HETEROCYCLES

■ Contents

■ Three New Synthetic Methods for the 1,2,3,3a,8,8a-Hexahydropyrrolo[2,3-b]indoles Having an Alkoxy Group at the 3a-Position

Takako Iwaki, Fumio Yamada, Shiho Funaki, and Masanori Somei*

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

Abstract

Three methods have been newly developed for the synthesis of 1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indoles. Employing them, 3a-chloro-, 3a-bromo-, 3a-hydroxy-, and various 3a-alkoxy-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indoles are now readily available.

■ Synthetic Models Related to Furanocoumarin — CYP3A4 Interactions. Synthesis of Furanocoumarin Dimers that Have Inhibitory Effects on Activity of Human CYP3A4

Kazuaki Oda,* Hitomi Kasai, Yuki Yamaguchi, Teruki Yoshimura, Keiji Wada, Minoru Machida, and Naozumi Nishizono*

*Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido 061-0293, Japan

Abstract

Synthesis of a series of furanocoumarin dimers that have inhibitory effects on the activity of human cytochrome P450 (CYP) 3A4 is described. The reported furanocoumarin dimers paradisins A and B from grapefruit juice showed potent CYP3A4 inhibition with an IC₅₀ value of 0.07 μM. Synthetic furanocoumarin dimer (10), which is more stable and accessible than paradisins, exhibited comparable activity against CYP 3A4 (IC₅₀ = 0.02 μM).

■ High Throughput Synthesis of Pyrazolopyrimidines via Copper-catalysed Cyclization, and X-Ray Study

Raid J. Abdel-Jalil,* Monther Khanfar, Samer Al-Gharabli, Mustafa M. El-Abadelah, Klaus Eichele, Muhammad Usman Anwar, and Wolfgang Voelter*

*Institute of Physiological Chemistry, University of Tuebingen, Hoppe-Seyler-Srasse 4, D-72076 Tuebingen, Hoppe-Seyler-Srasse 4, D-72076 Tuebingen, Germany

Abstract

A rapid and easy high-yielding synthesis of pyrazolopyrimidinones in the presensce of copper chloride is described. To fully confirm the structure of a Viagra® intermediate, the X-Ray structure of 5-(2-ethoxyphenyl)-1-methyl-3-propyl-1,6-dihydropyrazolo[4,3-d]pyrimidin-7-one (2a) was determined.

■ A Convenient Preparaion of a Series of 2-Aryl-substituted Imidazolidines through Diamine Transfer Reaction

Donghong Li, Yongbin Zhang, Chizhong Xia, and Wei Guo*

*School of Chemistry and Chemical Engineering, Shanxi University, Taiyuan 030006, China

Abstract

A series of 2-aryl-substituted imidazolidines were prepared through the simple diamine transfer reactions between 2-alkyl-substituted imidazolidines and aromatic aldehydes under the catalysis of n-butylamine.

■ A New α-Glucosidase Inhibiting Dithiadiazetidin Derivative from Symplocos racemosa

Muhammad Athar Abbasi, Viqar Uddin Ahmad,* Muhammad Zubair, Muhammad Abid Rashid, Shamsun Nahar Khan, Umar Farooq, M. Iqbal Choudhary, and Klaus-Peter Zeller

*International Centre for Chemical Sciences, H. E. J. Research Institute of Chemistry, University of Karachi, Karachi-75270, Pakistan

Abstract

The phytochemical investigation of the n-butanol soluble fraction of Symplocos racemosa Roxb. resulted in the isolation of a new dithiadiazetidin derivative; symploate (1). Its structure was established through various 1D and 2D NMR techniques together with high-resolution mass spectrometric techniques and spectral evidences. The symploate (1) showed moderate inhibitory activity against α-glucosidase in a concentration-dependent fashion with an IC₅₀ value of 691.1 ± 3.29 μM.

■ Selective Reduction of Nitrocinnamoylfumagillols with α,β-Unsaturated Ester Using Borohydride Exchange Resin (BER)-Nickel Acetate

Hong Woo Lee,* Joong Bok Ahn, Jung Hwa Lee, Sung Kwon Kang, Soon Kil Ahn, and Sang Joon Lee

*Chemical Process Development Laboratories, Chong Kun Dang Research Institute, Chonan P.O. Box 74, Chonan, 330-831, Korea

Abstract

Borohydride Exchange Resin (BER) — nickel acetate system readily reduces nitrocinnamoylfumagillols to the corresponding amines in excellent yields, high chemoselectivity, and simple procedure. Especially, this system tolerates two epoxides (spiro-epoxide and the one on C4 alkene side chain) and the α,β-unsaturated ester moiety at C6 on the fumagillol.

