HETEROCYCLES

■ Contents

■ Total Synthesis of (−)-Exiguolide, a Potent Anticancer Marine Macrolide

Haruhiko Fuwa*

*Department of Applied Chemistry, Faculty of Science and Engineering, Chuo University, 1-13-27 Kasuga, Bunkyo-ku, Tokyo 112-8551, Japan

Abstract

(−)-Exiguolide is a marine macrolide natural product, isolated by Ohta and co-workers from a rare marine sponge, Geodia exigua Thiele, collected off Amami-Oshima, Japan. The structural complexity and potent anticancer activity of this natural product spurred the interest of the synthetic chemistry community. This review will focus on total and formal syntheses of exiguolide by Lee, Fuwa, Roulland, Scheidt, Reddy, Song, and Ishihara to illustrate advances in strategies for macrolide synthesis.

■ Microwave-Induced One Step Synthesis of Structurally Diverse Linear Indoloquinolines: Concise Synthesis of Norneocryptolepine

Krisztián Biró, János Tatai, Bence Pollák, Márk Molnár, and Miklós Nyerges*

*Servier Research Institute of Medicinal Chemistry, 7, Záhony utca, 1031, Budapest, Hungary

Abstract

A general and efficient synthesis of diverse tetra- and pentacyclic indolo[2,3-b]quinoline derivatives was achieved through a microwave assisted, metal-free, base catalyzed domino Knoevenagel condensation, intramolecular cyclization process starting from simple oxindole and 2-amino-arylaldheydes. This approach provides a straightforward, atom-economical and concise route to access a diverse range of otherwise not easily available heterocycles in excellent yields with good tolerance of functional groups.

■ Direct Arylation of Furoxan Using Potassium Aryltrifluoroborates

Chenlu Dong, Masahiko Hayashi, and Ryosuke Matsubara*

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

Abstract

Direct arylation of a furoxan ring with potassium aryltrifluoroborates is proposed. A series of aryl-substituted furoxan derivatives have been constructed through the formation of a new C−C bond via a radical pathway. The plausible reaction mechanism is proposed based on the DFT-calculation study.

■ A Microwave-Assisted, Two-Step Synthesis of Indolo[3,2-c]quinolines via Fischer Indolization and Oxidative Aromatization

Sezgin Kiren,* Faisal Mahmud Yakubu, Hassan Mohammed, and Felicia Grimes

*Winston Salem State University, 601 MLK, Jr., Winston Salem, NC 27110, USA

Abstract

Herein, we describe a practical two-step synthesis of an indolo[3,2-c]quinoline scaffold from substituted 4-methoxyquinolines using Fischer indole method and oxidative aromatization in one-pot under microwave radiation. With this protocol, a biologically active natural product, isocryptolepine, and its analogues can be readily and efficiently accessed. Also, this method has been efficiently utilized to generate a series of novel pyrrole-containing derivatives of this heterocyclic system.

■ Ruthenium(II)-Catalyzed ortho Hydroxymethylation of 6-Arylpurines with Paraformaldehyde via Purine-Directed C-H Activation

Jiaqi Jiang, Junli Yang, Siqi Li, Yaxi Yang,* and Bing Zhou*

*State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China

Abstract

A Ru-catalyzed ortho C-H hydroxymethylation of 6-arylpurines has been developed. A wide range of functional groups were tolerated, providing the hydroxymethylated products in good or excellent yields using the readily available paraformaldehyde as a C1 synthon. Moreover, this protocol could be carried out in the presence of water and air, without stoichiometric undesirable waste under mild reaction conditions.

■ Design, Synthesis, and Biological Activity Analysis of Novel Quinazolinyl Ether Derivatives Containing Piperidinamide Structure

Peijia Li, Yehui Yang, Nan Wu, Ya Yan, Lian An, Guangmin Tian, and Xiaoping Bao*

*State Key Laboratory Breeding Base of Green Pesticide and Agricultural Bioengineering, Key Laboratory of Green Pesticide and Agricultural Bioengineering, Ministry of Education, Centre for Research and Development of Fine Chemicals, Guizhou University, Guiyang 550025, People’s Republic of China

Abstract

We designed and synthesized 27 ether derivatives containing quinazolinyl piperidinamide structures and characterized them by 1H NMR, 13C NMR, and HRMS. Bioassay results indicate that several target compounds display higher inhibition activities in vitro against phytopathogenic bacteria. For example, the EC50 of compound III-24 against Xanthomonas axonopodis pv. citri (Xac) is 33.9 µg/mL, which is double that of the commercialized bismerthiazol (EC50 = 75.5 µg/mL). Anti-Xac mechanisms show that compound III-24 exerts antibacterial effects by increasing the permeability of bacterial membranes, reducing their exopolysaccharide content, and inducing morphological changes in bacterial cells.

