HETEROCYCLES

■ Contents

■ First Total Syntheses of New Phenylpropanoid Lignans, (±)-Aglacin K Stereoisomer and (±)-Arborone

Masaki Takahashi, Koji Takada, Daisuke Matsuura, Kunihiko Takabe, and Hidemi Yoda*

*Department of Materials Science, Faculty of Engineering, Shizuoka University, Johoku 3-5-1, Naka-ku, Hamamatsu 432-8561, Japan

Abstract

An efficient and convergent process is described for the first preparation of new phenylpropanoid lignans, (±)-aglacin K stereoisomer and (±)-arborone, isolated from the stem bark of Algaia cordata and the stems of Piper arborescens, respectively. The key substituted tetrahydrofuran rings were constructed through chemoselective hydrogenation of functionalized lactol derivatives, which were in turn elaborated via requisite reverse stereoselective addition of organometallic reagent to the amide-aldehyde intermediates derived from a terpene lactone.

■ Synthesis, Structure, and Fluorescent Properties of [2.1.2.1]Metacyclophane Containing 2-(9-Anthralyl)imidazoles

Yousuke Nishiyama, Tsuyoshi Sawada,* Akiko Furuta, Aiko Sato, Kazuhumi Chifuku, Yutaka Kuwahara, and Hideto Shosenji

*Graduate School of Science and Technology, Kumamoto University, 2-39-1 Kurokami, Kumamoto-shi, Kumamoto 860-8555, Japan

Abstract

The Albright-Goldman oxidation of [2.1.2.1]metacyclophane ([2.1.2.1]MCP, 2) containing hydroxy groups at the bridge yielded [2.1.2.1]MCP tetraone 3. The subsequent condensation reaction of 9-anthraldehyde afforded 2-(9-anthryl)imidazole-annulated [2.1.2.1]MCP 3. The UV and fluorescence spectra and their influence of sodium and lithium ion of the [2.1.2.1]MCP 2-(9-anthryl)imidazole adduct 4 were reported.

■ Design, Synthesis, and Evaluation of Tetrahydroquinoline-Linked Thiazolidinedione Derivatives as PPARγ Selective Activators

HyeSung Kim, HyoJin Gim, Mihi Yang, Jae-Ha Ryu, and Raok Jeon*

*College of Pharmacy, Sookmyung Women’s University, 52 Hyochangwon-Gil, Yongsan-Ku, Seoul 140-742, Korea

Abstract

A series of tetrahydroquinoline-linked thiazolidinediones was designed and synthesized and their peroxisome proliferator activated receptor-γ (PPARγ) agonistic activities were evaluated. A number of analogs were revealed to have significant PPARγ agonistic activity. Among these compounds, compound 1h possessing N-heptyl moiety was found to be the most active in PPARγ transactivation assay. Molecular modeling suggested that the heptyl group of 1h appropriately interacts with hydrophobic amino acid residues in the active site of PPARγ.

■ Heterocycles [h]-Fused onto 4-Oxoqunoline-3-carboxylic Acid, III. Facile Synthesis and Antitumor Activity of Model Heterocycles [a]-Fused onto Pyrido[2,3-f]quinoxaline-3-carboxylic Acids

Mohammad Y. Abu Shuheil, Mona R. Hassuneh, Yusuf M. Al-Hiari, Ali M. Qaisi, and Mustafa M. El-Abadelah*

*Department of Chemistry, Faculty of Science, The University of Jordan, Amman, Jordan

Abstract

Direct interaction between 7-chloro-1-cyclopropyl-6-fluoro-8-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid and each of (S)-proline, (2S,4R)-4-hydroxyproline and (S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid in hot aqueous ethanolic NaHCO₃ yielded the corresponding optically pure N-(4-oxoquinolin-7-yl)-α-amino acids. The latter derivatives underwent reductive lactamization upon treatment with Na₂S₂O₄ in aqueous ethanol to afford moderate yields of the respective pyrido[2,3-f]quinoxaline-3-carboxylic acid [fused]- to tetrahydropyrrolo[1,2-a]-, tetrahydrohydroxylpyrrolo[1,2-a]- and tetrahydroisoquin- olino[2,3-a]heterocyclics 10-12, respectively. The antitumor activity against four human tumor cell lines showed that 10-12 displayed high levels of cytotoxicity as compared with Cisplatin. Interestingly, these compounds were more potent against breast carcinoma cell lines (MCF-7 and T-47D) than the lymphoid origin tumor cell lines (Jurkat and BHL-89). In particular, the (S)-proline derivative 10 exhibited preferential cytotoxicity to adherent cells (IC₅₀ = 0.5 μM), indicative of better potential in blocking the growth of solid tumors rather than the disseminated ones.

