HETEROCYCLES

■ Contents

■ Berberine Analogues: Progress towards Versatile Applications

Jing Wang, Jie Tang, Li-Fang Yu, Jia Li, Jing-Ya Li, and Fan Yang*

*Shanghai Engineering Research Center of Molecular Theraputics and New Drug Development, East China Normal University, North Zhongshan Road, Shanghai 200062, China

Abstract

The promising activities shown by analogues of natural product berberine in numerous categories such as anti-hyperglycaemic, anti-cancer, anti-inflammatory, anti-alzheimer’s disease and anti-microbials, have made it an indispensable structure for development of new therapeutic agents. The compounds bearing various substituents on the berberine skeleton have exhibited a wide spectrum of biological activities. Short reviews on biological importance of this core structure have been showcased in literature. However, systematic review on the research advances of structure-activity relationship of berberine and its analogues seems lacking. In the present review, various analogues of berberine with different pharmacological activities were summarized and their SAR were discussed as well. The current review would provide useful information for further studies on structural modifications on berberine for discovering new drug leads.

■ Synthesis of Some Novel Thieno[3,2-d]pyrimidine Derivatives of Pharmaceutical Interest

Hala M. Refat,* Ahmed A. Fadda, Rasha E. El-Mekawy, and Aliaa M. Sleat

*Faculty of Science, Department of Chemistry, Suez Canal University, Al-Arish, 45511, Egypt

Abstract

New starting material, ethyl 6-amino-1,3-dimethyl-2,4-dioxo-1,2,3,4- tetrahydrothieno[3,2-d]pyrimidine-7-carboxylate (2) was prepared by Gewald reaction using N,N-dimethylbarbituric acid. The reaction of compound 2 with phenyl isothiocyanate yields the non-isolable intermediate 3, which gave thiocarbamoyl derivative 4 upon treatment with dilute HCl. Also compound 2 react with carbon disulfide afforded carbamodithioic acid derivative 5, followed by addition of aniline to give the same product 4. On the other hand, when compound 4 refluxed in DMF and TEA afforded the thieno[2,3-d:4,5-d']dipyrimidine derivative 6. Moreover, treatment of 3 with α-halo compounds in basic medium afforded the corresponding thiazole-2-ylidene derivatives (8a, 8b, 10), thiazolidin-2-ylidene derivative 12 and 1,3-thiazinan -2-ylidene derivative 15, respectively. Furthermore, the reaction of 2 with malononitrile and 2-cyano-3-phenylacrylamide afforded the corresponding pyrido[3',2':4,5]thieno[3,2-d]pyrimidine derivatives 16 and 17, respectively. All the newly synthesized compounds were characterized by IR, 1H-NMR, 13C-NMR, mass spectra and elemental analyses.

■ Synthesis of 7-Desmethyl Analogs of (+)- and (−)-Huperzine A

Marco Pieroni* and Suresh K. Tipparaju

*Department of Pharmacy, University of Parma, Parco Area delle Scienze 27/a 43124, Italy

Abstract

The natural alkaloid (−)-huperzine A is an inhibitor of AChE and has been demonstrated to exert neuroprotection and to possess other CNS related properties. In this manuscript, we report the synthesis of the analogs of huperzine A, in their enantiomeric form, starting from a common precursor, that has the advantage of being easily prepared in both the enantiomeric forms, in high enantiomeric excess, and at moderate costs.

■ P-Stereogenic Diphosphacrowns: Facile Incorporation of Aromatic Rings

Ryosuke Kato, Hiroyuki Watanabe, Yasuhiro Morisaki,* and Yoshiki Chujo*

*Applied Chemistry for Environment, School of Science and Technology, Kwansei Gakuin University, 2-1 Gakuen, Sanda, Hyogo 669-1337, Japan

Abstract

P-Stereogenic diphosphacrowns containing naphthalene and pyridine rings were synthesized. Facile incorporation of aromatic rings, and chains of different lengths, into the diphosphacrown skeleton was achieved by altering the electrophile in our previously reported synthetic method. Pyridine-containing diphosphacrown exhibited chiral recognition ability for chiral ammonium salts and carboxylic acids. This is the first example of chiral recognition using P-stereogenic diphosphacrowns. 1H and 31P NMR spectra indicated that the nitrogen, oxygen, and chiral phosphorus atoms contributed to the chiral recognition cooperatively.

