HETEROCYCLES

■ Contents

■ Chemical Pharma-Sciences that Incorporate Non-Covalent Bonded Interactions

Yoshimitsu Nagao*

*Graduate School of Pharmaceutical Sciences, University of Tokushima, Sho-machi, Tokushima 770-8505, Japan

Abstract

Molecular structure characteristics of organosulfur drugs and biologically active organosulfur compounds and the asymmetric Pummerer-type reactions are discussed in terms of non-covalent bonded S···X (X = O, N, S, halogens, etc.) interactions based on the data of X-ray crystallographic analysis, density functional theory (DFT) calculation, some spectroscopic analyses, and cold-spray ionization mass spectrometric (CSI-MS) analysis.

■ Boron and Phosphorus Complexes of meso-Aryl Expanded Porphyrins

Tomohiro Higashino and Atsuhiro Osuka*

*Department of Chemistry,, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8502, Japan

Abstract

Our recent efforts in the boron and phosphorus insertion reactions into meso-aryl expanded porphyrins are reviewed. Boron insertion into [28]hexaphyrin(1.1.1.1.1.1) 19 triggered a skeletal rearrangement to bis-boron complex of [28]hexaphyrin(2.1.1.0.1.1) 20. Boron-insertion into quadruply N-fused heptaphyrin 23 with BBr3 and EtNiPr2 followed by treatment with an alcohol gave corresponding boron complex 24-OR. Treatment of non-fused heptaphyrin mono-Cu(II) complex 25 with BBr3 and EtNiPr2 induced a splitting reaction to B(III) subporphyrin 26 and Cu(II) porphyrin 27. Phosphorus insertion to N-fused [24]pentaphyrin 30 led to the formation of multiply fused P(V) complex 31, which was reduced to P(III) complex 33 with BH3·Me2S as a rare P(III) porphyrinoid. Phosphorus insertion to 19 proceeded in a stepwise manner to give mono-P(V) complex 38 and bis-P(V) complex 39, which were, respectively, identified to be Möbius aromatic and antiaromatic molecules. Phosphorus insertion into [34]heptaphyrin 40 gave Möbius antiaromatic P(V) complex 43 and Hückel aromatic P(V) complex 44. Upon heating in acetonitrile, 43 was cleanly converted to 44, indicating that 43 was a kinetically formed Möbius antiaromatic product as the first case. Phosphorus insertion into [36]octaphyrin 5 led to the formation of [38]octaphyrin mono-P(V) complex 47 and [40]octaphyrin bis-P(V) complex 48. The latter complex is a fully reduced octaphyrin, hence representing the first example of expanded isophlorins, but is stable under ambient conditions.

■ Synthesis of Neodesmosine, a Crosslinking Pyridinium Amino Acid of Elastin, via a Negishi Cross-Coupling

Hiroto Yanuma and Toyonobu Usuki*

*Department of Materials and Life Sciences, Faculty of Science and Technology, Sophia University, 7-1 Kioicho, Chiyoda-ku, Tokyo 102-8554, Japan

Abstract

Neodesmosine, isolated from the hydrolysate of bovine ligamentum nuchae, is a crosslinking pyridinium amino acid of elastin. In this study, the first total synthesis of neodesmosine is reported via a Negishi cross-coupling reaction between 3,5-dihalogenated pyridines and the corresponding iodo amino acid.

