HETEROCYCLES

■ Contents

■ Directed Lithiation and Substitution of Pyridine Derivatives

Gamal A. El-Hiti,* Keith Smith,* and Amany S. Hegazy

*Department of Optometry, College of Applied Medical Sciences, King Saud University, P.O. Box 10219, Riyadh 11433, Saudi Arabia

Abstract

Directed lithiation of substituted pyridines containing a directing metalating group (DMG) with a lithium reagent in anhydrous solvent at low temperature gives the corresponding lithium intermediates in-situ, which on reactions with electrophiles produce the corresponding substituted derivatives. The method is simple, general, convenient and often high yielding.

■ Structures and Bioactivities of Xenicanes from an Okinawan Soft Coral Xenia sp.

Wilmar Maarisit, Kentaro Yano, Tomofumi Miyazato, Prodip K. Roy, Junsei Taira, and Katsuhiro Ueda*

*Department of Chemistry, Biology and Marine Sciences, Faculty of Science, University of Ryukyus, 1 Senbaru, Nishihara-cho, Okinawa 903-0213, Japan

Abstract

Three new xenicane diterpenoids 1–3 were isolated from a soft coral Xenia sp. together with the known xenicanes 4–7. Their structures were determined by spectroscopic methods and the structure of 1 was further confirmed by single X-ray diffraction analysis. Metabolites 1–7 showed weak cytotoxicity against HCT 116 cells and a dose dependent, anti-inflammatory effect in LPS/IFN-γ-stimulated inflammatory RAW 264.7 macrophage cells.

■ Development of a Probe Containing Novel Fluorescent Tricyclic-Nucleoside Analogs for Detecting Single Nucleotide Polymorphisms

Ayako Moriya, Tokimitsu Ohki, Aya Hayai, and Yoshihito Ueno*

*Faculty of Applied Biological Sciences, Gifu University , 1-1 Yanagido, Gifu, Gifu 501-1193, Japan

Abstract

Here we report the synthesis of nucleoside analogs containing several aryl groups at the 6-position of the fluorescent tricyclic base, 8-amino-3-(2,3-dihydroxypropyl)imidazo[4′,5′:5,6]pyrido[2,3-d]pyrimidine (1), to expand the fluorescence color range of single nucleotide polymorphism (SNP)-detecting probes. The identity of the RNA target bases could be determined using probes containing an analog with a phenyl group at the 6-position of 1.

■ Synthesis of N-Substituted (Z)-3-Arylbenzo[c]thiophen-1(3H)-imines by the Reaction of 1-[Aryl(methoxy)methyl]-2-lithiobenzenes with Isothiocyanates Followed by Acid-Mediated Cyclization

Kazuhiro Kobayashi,* Yuuho Shigemura, and Kosuke Ezaki

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

Abstract

A simple procedure for the preparation of N-substituted (Z)-3-arylbenzo[c]thiophen-1(3H)-imines has been developed. Thus, bromine/lithium exchange between 1-[aryl(methoxy)methyl]-2-bromobenzenes and butyllithium, followed by reaction of the resulting 1-[aryl(methoxy)methyl]-2-lithiobenzenes with aliphatic and aromatic isothiocyanates, yields the corresponding N-substituted 2-[aryl(methoxy)methyl]benzothioamides. These were treated with concentrated hydrobromic acid to give the desired products.

■ Novel Total Synthesis of the 2-Azaanthraquinone Alkaloid Scorpinone Using a Tandem Oxidation and Azaelectrocyclic Reaction

Tominari Choshi,* Miharu Hironaka, Miki Goto, Kaori Shimizu, Yuhki Kurata, Takashi Nishiyama, Noriyuki Hatae, and Satoshi Hibino*

*Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Fukuyama, Hiroshima 729-0292, Japan

Abstract

A new tandem oxidation and electrocyclic reaction of a 1-aza 6π-electron system derived from a known 3-hydroxynaphthalene derivative was developed for the synthesis of 2-azaanthraquinones. Total synthesis of scorpinone (1a) was achieved in seven steps using this new tandem reaction. In addition, the positional isomer, 7,9-dimethoxy-4-methylbenzo[g]isoquinoline-5,10-dione (1b) was also synthesized in the same way.

