Published online: 14th November, 2019

■ Piperidine and Azetidine Formation by Direct Cyclization of Diols with N-Nonsubstituted Sulfonamide under the Mitsunobu Conditions Utilizing (Cyanomethylene)tributylphosphorane (CMBP) and Its Application to the Synthesis of Lupinine

Hiroto Kaku,* Yuhei Sonoda, Hideyuki Hishida, Yuri Taniguchi, Akiko Kubo, Takumi Hamaguchi, Mitsuyo Horikawa, Makoto Inai, Kei Kitamura, and Tetsuto Tsunoda*

*Pharmaceutical Sciences, Tokushima Bunri University, 180 Nishihamabouji, Yamashiro-machi, Tokushima, 770-8514, Japan

Abstract

(Cyanomethylene)tributylphosphorane (CMBP) can promote the Mitsunobu reaction of 1,3- and 1,5-diols with N-nonsubstituted sulfonamides, such as tosylamide (TsNH2) and 3,3-dimethoxypropylsulfonamide (DimpsNH2), to prepare azetidine and piperidine ring systems directly. Utilizing this methodology, lupinine, a biologically active piperidine alkaloid, was synthesized.

Published online: 13th November, 2019

■ Isochromophilol A, a New Azaphilone Isolated from Penicillium sp. RO369, a Leaf Litter Inhabiting Fungus from Tsuga diversifolia

Kan'ichiro Ishiuchi,* Dai Hirose, Yoriko Takahashi, Ryu Miyagawa, Kohei Watanabe, and Susumu Kitanaka*

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

Abstract

A new sclerotiorin-type azaphilone, isochromophilol A (1), was isolated from Penicillium sp. RO369 associated with Tsuga diversifolia, along with eight known compounds (2−9). The structure of 1 was elucidated on the basis of spectroscopic data. Isochromophilol A (1) (16 μg) showed weak anti-methicillin-resistant Staphylococcus aureus (anti-MRSA) activity with an inhibition diameter of 8.8 ± 1.0 mm

Published online: 7th November, 2019

■ One-Pot Synthesis of Pyrrolo[2,1-α]isoquinolines via Tandem Reactions of Vinylselenonium Salt, 2-Bromoethanones, and Isoquinoline

Qi Sun, Minghong Liao, Yan Zhao, Yunxia Li, Shanshan Liu, Deshou Mao,* and E Tang*

*School of Chemical Science and Technology, Yunnan University, No. 2 Green Lake North Road, Kunming 650091, China

Abstract

An convenient and one-pot synthesis of pyrrolo[2,1-a]isoquinolines via the tandem reaction of methyl(phenyl)vinylselenonium salt with isoquinoline and 2-bromoethanones has been developed, which features very mild conditions, available substrates, simple experimental procedures, moderate to good yields, and wide functional group tolerance.

Published online: 6th November, 2019

■ A Highly Selective Fluorescence-Enhanced Probe for the Rapid Detection of SO2 Derivatives and Its Bio-Imaging in Living Cells

Yaogen Zhou, Yiwei Zhou, Hongying Wang,* and Baoquan Chen*

*School of Chemistry and Chemical Engineering, Tianjin University of Technology, 391 Binshui Xidao, Xiqing District Tianjin 300384, China

Published online: 1st November, 2019

■ Asymmetric Construction of Heterocycles via Dearomative Coupling and Addition Reactions of Phenol and Aniline Derivatives

Kotaro Kikushima,* Hideyasu China, and Toshifumi Dohi*

*College of Pharmaceutical Sciences, Ritsumeikan University, 1-1-1 Nojihigashi, Kusatsu, Shiga, 525-8577, Japan

Abstract

Efficient methods for the formation of chiral heterocycles are considerably important in the synthesis of naturally-occurring compounds and pharmaceutical products. This review highlights the formation of chiral heterocycles through dearomative bond-formations as the key reactions, wherein the phenol or aniline derivatives serve as the nucleophiles. Transition-metal-catalyzed intramolecular coupling reactions in the presence of chiral ligands afford the enantioenriched multicyclic compounds bearing heterocycles. Chiral bifunctional organocatalysts induce the formation of dearomative coupling products, which could be converted to heterocycles through further transformations.