■ Synthesis and Characterization of Some Fused Tricyclic Spermidine Derivatives of Cyclotriphosphazene

Hanife Ibisoglu

*Department of Chemistry, Gebze Institute of Technology, Gebze 41400, Kocaeli, Turkey

Abstract

A number of derivatives of 6-chloro-2, 2-X₂-1, 3, 5, 7, 11, 16-hexa aza-4,6-diphosphatricyclohexadeca-2, 4, 6-triene {X=SPh, [OCH₂(CF₂)₂CH₂O]_0.5, pyr, NMe₂, NHPrⁿ, Ph, NHBu^t} have been synthesised using two different reaction routes (1, 2) giving rise to penta-substituted-mono-chloro-compounds. The remaining chlorine atom in these products was reluctant to react with neutral nitrogen nucleophiles. The structures of the compounds were determined by elemental analysis, mass spectrometry and by ¹H and ³¹P-NMR spectrocsopy.

■ Novel 2H-1,2,3-Triazole Sodium Complex from N-[2-Amino-1,2-dicyanovinyl]alkanamides

Amal Al-Azmi,* Paulson George, and Osman M. E. El-Dusouqui

*Chemistry Department, Kuwait University, P.O. Box 5969, Safat 13060, Kuwait

Abstract

Diazotization at 0 ^oC of N-[2-amino-1,2-dicyanovinyl]ethanamide 2a or propanamide 2b prepared from diaminomaleonitrile (DAMN) 1 using aqueous acetic acid and NaNO₂ solution furnished sodium complex 3. The X-ray structure of the complex 3 showed that it is a 1:1 mixture of the neutral 2H-triazole heterocycle 4ii and its anion deprotonated at the central (N) atom of the ring, together with a sodium counter ion and two coordinated water molecules. However, when the diazotization reaction was carried out in the presence of aqueous HCl, the product was 5-cyano-2H-[1,2,3]triazole-4-carboxylic acid amide monohydrate 4ii. Diazotization of DAMN 1 using aqueous HCl furnished 1H-1,2,3-triazole-4,5-dicarbonitrile 5, whereas with acetic acid there was no reaction, and hence no route analogous to that leading to complex 3. The structure of both complex 3 and the triazole monohydrate 4ii were solved using X-ray crystallography, and the compounds under study were fully characterized using spectroscopic techniques.

■ Novel and Efficient Synthesis of 5,8-Dimethyl-9H-carbazol-3-ol via a Hydroxydeboronation Reaction

Anna Caruso, Anne Sophie Voisin-Chiret, Jean-Charles Lancelot, Maria Stefania Sinicropi, Antonio Garofalo, and Sylvain Rault*

*Université de Caen Basse-Normandie, U. F. R. des Sciences Pharmaceutiques, Centre d’Etudes et de Recherche sur le Médicament de Normandie, 14032 Caen, France

Abstract

N-Protected carbazol-3-yl-boronic acid derivatives have been efficiently hydroxydeboronated under mild conditions by employing hydrogen peroxide. The method allows to easily obtain 3-hydroxycarbazoles as precursors of new analogs of the anticancer agent 9-hydroxyellipticine.

■ Synthesis and Structure of Thiacalix[4]arene Derivatives Bearing Thiazole Functional Groups at Lower Rims

Bang-Tun Zhao,* Zhen Zhou, and Zhen-Ning Yan*

*Department of Chemistry, Luoyang Normal University, Luoyang 471022, China

Abstract

The p-tert-butylthiacalix[4]arene (1) was firstly alkylated with 1, 3-dibromopropane and 1,4-dibromobutane to give thiacalix[4]arene derivatives (2a and 2b) in the presence of potassium carbonate, respectively. A series of p-tert-butylthiacalix[4]arene derivatives (3a, 3b, 4a, 4b) which append thiadiazole groups at the lower rims were easily synthesized in good yields by the reaction of tetrabromoalkoxythiacalix[4]arene intermediates 2 with 2-mercaptothiadiazole compounds in the presence of potassium carbonate. All new compounds were characterized by ¹H NMR, ¹³C NMR, IR, MS, elemental analysis and X-ray diffraction on single crystals of 2b, 3b.

■ Reaction of 3-Hydrazono-1,1,1-trifluoro-2-alkanones with Lawesson Reagent Accessing 6-Trifluoromethyl-3,6-dihydro-2H-[1,3,4]thiadiazines

Yasuhiro Kamitori,* Tomoko Sekiyama, and Etsuji Okada

*Department of Chemical Science and Engineering, Graduate School of Engineering, Kobe University, Kobe 657-8501, Japan

Abstract

The reaction of 3-dimethylhydrazono-1,1,1-trifluoro-2-alkanones (1) with Lawesson reagent affording 6-trifluoromethyl-3,6-dihydro-2H-[1,3,4]thiadiazines (4) was elucidated in detail. The results indicate [1,5]sigmatropic hydrogen shift from N-methyl group to thiocarbonyl carbon on 3-dimethylhydrazono-1,1,1-trifluoro-2-alkanethiones (5) should readily proceed as a key step in this cyclization reaction. Similar [1,5]sigmatropic hydrogen shift on selenium analogues of 1 as well as that on imines derived from 1 are also studied on the basis of molecular orbital calculations.

