HETEROCYCLES

■ Contents

■ Synthesis of Triazole, Indole, and Five or Six-Membered Saturated Heterocyclic Compounds

Yasunari Monguchi,* Yoshinari Sawama, and Hironao Sajiki*

*Laboratory of Organic Chemistry, Department of Pharmaceutical Sciences, Gifu Pharmaceutical University, 1-25-4 Daigakunishi, Gifu 501-1196, Japan

Abstract

Heterogeneously-catalyzed synthetic methods for the preparation of 1,2,3-triazoles, indolines, indoles, and saturated heterocyclic compounds, such as piperidine and pyrrolidine, are demonstrated. Triazoles are intermolecularly synthesized by the 1,3-dipolar cycloaddition of alkynes with azides using heterogeneous copper catalysts. Solvent-free triazole syntheses are also described. Inter- and intramolecular annulations as indole syntheses are summarized; e.g., a palladium on carbon (Pd/C)-catalyzed Yamanaka–Larock method affords 2- or 2,3-substituted indoles from 2-iodoaniline derivatives and mono- or di-substituted alkynes; an intramolecular Pd/C-catalyzed Buchwald–Hartwig reaction of 2-bromophenethylamine derivatives temperature-dependently affords indolines or indoles. Pd/C can also catalyze an intermolecular aromatic amination of bromoarenes with indoles to generate the corresponding N-arylindoles. The application of the hydrogenation technology using 10% Pd/C, 10% rhodium on carbon (Rh/C), or 10% ruthenium on carbon (Ru/C) as a catalyst is finally introduced for the synthesis of indole by the intramolecular hydrogenative N-alkylation of 2-cyanomethylaniline and piperidine, pyrrolidine, and tetrahydrofuran derivatives by the arene hydrogenation of pyrridine, pyrrole, and furan derivatives under relatively mild conditions, respectively.

■ Iriomoteolide-2a, a Cytotoxic 23-Membered Macrolide from Marine Benthic Dinoflagellate Amphidinium Species

Keiko Kumagai, Masashi Tsuda,* Atsunori Masuda, Eri Fukushi, and Jun Kawabata

*Center for Advanced Marine Core Research , Kochi University, Nankoku, Kochi 783-8502, Japan

Abstract

The first 23-membered macrolide, iriomoteolide-2a (1), was isolated from cultivated algal cells of a marine benthic dinoflagellate Amphidinium species. The structure was determined based on detailed analysis of 2D NMR data. The relative stereochemistries were assigned on the basis of coupling constants and ROESY data, and the absolute configurations were elucidated by analyzing the NMR data of the MTPA esters for 1 and its reduced product. Iriomoteolide-2a (1) exhibited potent cytotoxic activities in vitro and in vivo.

■ Synthesis, Characterization, and Biological Evaluation of Some Novel Glycosyl 1,3,4-Thiadiazole Derivatives as Acetylcholinesterase Inhibitors

Wei-wei Liu,* Qu-xiang Li, Da-hua Shi, Zhi-ling Cao, Feng-chang Cheng, Chuan-zhou Tao, Long Yin, and Xuan Wang

*School of Chemical Engineering, Huaihai Institute of Technology, Lianyungang City, Jiangsu Province 222005, China

Abstract

The corresponding 4-substituted glycosyl thiosemicarbazide derivatives (6a-6l) were obtained by the reaction of glycosyl isothiocyanate 4 with various hydrazides. Further cyclization with the system of p-TsCl/TEA led to the formation of N-glycosyl-5-substituted 1,3,4-thiadiazole-2-amine (7a-7l). Subsequent removal of the acetyl groups were conducted using the system of NaOMe/ MeOH. The chemical structures of all new products were confirmed by IR, 1H NMR and ESI-HRMS. The acetylcholinesterase (AChE) inhibitory activities of those compounds were tested by Ellman’s method. Among them, the compound 8h possessed the best acetylcholinesterase-inhibition activity with IC50 of 18.38 ± 0.89 µM.