■ Intramolecular Methionine Residue and Its Peptide Segments Stabilize Dehydroandrographolide Succinate-Methoxypolyethylene Glycol Conjugates

Senhao Li, Siliang Feng, Lei Qiao, Qingbin Meng, Huajin Dong, Zehui Gong, Dongqin Quan, and Keliang Liu*

*Department of Medicinal Chemistry, Beijing Institute of Pharmacology and Toxicology, No. 27 Taiping Road, Haidian District, Beijing 100850, China

Abstract

The antipyretic, analgesic, and anti-inflammatory activities of dehydroandrographolide succinate (DAS), an andrographolide derivative, are superior to its parent compound. However, its instability and poor water solubility have restricted its clinical use. To solve these problems, a series of DAS conjugates with functional amino acids or peptides coupled to methoxypolyethylene glycol (mPEG) were designed and synthesized. Conjugation of DAS directly to mPEG improved the compound solubility in aqueous solution, but the thermostability of the conjugate was reduced compared with the parent compound. Introduction of methionine (Met) or oligomethionyl peptides, DAS-Metn-mPEG (n = 1, 2, or 3), protected the DAS skeleton from ring opening and double bond oxidation, thus improving the anti-inflammatory properties of these derivatives compared with DAS.

■ Decarboxylative Halogenation of Indolecarboxylic Acids Using Hypervalent Iodine(III) Reagent and Its Application to the Synthesis of Polybromoindoles

Hiromi Hamamoto,* Hideaki Umemoto, Misako Umemoto, Chiaki Ohta, Emi Fujita, Akira Nakamura, Tomohiro Maegawa, and Yasuyoshi Miki*

*Department of Applied Biological Chemistry, Faculty of Agriculture, Meijo University, 1-501 Shiogamaguchi, Tempaku-ku, Nagoya, Japan

Abstract

Hypervalent iodine mediated decarboxylative halogenation of indoledicarboxylic acid derivatives was studied. The treatment of 1-methylindole-2,3-dicarboxylic acid with phenyliodine diacetate (PIDA) in the presence of lithium bromide gave 1-methyl-3,3-bromooxindole. However, the reaction of 1-(phenylsulfonyl)indole-2,3-dicarboxylic acid with PIDA in the presence of lithium bromide afforded 2,3-dibromo-1-(phenylsulfonyl)indole. In a similar manner, the 2,3-dichloro- and 2,3-diiodoindole derivatives could be obtained by the reaction of the indole-2,3-dicarboxylic acids with PIDA in the presence of lithium chloride and iodide. This method was optimized to the synthesis of polybromoindole alkaloids.

■ Syntheses of a Pyrrolidine Analog of a Tetrahydrofuran Containing Acetogenin, cis-Solamin

Kouji Ohnishi, Haruka Sakurai, Kazuya Kobayashi, Hidefumi Makabe, Kenta Teruya, Kenichi Akaji, and Yasunao Hattori*

*Department of Medicinal Chemistry, Pharmacetuical Chemistry, Kyoto Pharmaceutical University, Misasagi, Yamashina-ku, Kyoto 607-8412, Japan

Abstract

Practical synthesis of a pyrrolidine analog of a mono-THF acetogenin as a proto-type analog to evaluate the effect of a heteroatom in the mono-THF ring of acetogenins was achieved using Pd(II)-catalyzed diastereo-selective cyclization. Ligand-less PdCl2 catalyzed cyclization yielded the desired pyrrolidine derivative as a single major product having the desired relative configurations. Coupling of the pyrrolidine fragment with a known γ-lactone-containing fragment via a Sonogashira cross-coupling reaction yielded the desired aza-cis-solamin analog.