■ Preparation of 1,4-Bis(2-ethynyl-3-thienyl)benzenes as Versatile Spacers for Connection of Heterocycles

Kozo Toyota,* Yoichi Goto, Kazuyuki Okada, and Noboru Morita

*Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan

Abstract

Iodination of 1,4-di(3-thienyl)benzene gave 1,4-bis(2-iodo-3-thienyl)benzene, which was converted to 1,4-bis(2-ethynyl-3-thienyl)benzene. Novel 1,4-bis[2-(pyridylethynyl)-3-thienyl]benzene ligands containing the bis(ethynylthienyl)benzene spacer were prepared by Sonogashira reaction. Advantage of the spacer was demonstrated by introducing functionalized alkyl groups to the 5-position of the thiophene ring of 1,4-bis[2-(trialkylsilylethynyl)-3-thienyl]benzene.

■ Synthesis of 1-(3-Isoxazolyl)- and 1-(3-Pyrazolyl)azulene Derivatives via Methyl 1-(3-Dimethylamino-2-propenoyl)azulene-3-carboxylate

Dao-Lin Wang,* Jin-Jun Deng, Jiao Xu, and Kimiaki Imafuku*

*Department of Chemistry, Graduate School of Science and Technology, Kumamoto University, Kurokami, Kumamoto 860-8555, Japan

Abstract

Methyl 1-acetylazulene-3-carboxylate (1) reacted with N,N-dimethylformamide dimethylacetal (DMFDMA) to give enaminone (2), which reacted with hydroxylamine and hydrazines to yield methyl 1-(3-isoxazolyl)-azulene-3-carboxylate (3) and methyl 1-(3-pyrazolyl)azulene-3-carboxylates (5a-f), respectively. Compound (1) was also gave the products (3 and 5b) via oxime (4) and phenylhydrazone (6).

■ Asymmetric Formal Synthesis of (-)-Formoterol and (-)-Tamsulosin

Yongeun Kim, Lae-Sung Kang, Hyun-Joon Ha,* Seung Whan Ko, and Won Koo Lee*

*Department of Chemistry, Hankuk University of Foreign Studies, Yongin, 449-791, Korea

Abstract

Biologically important (2R)-2-amino-3-phenylpropanes consisted in commercial drugs including (R,R)-formoterol, and (R)-tamsulosin were prepared from chiral (2R)-aziridine-2-carboxylate without any chromatographic separation. Key reactions include regio- and stereoselective ring opening reaction of aziridin-2-yl-phenylmethanol and subsequent cyclization toward enantiopure 4,5-disubastitued oxazolidin-2-ones as synthetic intermediates.

■ Synthesis and Friedländer Reactions of 5-Amino-4-cyano-1,3-oxazoles

M. Carmo Carreiras,* Ana Eleutério, Catarina Dias, M. Alexandra Brito, Dora Brites, J. Marco-Contelles, and Elena Gómez-Sánchez

*Faculdade de Farmácia, Universidade de Lisboa, Av. das Forças Armadas, 1600-083 Lisboa, Portugal

Abstract

The synthesis of 2-substituted 5-amino-4-cyano-1,3-oxazoles (1-4, 6-11) and the Friedländer-type reaction of compounds 1, 3, 4 is described. Compounds 13-17 are tacrine (18) analogues provided by the Friedländer reaction. The anti-cholinesterase activity of compounds 13, 14, 16 and 17 has been investigated.

■ Synthesis of 1,3-Diepi-ED-71, a Biologically Important Diastereomer of 1α,25-Dihydroxy-2β-(3-hydroxypropoxy)vitamin D₃ (ED-71)

Ayako Fujiyama, Mai Kaneko, Keisuke Takahashi, Jun Ishihara, Susumi Hatakeyama, and Noboru Kubodera*

*Chugai Pharmaceutical Co., Ltd., 2-1-1, Nihonbashi-Muromachi, Chuo-ku, Tokyo 103-8324, Japan

Abstract

The synthesis of biologically important 1,3-diepi-ED-71, a diastereomer of 1α,25-dihydroxy-2β-(3-hydroxypropoxy)vitamin D₃ (ED-71) at the 1-position and 3-position of the A-ring using Trost’s coupling methodology is described.