■ Synthesis of Bicyclic Dioxetanes Bearing a 4-(Benzimidazol-2-yl)-3-hydroxyphenyl Group and Their Base-Induced Chemiluminescent Decomposition in an Aprotic Medium and in an Aqueous Medium

Hiromasa Hagiwara, Nobuko Watanabe, Hisako K. Ijuin, Masashi Yamada, and Masakatsu Matsumoto*

*Department of Chemistry, Faculty of Science, Kanagawa University, 2946 Tsuchiya, Hiratsuka 259-1293, Japan

Abstract

Bicyclic dioxetane, 5-tert-butyl-4,4-dimethyl-2,6,7-trioxabicyclo[3.2.0]heptane, bearing a 4-(benzimidazol-2-yl)-3-hydroxyphenyl group at the 1-position and its N-substituted benzimidazolyl-analogs were synthesized. N-Methylbenzimidazolyl-analog and N-phenylbenzimidazolyl-analog were found to undergo charge-transfer-induced decomposition (CTID) to effectively give light in both TBAF/MeCN and in NaOH/H2O. The CTID of N-(4-carboxybutyl)benzimidazolyl-analog gave also effectively light both in MeCN and in H2O. On the other hand, chemiluminescent CTID of the unsubstituted benzimidazolyl-analog changed depending on the base used: TBAF/MeCN induced weak emission of yellow light due to a dianion of the dioxetane, while TMG(tetramethylguanidine)/MeCN induced strong emission of blue light due to a monoanion of the dioxetane.

■ Preparation of 6-Ethynylpteridine Derivatives by Sonogashira Coupling

Winston Nxumalo* and Andrew Dinsmore

*Department of Chemistry, University of Limpopo, Private Bag X 1106, Sovenga 0727, South Africa

Abstract

Sonogashira coupling of 6-sulfonyloxypteridine with various acetylenes is reported. Hydrolysis of the protecting groups with 1M NH3 gave the 6-subustituted 2,4-diaminopteridine while hydrolysis with 1M NaOH gave the 6-subsituted pterin.

■ Preparation of a Diverse Purine-Scaffold Library via One-Step Palladium Catalyzed Cross-Coupling

Tony Taldone,* Danuta Zatorska, Hardik J. Patel, Weilin Sun, Maulik R. Patel, and Gabriela Chiosis

*Sloan-Kettering Institute, Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York 10065, U.S.A.

Abstract

In our ongoing efforts to prepare Hsp90 inhibitors, various cross-coupling reactions (Suzuki, Stille, Heck, and Sonogashira) were used to construct a diverse library of substituted purines in a single step from PU-H71 (1). We show that these reactions, particularly Suzuki coupling, are highly efficient, do not require protection of the pendant amine, and due to the wide variety of commercially available substrates, allow for the rapid development of a diverse purine library. The products derived from these reactions will enable us to explore the chemical space occupied by the key 6’-iodine of PU-H71 through molecules with diverse physical and chemical properties with the potential to be useful for diseases in which Hsp90 is implicated.

■ Cyclocondensation Reaction of Mesoionic 4-Trifluoroacetyl-1,3-oxazolium-5-olates with Hydroxylamine affording 6-Trifluoromethyl-5,6-dihydro-4H-1,2,4-oxadiazin-6-ols

Ryosuke Saijo, Ken-ichi Kurihara, Kazuki Akira, and Masami Kawase*

*Faculty of Pharmaceutical Sciences, Matsuyama University, 4-2 Bunkyo-cho, Matsuyama, Ehime 790-8578, Japan

Abstract

Mesoionic 4-trifluoroacetyl-1,3-oxazolium-5-olates (1) undergo tandem addition of hydroxylamine to afford 6-trifluoromethyl-1,2,4-oxadiazin-6-ols (3) in high yields.

■ Isoaurones from the Stem of Cassia siamea and Their Anti-Tobacco Mosaic Virus (Anti-TMV) Activity

Xue-mei Gao, Li-dan Shu, Li-ying Yang, Yan-qiong Shen, Ming-zhu Cui, Xue-mei 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 650031, China

Abstract

Two new isoaurones, siamaurones A and B (1-2), together with three known isoaurones (3-5) were isolated from the stems of Cassia siamea. The structures of 1-5 were elucidated by spectroscopic methods including 1D- and 2D-NMR techniques. Compounds 1-5 were evaluated for their anti-tobacco mosaic virus (anti-TMV) activity. As a result, compound 2 showed high anti-TMV activity with inhibition rate of 31.8%, which is higher than that of Ningnanmycin (26.5%). Compounds 1, 3, and 5 showed modest anti-TMV activity with inhibition rate of 15.2%, 16.4%, and 12.8%, respectively.