■ Reaction of Polychloroacetamides with Amines: Reductive Dechlorination and Aziridine Formation

Takeaki Naito,* Ayako Saito, Masafumi Ueda, and Okiko Miyata

*Kobe Pharmaceutical University, Motoyamakita, Higashinada, Kobe 658-8558, Japan

Abstract

Treatment of trichloroacetamides with amines undergoes reductive dechlorination via single-electron transfer process to afford dichloroacetamides in good yields. Reaction of trichloro- and dichloroacetamides with DBU provides a new synthetic method of aziridinopyrrolidines.

■ Synthesis and Antimicrobial Activity of Some New Pyridazine Derivatives

Maria D. Caprosu, Roxana M. Butnariu, and Ionel I. Mangalagiu*

*Department of Organic and Biochemistry, “Al. I. Cuza” University Iasi, 11 Carol I Bd., 700506 Iasi-6, Romania

Abstract

Five new pyridazine derivatives (1 salt and 4 pyrrolopyridazine cycloadducts) were prepared and tested in vitro as antimicrobial compounds. Some of them have proved to have a remarkable activity against different micro organisms (germs and fungi). The influence of microwave irradiation concerning cycloaddition reactions of pyridazinium ylides was studied. Stereo- and regiochemistry involved in these reactions are also discussed.

■ New Syntheses of 1-Benzoyltetrahydroisoquinoline Derivatives Using Polymer-supported Bis(trifluoroacetoxyiodo)benzene

Hsin-Yu Huang, Rei-Sheu Hou, Huey-Min Wang, and Ling-Ching Chen*

*Graduate Institute of Pharmaceutical Sciences, Kaohsiung Medical University, 100 Shin Chuan 1st Rd., Kaohsiung 80708, Taiwan, R.O.C.

Abstract

The reaction of N-benzenesulfonyl-β-phenethylamines with α-benzoyl sulfides using polymer-supported bis(trifluoroacetoxyiodo)benzene (PSBTI) gives moderate to good yields of the corresponding 1-benzoyltetrahydroisoquinoline derivatives.

■ Regio- and Stereoselective Cycloadditions and Further Transformations of Azomethine Imine Derivatives of Fused [1,2,4]Triazines

Csilla Gróf, Zsuzsanna Riedl, György Hajós,* Orsolya Egyed, Antal Csámpai, and Branko Stanovnik

*Institute of Chemistry, Chemical Research Center, Hungarian Academy of Sciences, H-1525 Budpest II, Pusztaszeri ut 59-67, P.O. Box 17, Hungary

Abstract

1,3-Dipolar cycloadditions of azomethine imine derivatives of dihydro[1,2,4]triazolo[3,4-c]benzo[1,2,4]triazines with asymmetric dienophiles proceeded in regio- and stereoselective manner. Cycloadditions with fumaronitrile resulted in a mixture of epimeric products, which under more forced conditions underwent ring opening reaction. Comparison of results obtained with cycloadditions with fumaric and maleic acid derivatives provided experimental support for the suggested epimerization. The dipolar cycloadditions were extended for isocyanates and isothiocyanates to yield new fused triazolinones and triazoline thiones.

■ Synthesis of 2-Selenoxo-1,3-thiazolidin-4-ones and 2-Selenoxo-1,3-thiazinan-4-ones from Isoselenocyanates

Geoffroy L. Sommen, Anthony Linden, and Heinz Heimgartner*

*Institute of Organic Chemistry, University of Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland

Abstract

2-Selenoxo-1,3-thiazolidin-4-ones (selenorhodanines) (7a-h) and 2-selenoxo-1,3-thiazinanes (8a-c) can easily be synthesized in a one-pot procedure from aryl isoselenocyanates and α- and β-mercapto carboxylic acids, respectively.