■ Synthesis and Antitumor Activity of 1,3,4-Thiadiazole Derivatives Bearing Coumarine Ring

Sobhi M. Gomha* and Hassan M. Abdel-aziz

*Department of Organic Chemistry, Cairo University, Giza-Haram 12613, Egypt

Abstract

In the present study, preparation of a novel series of N'-(3,5-diphenyl-1,3,4-thiadiazol-2(3H)-ylidene)-2-oxo-2H-chromene-3-carbohydrazide (8a-m) was prepared by two methods via the reaction of hydrazonoyl halides with methyl 2-(2-oxo-2H-chromene-3-carbonyl)hydrazinecarbodithioate or 3-(5-mercapto-1,3,4-oxadiazol-2-yl)-2H-chromen-2-one. Structures of the newly synthesized compounds were elucidated on the basis of elemental analyses and spectral data. All the newly synthesized compounds have been evaluated for their antitumor activity against a liver carcinoma cell line HEPG2-1. Also, their structure activity relationship (SAR) was studied. Many of the tested compounds showed moderate to high anticancer activity with respective to doxorubicin as a reference drug.

■ One-Carbon Homologation of Pyrrole Carboxaldehyde via Wittig Reaction and Mild Hydrolysis of Vinyl Ether – toward the Synthesis of a Sterically Locked Phytochrome Chromophore

Ryo Sakata, Takahiro Soeta, and Yutaka Ukaji*

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

Abstract

Mild hydrolysis of vinyl ether derived from a pyrrole carboxaldehyde corresponding to the B,C-ring component of phytochromobilin chromophore was achieved by treatment with oxalyl chloride in chloroform in the presence of water and ethanol to afford a one-carbon homologated aldehyde. This aldehyde was applied to the synthesis of the sterically locked 15E-anti CD-ring component of the chromophore. Furthermore, the aldehyde could be converted to the intermediate for the sterically locked 5Z-anti AB-ring component.

■ New Xanthones from Comastoma Pulmonarium and Their Anti-Tobacco Mosaic Virus Activity

Min Zhou, Kun Zhou, Ying-Liang Zhao, Neng-Jun Xiang, Tian-Dong Zhang, Cheng-Ming Zhang, Yue-De Wang, Wei Dong, Bing-Kun Ji, Li-Mei Li, Jie Lou, Gan-Peng Li,* and Qiu-Fen Hu*

*Key Laboratory of Ethnic Medicine Resource Chemistry, State Ethnic Affairs Commission & Ministry of Education, School of Chemistry and Biotechnology, Yunnan University of Nationalities, Kunming, Jingming South Road, Chenggong New District, Kunming, Yunnan 650500, China

Abstract

Two new xanthones, pulmonarxanthone A (1) and pulmonarxanthone B (2), together with four known ones (3-6), were isolated from the whole plants of Comastoma pulmonarium. The structures of compounds 1–6 was elucidated by spectroscopic methods including extensive 1D- and 2D-NMR techniques. Compounds 1–6 were also evaluated for their anti-tobacco mosaic virus (Anti-TMV) activity. The results showed that all the isolated compounds exhibited weak anti-TMV activity with inhibition rates in the range of 14.4–22.3%.

■ Synthesis and Reactivity of Cyanomethyl Thiazolyl Ketone: A Facile Synthesis of Some New Azoles, Chromene, Pyridine, Thiophene, Pyrazolo[3,4-b]pyridine and Pyrimido[1,2-a]benzimidazole Derivatives

Mohamed A. Raslan, Mohamed A. Khalil, and Samia M. Sayed*

*Department of Chemistry, Faculty of Science, Aswan University, Aswan 81528, Egypt

Abstract

Several new heterocyclic compounds such as chromene, pyrazole, isoxazole, dihydropyridine, thiazole, thiophene, pyrazolopyridine and pyrimidobenzimidazole derivatives have been synthesized by the reactions of the versatile multifunctional unreported 3-(4-methyl-2-(tosylamino)thiazol-5-yl)-3-oxopropanenitrile with several nitrogen binucleophiles. A one-pot three component reaction of an aldehyde, the 3-oxopropanenitrile derivative, and electron-rich heterocyclic amines has been decribed.