■ Synthesis of Some New 5-Dialkylaminomethylhydantoins and Related Compounds

Fumiko Fujisaki, Mayu Egami, Keiko Toyofuku, and Kunihiro Sumoto*

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

Abstract

In this paper, we describe the synthesis of new 5-dialkylaminomethyl-substituted hydantoin derivatives (3 and 9) from β-aminoalanines (1 or 6) and some chemical properties of the synthesized compounds. A synthetic trial for the preparation of a new twin-drug type molecule (12) is also described.

■ A New Synthesis of Amino Substituted Azolo[1,3,5]triazines via Reaction of N1,N1-Dimethyl-N2-azolylformamidines with Cyanamide

Dmitrii V. Kalinin, Svetlana A. Kalinina, and Anton V. Dolzhenko*

*School of Pharmacy, Curtin University of Technology, GPO Box U1987, Perth, Western Australia 6845, Australia

Abstract

The amino substituted triazine ring was annelated to aminoazoles using a new effective synthetic procedure. The method of preparation involved initial formation of azolylformamidines in the reaction of aminoazoles with N,N-dimethylformamide dimethyl acetal followed by the triazine ring closure with cyanamide affording therefore fused aminotriazines.

■ Synthesis of Indoles from o,β-Dinitrostyrenes via Indium/Acetic Acid-Mediated Reductive Heterocyclizations

Geunsoo Lee, Jaehwan Choi, Byung Min Lee, and Byeong Hyo Kim*

*Department of Chemistry, Kwangwoon University, 447-1, Wolgye-Dong Nowon-ku, Seoul, 139-701, Korea

Abstract

Reductive heterocyclization reactions of various 1-nitro-2-(2-nitroaryl)ethenes to indoles were investigated. In the presence of indium/AcOH in toluene or benzene, 1-nitro-2-(2-nitroaryl)ethenes were cyclized to give corresponding indoles in good yields.

■ The New Convenient Synthesis of Novel γ-Alkylidenebutenolides from 6-Aminopenicillanic Acid

Bin Yu, En Zhang, Yuan Fang, Xiao-nan Sun, Jing-li Ren, De-quan Yu,* and Hong-min Liu*

*New Drug Research & Development Center, School of Pharmaceutical Science, Zhengzhou University, Zhengzhou 450001, China

Abstract

Butenolides have good biological activity and serve as the important unit of pharmaceutical intermediates, of which γ-alkylidenebutenolides have gained wide attention over the last past decades particularly. A simple and practical method for the synthesis of butenolide 6 and its 5-substituted analogues 7a-t via vinylogous aldol reaction from 6-aminopenicillanic acid (6-APA) with the ratio of Z/E isomers between 1.1/1.0 and 1.0/0 under mild conditions in 6 steps was first reported. Besides, we also reported the methanolysis behaviors of azetidinone fused oxazoline derivatives. All the synthesized γ-alkylidenebutenolides are new and are currently being evaluated for their biological activities.

■ A Novel One-Step Synthesis of Benzo[b]furo[3,2-b]pyridines Having an Amino Group at the 4-Position from Benzo[b]furo[3,2-d][1,3]oxazine

Yukako Tabuchi, Yusa Kakumoto, Hitomi Uchimoto, Ikuo Kawasaki,* Yoshitaka Ohishi, and Kiyoharu Nishide*

*Faculty of Pharmaceutical Sciences, Mukogawa-Women's University, 11-68 Koushien Kyuban-Cho, Nishinomiya, Hyogo 663-8179,

Abstract

A novel one-step synthesis of benzo[b]furo[3,2-b]pyridines having an amino group at the 4-position from benzo[b]furo[3,2-d][1,3]oxazine by treatment of various amines is described.