■ Allylation of Meldrum’s Acids by Allylic Alcohols Using Tetrakis[triphenylphosphine]palladium(0) Catalysts

Rei-Sheu Hou,* Huey-Min Wang, Hsin-Yu Huang, and Ling-Ching Chen*

*Graduate Institute of Pharmaceutical Sciences, Kaohsiung Medical University, 100 Shin Chuan 1st Rd., Kaohsiung 80708, Taiwan, R.O.C.

Abstract

Meldrum’s acids can be allylated by allylic alcohols using tetrakis[triphenylphosphine]palladium(0) [(PPh₃)₄Pd] as a catalyst in benzene at 80 °C without prior activation of allylic hydroxy group.

■ Total Synthesis of Styelsamine C, and Formal Synthesis of Norsegoline

Shinsuke Nakahara* and Akinori Kubo

*Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan

Abstract

Two fused tetracyclic aromatic alkaloids, styelsamine C (3) from the ascidian Eusynstyela latericius, and norsegoline (5) from the marine tunicate Eudistoma sp., were synthesized using a biaryl cross-coupling reaction.

■ The Library of Cinchona Alkaloids-1,2,3-triazole Derivatives: Structure and Facile Access by “Click Chemistry”

Karol Kacprzak,* Michal Migas, Agnieszka Plutecka, Urszula Rychlewska, and Jacek Gawronski

*Department of Chemistry, Adam Mickiewicz University, ul. Grunwaldzka 6, 60-780 Poznán, Poland

Abstract

New Cinchona alkaloids-1,2,3-triazole derivatives library was prepared readily and efficiently using Huisgen 1,3-dipolar cycloaddition of 9-azido substituted Cinchona alkaloids and various terminal and disubstituted alkynes (click chemistry). Spectroscopic, X-Ray, and molecular modelling data show that these derivatives maintain the conformation of the parent alkaloids.

■ 5H-[1,2,5]Selenadiazolo[3,4-f]indole as a Masked Form of 5,6-Diaminoindole

Jealux Okwakol and Spiros Grivas*

*Department of Biosciences, Karolinska Institutet, Södertörn University College, Novum Research Park, SE-141 57 Huddinge, Sweden

Abstract

6-Nitroindoline (9) was converted into 1-acetyl-5,6-aminoindoline (12) which was then transformed via selenadiazoles (13–15) to the title selenadiazoloindole (4) by two alternative 3-step synthetic sequences in 38–42% overall yield from 12. The unstable 5,6-diaminoindole (16) was then obtained by reductive deselenation of 4. Fully assigned ¹H, ¹³C and ⁷⁷Se NMR spectral data for the title indole (4) and ⁷⁷Se NMR spectral data for the intermediate selenadiazoles (13–15) are presented.

■ Syntheses and Crystal Structures of Diethylated Daidzein Sulfonates

Zun-Ting Zhang* and Qiu-Ya Wang

*School of Chemistry and Materials Science, Shaanxi Normal University, Xi’an 710062, China

Abstract

The water soluble derivatives of daidzein, sodium 4’,7- diethoxyisoflavone-3’-sulfonate (1), magnesium 4’,7-diethoxyisoflavone-3’- sulfonate (2) and zinc 4’,7-diethoxylisoflavone-3’-sulfonate (3) have been synthesized. 1 was characterized by ¹H NMR and IR spectra, 2 and 3 were determined by single-crystal X-Ray diffraction analysis. The molecular structural characteristic of 2 is similar to that of 3. Their molecular contents are [Mg(H₂O)]₆(X)₂·8H₂O and [Zn(H₂O)]₆(X)₂·8H₂O (X=C₁₉H₁₇O₄SO₃^-), respectively. Two isoflavone skeletons of them have two different conformations. Twelve H atoms of six coordinated water molecules form hydrogen bonds with four oxygen atoms of sulfo-groups of two isoflavone skeletons and eight oxygen atoms of eight lattice water molecules. In addition, the π-π stacking interaction exists between isoflavone skeletons in the crystal structure of 2 and 3, which together with many kinds of hydrogen bonds lead to supramolecular formation with a three-dimensional network structure.

■ Microwave-assisted and Efficient One-Pot Synthesis of Substituted 1,2,4-Triazoles

Daliang Li, Hongli Bao, and Tianpa You*

*Department of Chemistry, University of Science and Technology of China, 96 Jinzhai Road, Hefei 230026, China

Abstract

An efficient microwave-assisted one-pot and three-component synthesis of substituted 1,2,4-triazoles has been achieved utilizing substituted primary amines.

