HETEROCYCLES

■ Viridobrunnines A and B, Antimicrobial Phenoxazinone Alkaloids from A Soil Associated Streptomyces sp.

Xiu Mei Zhang, Xu Liu, Zhe Wang, Zhen Hua Tian, and Wei Dong Xie*

*Department of Pharmacy, Marine College, Shangdong University at Weihai, Wenhua Xilu 180, Weihai 264209, China

Abstract

Chemical investigation of a Streptomyces sp. strain designated A1302 isolated from soil sample led to the discovery of two new phenoxazinone alkaloids, viridobrunnines A and B (1 - 2), along with two known analogues exfoliazone (3) and chandrananimycin D (4). Their structures were established by means of spectroscopic methods. The antibacterial and antifungal activity of isolated compounds was assayed. Viridobrunnine B (2) exhibited potent antibacterial activity against Bacillus subtilis with inhibition zone from 13 mm to 15 mm.

■ Recent Developments of Free-Radical Substitutions of Heteroaromatic Bases

Francesco Minisci,* Elena Vismara, and Francesca Fontana

*Dipartimento di Chimica, Politecnico di Milano, Piazza Leonardo da Vinci 32, 20133 Milano, Italy

Abstract

The most recent mechanistic and synthetic aspects of the substitution of protonated heteroaromatic bases by nucleophilic carbon-centered radicals are reviewed. From mechanistic point of view the following aspects are discussed; i ) Structurereactivity relationship; i i ) Rearomatization of the radical adducts; iii) Solvent and isotope effects; iv) Overlap area with ionic reactions. The synthetic developments concern the following topics: i) Selectivity with carbonyl radicals; ii) Alkyl iodides as sources of alkyl radicals; iii) Alkylation by carboxylic acids; iv) Vinylation by olefins; v) Oxyalkylation by ethers; vi) Catalytic processes; vii) Substitution with strongly nucleophilic radicals.

■ Survey of Oxygenated 2,11-Cyclized Cembranoids of Marine Origin

Patrick Bernardelli and Leo A. Paquette*

*Evans Chemical Laboratories, The Ohio State University, Columbus, OH 43210, U.S.A.

Abstract

The structure, source, and biological activities of the many known members of the four classes of oxygenated 2,11-cyclized cembranoid natural products are compiled in tabular form. The cladiellins, briarellins, asbestinins, and sarcodictyins have been purposefully organized to highlight biological activity interrelationships.

■ Brevisulcatic Acids from a Marine Microalgal Species Implicated in a Toxic Event in New Zealand

Raku Irie, Rina Suzuki, Kazuo Tachibana, Patrick T. Holland, D. Tim Harwood, Feng Shi, Paul McNabb, Veronica Beuzenberg, Fumiaki Hayashi, Huiping Zhang, and Masayuki Satake*

*Department of Chemistry, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan

Abstract

Ladder-frame polyethers, known as brevisulcatic acids (BSXs) -1 (1), -2 (2), -4 (3), -5 (4) and -7 (5), were isolated from the dinoflagellate Karenia brevisulcata as potential causative toxins of a harmful algal event in New Zealand in 1998. The structures of 2, 4, and 5 were elucidated in this study. Brevisulcatic acids possessed a common fused nine ether-ring backbone, with a size and sequence determined to be 8/6/8/9/7/7/6/6/6. Rings B, C, H, I and J of the brevisulcatic acids were similar to those of brevetoxin A, a well-known polyether toxin. BSX-5 (4) had a γ-lactone as the 5-membered A-ring, analogous to brevetoxin A, while in BSX-2 (2) and BSX-7 (5) the lactone was present in its seco-acid form. In addition to this backbone variation, there were also some structural difference in side-chain substituents, with 2 and 4 having a 2-methylenepropionic acid unit, and 5 a 2-methylenepropanol unit. Cytotoxicity of 4 against neuroblastoma cells indicated that not only the structures but also activity of brevisulcatic acids are similar to those of brevetoxin A. This indicates that brevisulcatic acids potentially played a significant role in the toxicity observed during the only documented Karenia brevisulcata bloom to date.

■ A Highly Efficient Synthetic Route to (-)-Furaquinocin C

Amos B. Smith, III*, José Pérez Sestelo, and Peter G. Dormer

*Department of Chemistry, University of Pennsylvania, 231 South 34th Street Philadelphia, PA 19104, U.S.A.