■ Synthesis of Some New Isoindoline-1,3-dione Based Heterocycles

Islam H. El Azab* and Mohamed R. E. Aly

*Department of Chemistry, Faculty of Science, Aswan University, Aswan 81528, Egypt

Abstract

2-(4-((4-Oxothiazolidin-2-ylidene)amino)-1-phenyl-1H-pyrazole-3-carbonyl)-isoindoline-1,3-dione 7 was prepared as new three−pharmacophoric−motif key intermediate. Compound 7 was incorporated in a series of manipulations including cyclocondensation reactions to afford a series of four−pharmacophoric−motif conjugates 9, 11, 12, 15, 16, 19 and 21 in good yields. The newly synthesized compounds were characterized by IR, NMR, MS and elemental analyses.

■ Design, Synthesis and Evaluation of Nitric Oxide-Releasing Derivatives of N-(n-Butyl)matrinic Acid And N-(n-Butyl)matrinol as Anti-Hepatocellular Carcinoma Agents

Ya-Xian Wu, Jun-Kai Huang, Lei-Lei Gao, Li-Qin He,* Peng Huang,* and Xiao-Shan Wang

*School of Pharmacy, Anhui University of Chinese Medicine, Yaohai District of Hefei City, Anhui Province, Mo Dian Xiang Anhui University of Chinese medicine shaoquan Lake Campus, 230012, China

Abstract

A series of novel furoxan-based derivatives of N-n-butyl matrinic acid (9a-m) and N-n-butyl matrinol (10a-m) were synthesized and their anti-human hepatocellular carcinoma (HCC) activities were evaluated. All derivatives displayed potential inhibition of HepG2 cell proliferation. Among these derivatives, compounds 9a-f, 9j and 10b, 10g-i (IC50: 0.69−4.66 μM) were superior to 5-FU (IC50: 5.82 μM). The further study showed that compounds 9a, 9c and 9f had higher antiproliferative activity on human hepatocellular carcinoma cells Bel-7402 (IC50: 2.55-3.26 μM) and SMMC-7721 (IC50: 5.26-5.79 μM).

■ Synthesis and Photophysical Properties of Some Dithienylbenzo[c]thiophene Derivatives

Maurizio D'Auria,* Ambra Guarnaccio, Rocco Racioppi, Antonio Santagata, and Roberto Teghil

*Departament of Science, Università della Basilicata, viale dell'Ateneo Lucano 10, 00137, Italy

Abstract

The synthesis of a new fullerene - dithienylbenzo[c]thiophene (DTBT) - fullerene triad has been reported. The synthetic scheme provides the synthesis of DTBT unit, a Sonogashira reaction to introduce two acetylenic groups and the coupling with fullerene. The product showed an absorption at 485 nm and a fluorescence band at 575 nm. Treatment of 5-(3-(5-ethynyl-2-thienyl)benzo-[c]-1-thienyl)thiophene-2-carbaldehyde with LHDMS gave a dimeric product that showed an absorption at 475 nm and a fluorescence band at 595 nm. Furthermore, 5-(3-(2-thienyl)benzo[c]-1-thienyl)thiophene-2-carbaldehyde was treated with hydrazine to give the corresponding adduct that showed an absorption at 480 nm and a fluorescence band at 605 nm.

■ Enantioselective Total Synthesis of (+)-Bucidarasins A and C

Kenji Usui and Masahisa Nakada*

*Department of Chemistry and Biochemistry, School of Advanced Science and Engineering, Waseda University, 3-4-1 Okubo, Shinjuku-ku, Tokyo 169-8555, Japan

Abstract

In this paper, the first total synthesis of (+)-bucidarasins A and C is described. The chiral starting material was successfully obtained via reduction using a CBS catalyst and selective mono-TBS ether formation of trans-2-benzyloxymethyl-2-methylcyclohexane-1,3-diol, which was crucial to the successful enantioselective total synthesis of (+)-bucidarasins A and C. A synthetic approach towards (+)-bucidarasin C, based on the Barton-McCombie protocol, using V-70 as a radical promoter at low temperature to remove the C6-hydroxy moiety is also described.

■ Design, Synthesis, and Biological Activity Evaluation of Thiazolidinones Containing Alkynyl and Alkenyl Furans for Disrupting Protein–Protein Interactions between HIF-1α and p300

Norihiko Takeda, Tomoyo Taguchi, Takeshi Nakajima,* and Mitsuyoshi Azuma

*Senju Laboratory of Ocular Sciences, Senju Pharmaceutical Co., Ltd., 1-5-5, Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan

Abstract

Based on the structure of the potent hypoxia-inducible factor (HIF) inhibitor 1, a novel series of furanylidene-thiazolidinones 6 were designed and synthesized using Sonogashira or Suzuki–Miyaura cross-couplings, and subsequent Knoevenagel condensation. In particular, derivatives 6aA, 6cA, 6dA, 6hA, 6iA, and 6cC, bearing an alkynyl or alkenyl group on the furan ring, exhibited four- to five-fold higher activities than 1. These potent compounds will serve as leads for the development of novel small molecules for targeting the HIF-1α/p300 complex.