Published online: 30th October, 2019

■ Facile Synthesis of (Guaiazulen-1-yl)-1H-pyrroles via Paal-Knorr Reaction

Lu Zhang, Dao-Lin Wang,* Jin-Juan Xing, and Lin Liu

*College of Chemistry and Chemical Engineering, Bohai University, 19, Keji Rd., New Songshan District, Jinzhou City, Liaoning Province 121001, China

Abstract

An efficient and simple method for the synthesis of (guaiazulen-1-yl)-1H-pyrroles was described. The construction of this new heteroarylazulene system was achieved by a the Paal-Knorr reaction of 3-acetyl-4-(guaiazulen-1-yl)hexane- 2,5-dione (4), easily preparation by a three-component condensation of guaiazulene (1), methylglyoxal (2) and acetylacetone (3), with primary amines (5).

Published online: 16th October, 2019

■ Synthesis of Cycloalkyl/Steroidal Heteroaryl Sulfides Using Rhodium-Catalyzed Heteroaryl Exchange Reaction

Mieko Arisawa,* Katsuya Nakai, Tomoki Yamada, Ren Suzuki, and Masahiko Yamaguchi*

*Graduate School of Pharmaceutical Sciences, Tohoku University, Aramaki, Aoba-ku, sendai 980-8578, Japan

Abstract

Cycloalkyl heteroaryl sulfides are efficiently synthesized by the single-bond cleavage and exchange reaction of S-cycloalkyl thioesters and heteroaryl ethers without using a base. The method is applicable to steroids at the A- and D-rings, and provides diverse heteroarylthiolated steroids with five- and six-membered heteroarenes.

Published online: 8th October, 2019

■ Synthetic Studies on Keramaphidin B: Formation of a Macrocyclic Ring by Intramolecular Diels-Alder Reaction

Hiroki Shimoda, Takahiro Shibata, Daisuke Sekine, 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

The possibility of constructing the macrocyclic ring of keramaphidin B via an intramolecular Diels-Alder (IMDA) reaction has been investigated. The IMDA reaction of a substrate possessing dihydropyridone and diene moieties, which were tethered by an alkyl chain including a linear triple bond, was found to proceed in the presence of SnCl4 at 80 °C.

Published online: 8th October, 2019

■ Benzylic Oxidation and Functionalizations of Xanthenes by Ligand Trasfer Reactions of Hypervalent Iodine Reagents

Toshifumi Dohi,* Keina Komiyama, Shohei Ueda, Nobutaka Yamaoka, Motoki Ito, and Yasuyuki Kita*

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

Abstract

The benzylic oxidation, amidation, and unprecedented heteroarylation proceed at room temperature using iodosobenzene, (sulfonylimido)iodobenzenes, and diaryliodonium(III) salts are described for the direct Csp3-H functionalizations of xanthene molecules. This study has demonstrated that hypervalent iodine reagents serve as unified synthetic tools for versatile xanthene Csp3-H transformations based on the radical and SET oxidation processes.

Published online: 24th September, 2019

■ Synthetic Studies on Marineosins Based on a Direct Coupling Reaction of Pyrrole and δ-Lactone

Kohei Yamamoto, Yuki Morii, Akihisa Suga, Keita Komine, Hayato Fukuda, Jun Ishihara,* and Susumi Hatakeyama*

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

Abstract

A promising precursor of marineosins A and B, unusual macrocyclic pyrrole and spiroiminal alkaloids isolated from marine microorganism has been synthesized employing a direct coupling of pyrrole and δ-lactone.

Published online: 24th September, 2019

■ Alternative Chiral Preparations of a Swaminathan Ketone via Asymmetric Aldol Reactions Mediated by Chiral Amines Bearing a Pyrrolidine

Yuichi Akahane, Arisa Miura, and Kohei Inomata*

*Phamaceutical Department, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan

Abstract

We established a novel chiral route to provide a Swaminathan ketone (3) bearing a 7-membered ring via intramolecular aldol reaction of trione (7) mediated by chiral pyrrodinylmethylamine derivatives. Despite the moderate enantioselectivity of 3, we succeeded in increasing optical purities by using a lipase-mediated asymmetric esterification of an alcohol (16) at a later synthetic stage. The absolute configuration was determined by Mosher’s ester method, and relations between absolute configurations and optical rotations of 3 were clarified.