Abstract

The first total synthesis of (-)-furaquinocin C, a member of the furaquinocin family of cytotoxic antibiotics, has been achieved. Central features of the successful synthetic strategy include Diels-Alder construction of the furanonaphthoquinic skeleton and sequential cuprate-mediated conjugate additions to an α,β-unsaturated lactone. The synthetic route proved remarkably efficient requiring only six steps from (R)-(+)-angelicalactone, and utilizing a mere four reaction vessels. This stereospecific construction of (-)-furaquinocin C confirms earlier assignments of absolute and relative stereochemistry for the furaquinocins and also constitutes completion of a formal synthesis of (-)-furaquinocin F.

■ Curriculum Vitae

Ekkehard Winterfeldt

*Institute of Organic Chemistry, University of Hannover, Schneiderberg 1B, D-30167 Hannover, Germany

■ Tuning the Solubilities of Bis-triazinylphenanthroline Ligands (BTPhens) and Their Complexes

Dominic M. Laventine, Ashfaq Afsar, Michael J. Hudson, and Laurence M. Harwood*

*Department of Chemistry, University of Reading, Reading RG6 6AD, U.K.

Abstract

A series of bis-triazinylphenanthroline ligands (BTPhens) was synthesized by modifying the triazine substituents. It was found that varying these substituents altered the solubilities of the ligands in a number of non-polar solvents. Thus C5-BTPhen showed significantly higher solubility in octanol than C1-BTPhen. The high solubility of C5-BTPhen and its complexes was exploited to facilitate the NMR titration experiments. These experiments shown that the dominant species in solution were the 1:2 complexes [Ln(III)(BTPhen)2], even at high Ln concentrations, and that the relative stability of the 2:1 to 1:1 BTPhen-Ln complexes varied with different lanthanides. C5-BTPhen therefore shows considerable promise for a once-through selective actinide separation process.

■ Multigram-Scale and Column Chromatography-Free Synthesis of L-Azetidine-2-carboxylic Acid for the Synthesis of Nicotianamine and Its Derivatives

Tomohiro Takaishi, Kyosuke Wakisaka, Christopher J Vavricka, Hiromasa Kiyota, and Minoru Izumi*

*Graduate School of Environmental and Life Science, Okayama University, 1-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530, Japan

Abstract

Multigram-scale synthesis of L-azetidine-2-carboxylic acid from L-aspartic acid was achieved in 13 conventional synthetic steps, without the need for purification by silica-gel column chromatography and expensive reagents. Nicotianamine and its fluorescence-labeled derivatives could be obtained from this synthetic strategy.

■ Stereoselective Aza-Henry Reaction of 3-Nitro-dihydro-2(1H)-quinolones with N-Boc-Aldimines under the Catalysis of Chiral Ammonium Betaines

Daisuke Uraguchi, Masahiro Torii, Kohsuke Kato, and Takashi Ooi*

*Institute of Transformative Bio-Molecules (WPI-ITbM) and Department of Applied Chemistry, Graduate School of Engineering, Nagoya University, Nagoya 464-8601, Japan

Abstract

A highly enantioselective aza-Henry reaction between 3-nitro-dihydro-2(1H)-quinolones and N-Boc-aldimines was developed by using a chiral ammonium betaine as a catalyst. This protocol provides a direct synthetic method for accessing hydroquinoline derivatives possessing a tetrasubstituted stereogenic center at the C3 position and casts light on the utility of the α-functionalization of dihydroquinolones.

■ Addition of Phthalimidonitrene to Substituted Indoles

Perumal Raja Kumar

*Department of Chemistry, University of Madras, Madras 600 025, India

Abstract

The aziridine 2a obtained by the addition of phthalimidonitrene to N-phenylsulphonylindole was treated with methanolic potassium hydroxide to give desulphonated indole and quinazoline. The aziridine 2b and 2c derived from phthalimidonitrene and 2-methylindole or 2-phenylindole were treated with dimsyl anion to give 2-methylquinazoline and 2-phenylquinazoline. However the nitrene adducts 2d and 2e derived from 1,2,3,4-tetrahydrocarbazole and 1-oxo-1,2,3,4-tetrahydrocarbazole afford carbazole and 1-hydroxycarbazole under similar conditions. Hydrazinolysis of the nitrene adducts-2a, b, c, d and e regenerated the parent indole.

