HETEROCYCLES

■ Contents

■ Total Synthesis of Manzacidins. An Overview and Perspective

Yasufumi Ohfune,* Kentaro Oe, Kosuke Namba, and Tetsuro Shinada

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

Abstract

Manzacidins belong to a class of non-oroidin bromopyrrole alkaloids and have attracted significant attention from the synthetic community due to not only their expected biological activities but also to their novel structure consisting of a tetrahydropyrimidinecarboxylic acid with an ester-linked bromopyrrole unit. Of particular interest was the stereoselsective construction of the 1,3-diamino groups attached to chiral tertiary and quaternary carbon centers in the tetrahydropyrimidine unit. Since our total synthesis and structure confirmation of manzacidins A and C in 2000, many groups have accessed the enantio- and diastereoselective total syntheses of these alkaloidal amino acids based on novel synthetic methods. This review will focus on recent studies from our laboratory as well as others regarding the total syntheses of manzacidins A, B, C, and D reported to date.

■ Imidazoquinolines as Diverse and Interesting Building Blocks: Review of Synthetic Methodologies

Zeinab Mahmoud and Mohsen Daneshtalab*

*School of Pharmacy, Memorial University of Newfoundland, St. John’s, NL, A1B 3V6, Canada

Abstract

Imidazoquinolines are interesting heterocyclic systems that depending on the position of fusion and the type of substituents display diverse biological and pharmaceutical properties. From the chemistry point of view, imidazoquinolines are heterocylic scaffolds resulting from the fusion between the 5-membered ring imidazole and the benzopyridine ring, quinoline. At least eight different combinations can be identified for these significant scaffolds. From the retrosynthetic point of view, imidazoquinolines can be prepared using one of two general approaches: imidazole-ring formation or pyridine-ring one. According to the type of imidazoquinoline and the position of the substituents either one of these two plans can be adopted. Pertinent to the specific plan to be used, different starting materials can be implanted as well. The most general starting materials are the diaminoquinolines and the aminobenzimidazoles. The main objective of this review article is to shed light on the reported synthetic pathways for each imidazoquinoline system.

■ Application of SO3H Silica Gel to Deprotection of Silyl Ethers

Hideaki Fujii, Takaaki Yamada, Kohei Hayashida, Miki Kuwada, Atom Hamasaki, Kazunori Nobuhara, Sumio Ozeki, and Hiroshi Nagase*

*Laboratory of Medicinal Chemistry, School of Pharmacy, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan

Abstract

A newly developed SO3H silica gel cleaved the O-Si bonds in various aryl and alkyl silyl ethers to give the corresponding phenols and alcohols in good to excellent yield. The crude filtrates contained no silyl residues. The solid phase 29Si NMR analyses of the SO3H silica gel strongly suggested that the silyl residues were captured by silanol groups on the surface of the silica gel. The SO3H silica gel could be recycled at least ten times without any loss of activity. The disappearance of silyl residues in the crude filtrate was observed in even the 10th repetition. Our method provides an easily handled desilylation method that requires no further purification. Our method was also applicable to a selective desilylation reaction of a derivative 5 with different siloxy groups or desilylation of an alkaloid derivative 7.

■ Design, Synthesis and Biological Activity Evaluation of 2,5-Diphenyl-1,3,4-oxadiazole Derivatives as Novel Inhibitors of Fructose-1,6-bisphosphatase

Hai-Bing He, Li-Xin Gao, Yue-Yang Zhou, Ting Liu, Jie Tang, Xue-Ping Gong, Wen-Wei Qiu, Jing-Ya Li,* Jia 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

Fructose-1,6-bisphosphatase (FBPase), an important gluconeogenic enzyme, catalyzes the hydrolysis of fructose 1,6-bisphosphate to fructose 6-phosphate. The effort to discover new FBPase inhibitors was carried out by high-throughput screening (HTS) of a library of 56,000 lead-like compounds, and a 2,5-diphenyl-1,3,4-oxadiazole (3a, IC50 = 15.45 μM) which bearing no phosphate group was identified as a potential FBPase inhibitor for the first time. Structure-activity-relationship (SAR) research of a series of analogues obtained by modifying the substituent groups and replacing the 1,3,4-oxadiazole with several other heterocycles disclosed the key structure and substituent groups related to the binding with FBPase.

■ Novel Synthesis of Some New Fluorescent 2-Amino-3-cyanopyridines

Afsaneh Zonouzi,* Zakieh Izakian, and Seik Weng Ng

*School of Chemistry, College of Science, University of Tehran, Tehran 14155-6455, Iran

Abstract

Novel synthesis of some new fluorescent 2-amino-3-cyanopyridines 2a-m in the presence of N-hydroxybenzamide or p-toluenesulfonic acid is described. Photophysical data including λAbs. and λFlu. of 2a-m in CH2Cl2, MeCN and MeOH have been measured.

■ Oximes of 3-Hydroxyprenylflavanones and Their Cytotoxic Activities

Sanit Thongnest, Ranu Sawangsri, Korakot Navakhun, Jantana Yahuafai, Pongpun Siripong, and Somyote Sutthivaiyakit*

*Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Ramkhamhaeng University, Ramkhamhaeng Road, Bangkapi, Bangkok 10240, Thailand

Abstract

Oximination of 3-hydroxyprenylflavanones using hydroxylamine hydrochloride yielded 4-hydroxy-3-oxime and 3-hydroxy-4-oxime derivatives. The 3β-O-acetylhydroxyprenylflavanones, under similar reaction condition, yielded corresponding 4-O-acetyl-3-oximes. The configurations at C-4 of the 4-hydroxy-3-oximes obtained from both 3α- and 3β-hydroxyprenylflavanones and of 4-O-acetyl-3-oxime derivative from 3β-O-acetylprenylflavanones were proposed. Cytotoxic activities of the oximes and their parent compounds were evaluated against a panel of human cancer cell lines.