■ New Coumarins from the Ailanthus altissima

Seon Woo Hwang, Jong Rok Lee, Jun Lee, Hyun Sook Kwon, Min Suk Yang, and Ki Hun Park*

*Department of Chemistry, Division of Applied Life Science, Gyeongsang National University, 900, Gaja-Dong, Chinju, 660-701, Korea

Abstract

Two new coumarin derivatives were isolated together with three known coumarins, artelin (3), isofraxidin (4), and scoploetin (5) from the bark of Ailanthus altissima (Simaroubaceae). New coumarin derivatives were elucidated as terpenylated coumarins, named altissimacoumarin A (1) and altissimacoumarin B (2), respectively. trans-Configuration of between C-2’ and C-9’ in compound (1) was clearly confirmed by NOESY experiments.

■ A Practical Synthesis of 8-Hydroxyacyclovir and 9-(Carboxymethoxymethyl)guanine, Metabolites of Acyclovir

Teruo Kutsuma, Yasuo Sakai, Hiroyuki Ouchi, Noriaki Shiina, Takehiro Yamagishi, Shiroshi Shibuya, and Tsutomu Yokomatsu*

*School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan

Abstract

Improved methods for the synthesis of 8-hydroxyacyclovir and 9-(carboxymethoxymethyl)guanine, metabolites of acyclovir, were examined. The methods were found to be useful for practical preparation of 8-hydoxyacyclovir and 9-(caboxymethoxymethyl)guanine of high purity. Careful spectroscopic analysis of 8-hydroxyacyclovir in DMSO-d₆ suggested that it may be exist in an 8-oxo tautomer rather than an 8-hydroxy tautomer under the solution conditions.

■ Synthesis of 2,4-Diarylimidazoles through Suzuki Cross-coupling Reactions of Imidazole Halides with Arylboronic Acids

Ingo Langhammer and Thomas Erker*

*Department of Medicinal/Pharmaceutical Chemistry, University of Vienna, Althanstraße 14, A-1090 Vienna, Austria

Abstract

The Suzuki coupling, a Pd-catalyzed cross-coupling reaction of a boronic acid with an aryl halide, was used to prepare several 2,4-diarylimidazoles. Iodinated and brominated imidazoles (3) and (9) proved to be suitable aryl halides for Suzuki coupling. These imidazole halides readily reacted with phenyl-, naphthyl- and biphenylboronic acids under Suzuki conditions to give arylated imidazoles.

■ An Efficient Synthesis of Bergapten

Kazuaki Oda,* Naozumi Nishizono, Yukio Tamai, Yuki Yamaguchi, Teruki Yoshimura, Keiji Wada, and Minoru Machida

*Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido 061-0293, Japan

Abstract

An efficient synthesis of the linear furanocoumarin, bergapten, is reported. In order to avoid the formation of the angular furanocoumarin, we have adopted iodine as protecting group at the 8 position of the coumarin ring.

■ Tautomerization of 3a,7a-Dihydroindole-2,3,3a,4-tetracarboxylate

Kyu Ok Jeon, Ji Sook Yu, and Chang Kiu Lee*

*Department of Chemistry, Kangwon National University, Chuncheon, Kangwon 200-701, Korea

Abstract

Tetramethyl 3a,7a-dihydroindole-2,3,3a,4-tetracarboxylate which is a 1:2 adduct of pyrrole with dimethyl acetylenedicarboxylate dissolved in various solvents underwent tautomerization to 3a,7a-dihydroindolenine esters. Acid or base externally added to the pure solvents promotes the isomerization.

■ Synthetic Study toward Pancracine

Meng-Yang Chang,* Hua-Ping Chen, Chun-Yu Lin, and Chun-Li Pai

*Department of Applied Chemistry, National University of Kaohsiung, No. 700 Kaohsiung University Rd., Nan-Tzu District, Kaohsiung 811, Taiwan, R.O.C.

Abstract

A synthetic study toward pancracine (2) has been established starting from trans-(2S,4R)-4-hydroxyproline (1).

■ Recent Progress of Halogen-Dance Reactions in Heterocycles

Xin-Fang Duan* and Zhan-Bin Zhang

*Department of Chemistry, Beijing Normal University, Beijing, 100875, China

Abstract

This paper summarizes recent progress of halogen-dance reactions and its applications in heterocycles.