■ 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.

■ 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.

■ Palladium-Catalyzed Borylation of Aryl Iodides with 2,3-Dihydro-1H-benzo[d][1,3,2]diazaboroles

Miki Murata,* Nobuyoshi Hirai, Michihiro Okuyama, Takeshi Namikoshi, and Shinji Watanabe

*Department of Materials Science and Engineering, Kitami Institute of Technology, Koen-cho 165, Kitami, Hokkaido 090-8507, Japan

Abstract

The palladium-catalyzed borylation of aryl iodides with 2,3-dihydro-1H-benzo[d][1,3,2]diazaboroles was achieved. The mild reaction conditions employed allowed for the inclusion of a wide variety of functional groups in aryl iodides to be tolerated. Additionally, the borylated products can be transformed into the corresponding boronic acids or their esters under acidic conditions.

■ Facile Synthesis of 5- to 7-Membered Benzolactam Compounds via Strongly Facilitated Electrophilic Aromtic Substitution Reaction†

Hiroaki Kurouchi, Yuko Otani, and Tomohiko Ohwada*

*Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan

Abstract

We employed our system to activate aromatic ring-tethered carbamate compounds with trifluoromethanesulfonic acid to obtain benzolactams with 5- to 7-membered rings, and examined the substrate scope and limitations of this activation method. In 5-membered ring formation, a halogen group on the aromatic ring did not greatly affect the reaction yield, but other electron-donating groups inhibited the cyclization reaction, and various side-reactions occurred. In 7-membered ring formation, eletron-donating groups on aromatic ring promoted the cyclization reaction, but cyclization of electron-deficient aromatic rings did not proceed well. The 6-membered ring formation reaction showed the greatest substrate generality.

■ Hydrolysable Tannins Isolated from Syzygium aromaticum: Structure of a New C-Glucosidic Ellagitannin and Spectral Features of Tannins with a Tergalloyl Group

Li-Ming Bao, _ Eerdunbayaer, Akiko Nozaki, Eizo Takahashi, Keinosuke Okamoto, Hideyuki Ito, and Tsutomu Hatano*

*Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushima-naka, Okayama 700-8530, Japan

Abstract

Eighteen hydrolysable tannins, including a new C-glucosidic tannin named aromatinin A (1), were isolated from an aqueous acetone extract of dried flower buds of Syzygium aromaticum Merr. et Perry. We determined that 1 had a gallic acid C-glucoside structure, based on the spectral data and synthesis from casuarinin (18) and gallic acid (20). This is a rare example of hydrolysable tannins with gallic acid C-glucoside structure. We also report the 1H nuclear magnetic resonance (NMR) spectral features of syzyginin A (2), bicornin (3), and platycaryanin A (4), which were also isolated from S. aromaticum, based on their structures with a tergalloyl group or its depsidone form. The remaining known compounds were identified as alunusnin A (5), rugosin C (6), 1,2,3-tri-O-galloyl-β-D-glucose (7), 1,2,3,6-tetra-O-galloyl-β-D-glucose (8), tellimagrandin II (9), casuarictin (10), heterophylliin D (11), rugosin D (12), rugosin F (13), euprostin A (14), 1,2-di-O-galloyl-3-O-digalloyl-4,6-O-(S)-hexa- hydroxydiphenoy-β-D-glucose (15), alienanin B (16), squarrosanin A (17), and 18. The antifungal effects of hydrolysable tannins, 9, 12, and 18 against Candida strains are also described.

■ Synthesis of N-Heterocyclic Carbene Ligands for Site-Selective C-H Alkylation by Cooperative Nickel/Aluminum Catalysis

Shogo Okumura, Tomohiro Ebara, Kazuhiko Semba, and Yoshiaki Nakao*

*Department of Material Chemistry, Graduate School of Engineering, Kyoto University, Kyoudai-katsura, Nishikyo, Kyoto 615-8510, Japan

Abstract

We report synthesis of N-heterocyclic carbenes (NHCs), N,N'-bis{2,6-bis(3,5-dialkylphenyl)methy-4-methoxyphenyl}imidazol-2-ylidenes {alkyl = ethyl (L2) or n-propyl (L3)} and their applications to nickel-catalyzed C–H alkylation reactions of arenes. They showed site-selectivities and/or yields higher than NHCs used previously for the reactions.