■ Stereochemistries of Mariannamides C and D, Two Lipohexapeptides, Isolated from Mariannaea elegans NBRC102301

Kan'ichiro Ishiuchi,* Akiho Nagumo, Mitsuyasu Kawaguchi, Honoka Furuyashiki, Hidehiko Nakagawa, and Dai Hirose

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

Abstract

Two lipohexapeptides, mariannamides C (1) and D (2), were isolated from Mariannaea elegans NBRC102301, a filamentous fungus isolated from a decayed Pinus densiflora needle. The stereochemistries of 1 and 2 were fully elucidated based on Marfey’s method and modified phenylglycine methyl ester method. Mariannamides C (1) and D (2) significantly and selectively promoted the defatty-acylase activity of sirtuin 3.

■ Facile Protocol for the Synthesis of Electron-Rich Benzimidazole Derivatives

Robert D. Pike and Brian E. Love*

*Department of Chemistry, East Carolina University, Greenville, NC, 27858, U.S.A.

Abstract

A protocol is reported which allows preparation of electron-rich benzimidazole derivatives in good yield. The reaction proceeds directly from dinitrobenzene derivatives without need of isolation of air-sensitive diamines.

■ Antiviral Activity of Some C3-Symmetrical N-Methyl Benzylamine-Substituted 1,3,5-Triazines and Related Compounds

Shunsuke Shimomura, Kazumi Yokomizo, Jian-Rong Zhou, Nobuko Mibu, Makoto Furutachi, and Kunihiro Sumoto*

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

Abstract

We report a few new C3-symmetrical 1,3,5-triazine (TAZ) derivatives and the results of evaluation of their anti-herpes simplex virus type 1 (anti-HSV-1) activity and cytotoxic activity against Vero cells. Among the tested TAZ derivatives 3a~3f, a new C3-symmetrical trisubstituted TAZ molecule (3d-Me) showed a considerably high level of anti-HSV-1 activity (EC50 = 4.2 μM) with low cytotoxicity (CC50 => 200 μM) against Vero cells, but its activity was lower than that of original N-demethylated compound 3d-H (A). The results for N-methylated C3-symmetrical multivalent molecules (3c-Me~3e-Me) seem to provide interesting information for a derivatization in the search for new C3-type symmetrical antiviral TAZ derivatives.

■ An Improved and Practical Synthesis of Rivaroxaban

Shovkat Olimjonov, Xiaojun Yang, Yongjian Liu, Abdullajon Odilov, Hongjian Qin, Tianwen Hu, Sharafitdin Mirzaakhmedov, Yuanchao Xie, Fuqiang Zhu,* and Jingshan Shen*

*Topharman Shanghai Co., Ltd., Building 1, No.388 Jialilue Road, Zhangjiang Hitech Park, Shanghai 201203, People’s Republic of China

Abstract

Herein we report the development of an improved and practical synthesis of rivaroxaban, an oral anticoagulant drug as a factor Xa inhibitor. The synthesis of rivaroxaban was accomplished by five steps with a total yield of 68.5% on the 220 g scale with a purity of ≥ 99% (single impurity ≤ 0.10%). The epoxy ring-opening reaction was significantly improved with the addition of the magnesium salt. Then, a plausible mechanism was proposed according to our experimental results. Three process-related impurities were identified and controlled by process optimization. The optimized synthesis is expected to offer the technical support for large scale production.

■ Synthesis of Polysubstituted 5,6-Dihydropyrrolo[3,4-b]pyrrol-4(1H)-ones from 2-[Aryl(azido)methyl]-1H-pyrrole-3-carboxylates via a Concise Three-Step Sequence

Hideyuki Sugimura,* Yukino Nomura, Tomoaki Ohta, Haruka Uda, and Ikuo Sasaki

*Department of Chemistry and Bioscience, Faculty of Science and Technology, Aoyama Gakuin University, 5-10-1, Fuchinobe, Chuo-ku, Sagamihara 252-5258, Japan

Abstract

A concise approach to pyrrolopyrrolone skeletons via a three-step synthesis was developed. The substrates for the transformation could be readily prepared by the reaction of α,γ-diazido-α,β-unsaturated esters with 1,3-dicarbonyl compounds. A total of 14 examples were examined to show the broad substrate scope.