■ Highly Chemoselective Synthesis of Benzimidazoles in Sc(OTf)3-Catalyzed System

Liyan Fan,* Lulu Kong, and Wen Chen

*Department of Chemistry, Tongji University, Shanghai Siping Road 1239, China

Abstract

The present researches elicit a simple, green and efficient method for the synthesis of substituted benzimidazoles through the coupling of o-phenylenediames with aldehydes catalyzed by Sc(OTf)3 in ethanol, which obtains high chemoselectivity and excellent yield of many biologically active 1,2-disubstitued and 2-substituted benzimidazoles respectively and are also environment friendly.

■ Synthesis of Novel (S)-N-Boc-3-Pyrazolylalanine-Derived α-Amino Acids

Uroš Grošelj* and Jurij Svete

*Department of Chemistry and Biochemistry, Faculty of Chemistry and Chemical Technology, University of Ljubljana, Večna pot 113, SI – 1000 Ljubljana, Slovenia

Abstract

Di-tert-butyl (S,E)-4-[(dimethylamino)methylidene]-5-oxopyrrolidine -1,2-dicarboxylate (1), available in three steps from L-pyroglutamic acid, was used as the starting material for the preparation of a small library of N-Boc-protected 3-pyrazolylalanine tert-butyl esters 3 using 'ring-switching' strategy with different hydrazine derivatives 2. Acid-catalyzed deprotection (TFA/CH2Cl2) of 3 yielded free amino acids 4 isolated as dihydrochloride salts, while selective deprotection with HCl/EtOAc furnished N-Boc deprotected tert-butyl esters dihydrochlorides 5. Hydrolysis under basic conditions furnished N-Boc-protected amino acid 6.

■ Novel Synthesis of 1,2-Dihydro-4H-3,1-benzoxazine-4-thiones by the Reaction of Newsynthesized Methyl Dithioanthranilate Hydrobromide with Carbonyl Compounds and the Formation of Another New Class of 1,2-Dihydro-4H-3,1-benzothiazine-4-thiones from the Same Reactants in the Presence of Excess Sodium Hydrogensulfide

Tatsuo Yamamoto* and Motomu Muraoka

*Faculty of Science, Josai University, 1-1 Keyakidai, Sakado, Saitama 350-0295, Japan

Abstract

Methyl dithioanthranilate hydrobromide (6) was synthesized by the deprotection of Z-protected methyl dithioanthranilate (5) which was obtained by treatment of Z-protected methylthioiminium iodide 4 with H2S. The 1,2-dihydro-4H-3,1-benzoxazine-4-thiones 10a-m were first synthesized by the reaction of methyl dithioanthranilate hydrobromide (6) with each aldehyde or ketone. Formaldehyde, in this reaction, gave N-(methylthio)methyl-4H-3,1- benzoxazine-4-thione (11). Another new class of 1,2-dihydro-4H-3,1- benzothiazine-4-thiones 12a-e were synthesized from the same reactants in the presence of two equivalents of sodium hydrogensulfide.

■ Synthesis, Molecular Structure, And Morphological Properties of Dendritic Tetra-2-thienylmethane

Kouzou Matsumoto,* Sota Kugo, Takeshi Suzuki, Daisuke Takajo, Akira Inaba, Yasukazu Hirao, Hiroyuki Kurata, and Takashi Kubo*

*Institute of Natural Sciences, Senshu University, 2-1-1 Higashimita, Kawasaki, Kanagawa 214-8580, Japan

Abstract

Tetrakis(5-(tri-2-thienyl)methyl-2-thienyl)methane, in which as many as 16 thiophene rings connected with five sp3 carbon atoms, has been synthesized from tetra-2-thienylmethane in four steps. This compound can take both crystalline and glass state. Although a deformed structure is taken in the crystal, but it turns to be a metastable state. The second polymorph exhibits the melting point more than 30 °C higher than that of the metastable state, suggesting the effective intermolecular interaction.