■ Design, Synthesis and Structure-Activity Relationship Study of Pyrilamine Derivatives as Histone Deacetylase Inhibitors

Seiya Hiranaka, Mayumi Arata, Akiko Nakata, Akiko Tanaka, Yoshinobu Hashizume, Norio Kudo, Akihiro Ito, Minoru Yoshida, Shinichi Uesato, Yasuo Nagaoka, and Takaaki Sumiyoshi*

*Faculty of Chemistry, Materials and Bioengineering, Kansai University, 3-3-35 Yamate-cho, Suita, Osaka 564-8680, Japan

Abstract

For the study on the structure-activity relationship of pyrilamine-based histone deacetylase inhibitor 1, we focused on the structures of its benzyl and dimethylamino groups. Of the synthesized novel pyrilamine derivatives 2–7, compound 2 enhanced potency against hERG inhibition, as well as decreased molecular weight and topological polar surface area.

■ Aculeatusquinones A-D, Novel Metabolites from the Marine-Derived Fungus Aspergillus aculeatus

Li Chen,* Wei-Wei Zhang, Qiu-Hong Zheng, Qin-Ying Liu, Ping Zhong, Xiao Hu, Zhe-Xiang Fang, and Qi-Qing Zhang*

*Institute of Biomedical and Pharmaceutical Technology & College of Chemistry and Chemical Engineering, Fuzhou University, No. 523, Gongye Road, Fuzhou City, 350002, China

Abstract

Four new aculeatusquinones A–D (1–4) and five known compounds, (5aS,6S,7S)-3,7-dihydroxy-6-methoxy-1,4,6,9-tetramethyl-6,7-dihydro-5aH-dibenzo[b,e][1,4]dioxepine-8,11-dione (5), 3,8-dihydroxy-1,4,6,9-tetramethyldibenzo[b,e][1,4]dioxepin-11-one (6), 4-O-demethylbarbatic acid (7), atraric acid (8), and 2,5-dimethyl-1,3-benzenediol (9), were isolated from the marine-derived fungus Aspergillus aculeatus. The structures of the new compounds were elucidated by spectroscopic methods, including one- and two-dimensional NMR and high-resolution mass spectrometric analyses. Two new compounds (2 and 4) showed cytotoxic effects on the HL-60, K562, and A-549 cell lines, with IC50 values ranging from 5.4 μM to 76.1 μM.

■ Benzylic sp3 C-H Functionalization Reaction of 2-Methylazaarenes Catalyzed by Pepsin

Feng Ai, Guo-Qing Chen, Jiu-Jian Ji, Zhi-Qiang Zhu, Zhang-Gao Le,* and Zong-Bo Xie*

*Department of Applied Chemistry, East China University of Technology, Nanchang 330013, China

Abstract

In this work, the addition of 2-methylazaarenes benzylic sp3 C-H to electron-deficient olefins, catalyzed by pepsin from pig gastric mucosa was reported. A series of azaarene derivatives (1 mmol) were obtained in good yields at 60 °C for 60~72 h with 20 mg pepsin as catalyst. This is a facile method and the reaction conditions are mild, which expands the application of biocatalysis in sp3 C-H functionalization of azaarenes.

■ Fast, Solvent-Free, and Highly Efficient Synthesis of Pyrazolo[3,4-b]Pyridines Using Microwave Irradiation and Khso4 as A Reusable Green Catalyst

Jinjing Qin, Zhenhua Li,* Xiaomeng Sun, Yi Jin, and Weike Su

*Collaborative Innovation Centre of Yangtze River Delta Region Green Pharmaceuticals, College of Pharmaceutical Sciences, Zhejiang University of Technology, 18#, Chaowang Rd., Hangzhou, Zhejiang 310014, China

Abstract

A simple, ecofriendly, and effective method was described for forming pyrazolo[3,4-b]pyridines from 5-aminopyrazoles and 3-formylchromones, in good to excellent yields, under microwave irradiation in solvent-free conditions using KHSO4 as a reusable catalyst. Some noteworthy features of this method were its cleanliness, short reaction time, easy work-up, and broad substrate tolerance. The catalyst was reused several times without losing activity.