Published online: 20th September, 2019

■ Syntheses of Indirubins by Aldol Condensation of Isatins with Indoxyl Anion Generated in situ by Lipase-Catalyzed Deacetylation of Indoxyl Acetate

Takeshi Sugai,* Kengo Hanaya, and Shuhei Higashibayashi

*Department of Pharmaceutical Sciences, Faculty of Pharmacy, Keio University, 1-5-30 Shiba-Kouen, Minato-ku, Tokyo, Japan

Abstract

The syntheses of indirubin (76% yield), 6-bromoindirubin (82% yield), and 6-bromoindirubin-3′-oxime (78% yield in two steps) were achieved via the lipase-triggered aldol condensation between isatins and an indoxyl anion in tetrahydrofuran under anhydrous and anaerobic conditions as the key step. The aldol donor was generated in situ by Burkholderia cepacia lipase (Amano PS-IM)-catalyzed deacetylation of commercially available and stable indoxyl acetate in the presence of triethylamine and with 2-propanol as the transesterification reagent. The scale-up of the presently developed reactions is easier than that in the previously reported chemical aldol condensations, because of the simplicity of the isolation procedure and suppression of the oxidative byproduct formation from indoxyl acetate.

Published online: 20th September, 2019

■ Artificial Intelligence-Designed Stereoselective One-Pot Synthesis of trans-β-Lactams and Its Application to Cholesterol Absorption Inhibitor SCH 47949 Synthesis

Tetsuhiko Takabatake, Takumi Yoneda, Jyo Otsuka, Natsuko Kagawa, and Masahiro Toyota*

*Department of Chemistry, Graduate School of Science, Osaka Prefecture University, 1-1 Gakuencho, Sakai, Osaka 599-8531, Japan

Abstract

Cholesterol absorption inhibitor drug SCH 47949 is synthesized stereoselectively using an artificial intelligence design proposed by SYNSUP. The key step involves a stereoselective one-pot preparation of the trans-β-lactam system through thermal electrocyclization. The trans-β-lactam intermediate is converted to SCH 47949 by a series of functional group transformations proposed by SYNSUP.

Published online: 30th August, 2019

■ An Improved Synthesis of a Salicylated Divinylcarbinol Derivative as a Part of Salicylic Macrolides

Aki Kohyama, Yoshihito Oguma, Takumi Yamagishi, Kenji Sugimoto, and Yuji Matsuya*

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

Abstract

An improved enantioselective synthesis of (R)-salicylated divinyl carbinol derivative (4), the key intermediate for the total synthesis of natural salicyclic macrolides, has been achieved. Key steps of the synthesis involve the introduction of the chirality by reliable Sharpless asymmetric epoxidation, carbon-carbon bond formation via Heck reaction and the regeneration of a terminal alkene structure via deoxygenation. The efficient route shortened the reaction sequence and enabled the preparation of (R)-4 in 4 steps in 28% overall yield from divinyl carbinol.

Published online: 21st August, 2019

■ Synthesis of 4-Aroyl-5-arylpyrazoles and 4-Aroyl-3-arylpyrazoles via the Reaction of Enaminodiketones with Substituted Hydrazines

Rika Kotouge, Takashi Nishiyama, Akira Yamauchi, Kanako Ono, Noriyuki Hatae, Tsutomu Oikawa, Satoshi Hibino, and Tominari Choshi*

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

Abstract

Pyrazole is a five-membered heterocyclic compound and is one of the important heterocycles in the fields of medicine and pharmacology. Here, we demonstrate the reactivity of symmetrical enaminodiketones 8–14 with substituted hydrazines. When using alkylhydrazines, if the substituent size of the alkyl group is small, it is possible to selectively synthesize 1-substituted 4-aroyl-5-arylpyrazoles and their regioisomers, 1-substituted 4-aroyl-3-arylpyrazoles, by choosing the solvent (EtOH or toluene). When they react with bulky substituted hydrazines (e.g., cyclohexyl, phenyl, or pyridyl), only 1-substituted 4-aroyl-5-arylpyrazoles are selectively obtained.

Published online: 20th August, 2019

■ Platinum on Carbon–Catalyzed and Chemoselective Aqueous Oxygen Oxidation of Aromatic Acetals to Benzoic Acids

Naoki Yasukawa, Takumi Matsuda, Eisho Shimizu, Hironao Sajiki,* and Yoshinari Sawama*

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

Abstract

Novel chemoselective transformations can diversify the synthetic pathways of the target molecules. The chemoselective oxidation of aromatic acetals to benzoic acid derivatives under platinum on carbon (Pt/C)–catalyzed oxygen oxidation conditions has been newly developed with a tolerance of aliphatic acetals and ketals. The present oxidation was clean and useful from the viewpoint of the easy removal of Pt/C and the use of molecular oxygen as a green oxidant in water as an abundant, non-toxic and environmentally friendly solvent.

Published online: 12th March, 2019

■ 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.