■ Phenolic Derivatives from the Stems of Lagerstroemia indica and Their Biological Activity

Kyeong Wan Woo, Won Se Suh, Lalita Subedi, Sun Yeou Kim, Sang Un Choi, Ki Hyun Kim, and Kang Ro Lee*

*Natural Products Laboratory, School of Pharmacy, Sungkyunkwan University, 300 Chunchun-dong, Jangan-ku, Suwon 440-746, Korea

Abstract

The purification of a MeOH extract from the stems of Lagerstroemia indica (Lythraceae) using repeated column chromatography afforded three new phenolic glycosides (1-3), and a new flavone derivative (4) along with fifteen known compounds (5-19). The structures of new compounds were determined through spectral analysis, including 1D, 2D-NMR and MS data. Compounds 1-19 were evaluated for their inhibitory activities on nitric oxide (NO) production in an activated murine microglial cell line and cytotoxic activities against four human tumor cell lines (A549, SK-OV-3, SK-MEL-2, and HCT-15).

■ Microwave-Assisted One-Pot Synthesis of N-Substituted 2-Methyl-1H-pyrrole-3-carboxylate Derivatives without Catalyst and Solvent

Wei Kan, Tao Jing, Xiao-hong Zhang, Yong-jie Zheng, Lin Chen, and Bing Zhao

*,

Abstract

An efficient one-pot synthetic method for the N-substituted 2-methyl-1H-pyrrole-3-carboxylate derivatives has been accomplished via a microwave irradiation MCRs of various α-bromoacetophenone, amines, and ethyl acetoacetate without any solvent and catalyst. This approach provides a convenient one pot method for the synthesis of N-substituted 2-methyl-1H-pyrrole-3-carboxylate derivatives.

■ A Facile Synthesis of (2R/S,5R)-1-tert-Butyl 2-Methyl 5-(((tert-Butyldimethylsilyl)oxy)methyl)pyrrolidine-1,2-dicarboxylate

Yoko Yasuno, Yuya Yoshida, Akito Nishimura, Yasufumi Ohfune, and Tetsuro Shinada*

*Graduate School of Science, Osaka City University, Sugimoto, Sumiyoshi-ku, Osaka 558-8585, Japan

Abstract

A facile synthesis of (2R/S,5R)-1-tert-butyl 2-methyl 5-(((tert-butyldimethylsilyl)oxy)methyl)pyrrolidine-1,2-dicarboxylate (12) was efficiently accomplished in 5 steps from aminal 17 via the mild hydrolysis of nitrile 23.

■ Synthesis of Nelarabine with Pure β-Anomer through Late-Stage C-H Nitration/Nitro-Reduction

Ran Xia,* Li-Ping Sun, and Gui-Rong Qu

*Department of Chemistry and Chemical Engineering, Xinxiang University, East of JinSui Road, XinXiang City, Henan Province, 453003, China

Abstract

An efficient and pure β-anomer synthesis of the clinical drug nelarabine from the readily available vidarabine has been achieved for the first time. The C6 amino group of vidarabine was transformed to methoxy group by diazotization/chlorination followed by methoxylation using Na2CO3/MeOH system. The formation of C(2)-N bond was achieved via the highly selective C-H bond functionalization by reacting with 2,2,2-trifluoroacetic anhydride (TFAA) and tetrabutylammonium nitrate. The final product was obtained in total yield of 58.6% by 5 steps-synthesis from vidarabine after the reduction of nitro group to amino group. Moreover, the drug nelarabine could be obtained in 100 grams scale successfully and no chromatography was needed, which made this route more attractive for industrial application.