■ Modification of 3,5-Dioxo-2-phenyl-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile via Mitsunobu and Chan-Lam Coupling Reaction

Tomáš Ručil, Martin Grepl, and Petr Cankař*

*Department of Organic Chemistry, Palacký University, 17. listopadu 12, 77146 Olomouc, Czech Republic

Abstract

Modification of 3,5-dioxo-2-phenyl-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile at position 4 is described. Alkylations were carried out under Mitsunobu reaction conditions in DCM or dioxane with alcohols containing tertiary amines, pyridine and imidazole heterocyclic systems, and Boc-protected amino groups. The scope of modifications was extended with arylations performed via Chan-Lam coupling reaction using copper(I) oxide as a catalyst in a DMF solution at room temperature. In order to further extend peripheral structural diversity the nitrile group at position 6 of several alkylated 1,2,4-triazines was transformed into the amidoxime functionality.

■ Isoprenylated Flavones from Garcinia bracteata and Their Anti-Tobacco Mosaic Virus Activity

Yuehong Yang,1 Limei Li,2 Jie Lou,2 Yang Cheng,1 Yede Wang,2 Duntao Shu,1 Lei Shi,1 Xue-Mei Gao,2 Ping Ning,1,* and Qiufen Hu2,*

*1 Faculty of Environmental Science and Engineering, Kunming University of Science and Technology, Kunming 650500, China; 2 Key Laboratory of Chemistry in Ethnic Medicinal Resources, Yunnan University of Nationalities, Kunming 650500, P. R. China

Abstract

Two new isoprenylated flavones, bracteflavones A and B (1 and 2), together with four known isoprenylated flavones (3-6) were isolated from the twigs of Garcinia bracteata. Their structures were elucidated by spectroscopic methods, including extensive 1D- and 2D- NMR techniques. The anti-tobacco mosaic virus (anti-TMV) activities of compounds 1-6 were evaluated, and the results revealed that 1-6 showed potential anti-TMV activity with inhibition rates in the ranges of 17.6-24.3%, respectively.

■ Xanthones from the Fermentation Products of an Endophytic Fungus Phomopsis sp.

Lin Yuan,1 Wenzhong Huang,1 Kun Zhou,2 Yuede Wang,2 Wei Dong,2 Jie Lou,2 Limei Li,2 Gang Du,2 Haiying Yang,2 Yinhai Ma,1,* and Qiufen Hu2,*

*1 Chemical Science and Technology Department, Kunming University, Kunming 650214, P. R. China; 2 Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs Commission & Ministry of Education, Yunnan Minzu University, 650031, P. R. China

Abstract

Three new xanthones, dalienxanthones A-C (1-3), together with three known analogues (4-6), were isolated from the fermentation products of an endophytic fungus Phomopsis sp. cultivated on Paris daliensis. Their structures were identified by extensive spectroscopic techniques, especially 2D-NMR. The cytotoxicity activities of all compounds were evaluated against five cancer cell lines including NB4, A549, SHSY5Y, PC3, and MCF-7. Compounds 3 and 4 showed cytotoxicities against SHSY5Y cells with IC50 values of 3.8 and 3.5 μM, respectively. The other compounds also showed cytotoxicity for some tested cell lines with IC50 values between 4.6 - 9.2 μM.

■ Selective Synthesis of 2,3-Dihydrofuran or Cyclopropane Derivatives via Tandem Reaction of β,γ-Unsaturated α-Ketoesters with Halides

Dong Cheng,* Xiangzhen Meng, Guoxu Qin, and Yimin Hu*

*School of Chemical Engineering and Life Science, Chaohu College, Chaohu Anhui, Peoples 238000, China

Abstract

2,3-Dihydrofuran or cyclopropane derivatives were prepared with high selectivity via reaction of β,γ-unsaturated α-ketoesters with α-phenacyl bromide in different conditions.