■ Conversion of Two Eremophilane Glucosides from Pittocaulon praecox into Eremophilanolides

Amira Arciniegas, Jhon Ironzi Maldonado, Ana-L. Pérez-Castorena,* and Alfonso Romo de Vivar

*Instituto de Química, Universidad Nacional Autónoma de México, Circuito Exterior, Ciudad Universitaria, Coyoacán 04510, D.F., Mexico

Abstract

Two eremophilanolides (3, 4), an aldehyde (6), an intramolecular addition product (7), and two water addition products (8, 9) were obtained by acid treatment of the eremophilane glucosides 10 and 11. A reaction mechanism supported by deuterium labeling is proposed for the conversion of eremophilane glycosides into eremophilanolides.

■ Condensation Reaction of Ethyl 4-Oxo-4H-benzo[d][1,3]oxazine-2-carboxylates with Potassium Cyanate: 2,4(1H,3H)-Quinazolinediones Synthesis

Farzad Nikpour,* Forugh Havasi, and Zeinab Arzegar

*Department of Chemistry, Faculty of Science, University of Kurdistan, Sanandaj, Pasdaran Bivd., P.O.Box 66135-416, Iran

Abstract

The condensation reaction of ethyl 4-oxo-4H-benzo[d][1,3]oxazine-2-carboxylates with acidic solution of potassium cyanate offers a novel and expedient route to the synthesis of 2,4(1H,3H)-quinazolinediones under mild reaction conditions.

■ Structure-Activity Relationships of Biflavonoids for β-Secretase (BACE-1) Inhibitory Activity

Hiroaki Sasaki, Yuki Kitoh, Kazuhiko Miki, Kaoru Kinoshita, Kiyotaka Koyama, Miyuki Kaneda, and Kunio Takahashi*

*Department of Pharmacognosy and Phytochemistry, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan

Abstract

Bioactive natural products are useful sources of new pharmaceutics. Their analogues are also important for evaluating structure-activity relationships. In this study the structure-activity relationships of 2,3-dihydro-6-methylginketin (1) for BACE-1 inhibitory activity were studied. Biflavonoids consisting of flavanone and flavone, and also the presence of a methoxy group at the C-4’ position, were found to be important for strong activity. 2,3-Dihydro-6-methylbilobetin (2) showed strong activity with an IC50 value of 0.56 μM.

■ Sequential Three-Component Synthesis of 1,4-Bis[triazolo[4,5-d]pyrimidin-7(6H)-one]piperazines

Zheng Dong Fang* and Xian Hong Wei

*College of Chemistry and Environmental Engineering, Hubei Normal University, Huangshi 435002, Hubei, China

Abstract

A simple three-component reaction and efficient method is described for the synthesis of 1,4-bis[triazolo[4,5-d]pyrimidin-7(6H)-one]piperazines by a sequential three-component process involving an aza-Wittig reaction/heterocyclization in the presence of sodium ethoxide as catalyst. The iminophosphorane 1 reacted with aromatic isocyanate gave carbodiimides 2, followed by addition of piperazine derivatives to give the corresponding guanidine intermediates 3. The guanidine intermediates were cyclized in the presence of catalytic amount of sodium ethoxide to give 1,4-bis[triazolo[4,5-d]pyrimidin-7(6H)-one]piperazines 4 in good yields.

■ Behaviour of β-Keto-δ-carbethoxyphosphonates and Phosphine Oxides in the Biginelli Multicomponent Reaction: Regioselective Synthesis of 5-Carbethoxy-6-phosphonomethyl-3,4-dihydropyrimidin-2-ones

Emna Chebil and Soufiane Touil*

*Department of Chemistry, Faculty of Sciences of Bizerta, 7021-Jarzouna, Tunisia

Abstract

An efficient one-pot synthesis of the novel 5-carbethoxy-6-phosphonomethyl-3,4-dihydropyrimidin-2-ones via a three-component Biginelli-type condensation of β-keto-δ-carbethoxyphosphonates and phosphine oxides with aldehydes and urea in the presence of a catalytic amount of acetic acid, is described. The reaction proceeded efficiently at room temperature to afford regioselectively the title compounds in good to high yields. The factors governing the regioselectivity of the reaction are discussed.

■ Three New Iridoid Compounds from Swertia cincta Burkill

Jin Yang, Feiyan Huang, Yongfu Zhou, Wei Liu, Ping Yi, and Ganpeng Li*

*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

Three new iridoid compounds, 3,4,5,6-tetrahydro-8-hydroxy- 6-(hydroxymethyl)pyrano[3,4-c]pyran-1(8H)-one (1), 3,4,5,6-tetrahydro-8-hydroxy-6-methylpyrano[3,4-c]pyran-1(8H)-one (2), 5,6-dihydro-4-(1,3-dihydroxybutan-2-yl)-3-(hydroxymethyl)pyran-2-one (3), named swercinctolides A, B and C, were isolated from the 80% methanol extract of the whole plant of Swertia cincta Burkill, which is a traditional medicine in China. Their structures were defined on the basis of spectral evidences. Compounds 1, 2 and 3 showed TMV (Tobacco Mosaic Virus) inhibitory activity.