HETEROCYCLES

■ Contents

■ Chemistry of Macrocyclic β-Lactam: An Overveiw

Vijaya Bhaskar Vangala, Mahagundappa Rachappa Maddani, Rama Mohan Hindupur, and Hari Narayan Pati*

*Department of Chemistry, Advinus Therapeutics Ltd., 21 and 22 Peenya Industrial Area, 560058, India

Abstract

β-Lactam macrocycles displayed major contributions in the filed of drug discovery. The chemical potentiality of β-lactam has proved their usefulness in the discovery of variety of conformationally restricted macrocycles. Macrocycles containing versatile functionalities derived from β-lactam have also been employed in the fields of supramolecular chemistry. In this review, attempts were made to summarize the recent methods for synthesis of potential β-lactam containing macrocycles.

■ An Cost-Effective and Safe Process of L-cis-4,5-Methanoproline Amide, the Key Synthetic Intermediate of Saxagliptin, via an Improved Simmons-Smith Reaction

Ding ding, Xianhua Pan, Wansheng Yu, Xiaojun Li, Suke Chen, and Feng Liu*

*School of Perfume and Aroma Technology, Shanghai Institute of Technology, Haiquan Rd. 100 Shanghai, 201418, China

Abstract

L-cis-4,5-Methanoproline amide, a key intermediate of saxagliptin, was synthesized by an improved Simmons-Smith reaction. The zinc carbenoid was formed through Zn/CuBr and CH2I2, under the optimized condition, the title compound was gained with 68% yield and excellent diastereomeric selectivity (40:1 d.r.). The absence of the flammable and expensive ZnEt2 makes this procedure very attractive in large scale production.

■ Synthesis and Applications of a New Epoxy-isoindolinone

Shang-Shing P. Chou* and Sung-Lin Hsu

*Department of Chemistry, Fu Jen Catholic University, 510 Chung-Cheng Rd., Hsin-Chuang, New Taipei City 24205, Taiwan, R.O.C.

Abstract

A new epoxy-isoindolinone was stereoselectively synthesized, and its reactions gave several interesting products including a new 6-azabicyclo[3.2.1]octane derivative.

■ Environmental Friendly Synthesis of Bis-Perfluoropyridine and Pyrimidine in Water

Reza Ranjbar-Karimi* and Aliyeh Khaje-Khezri

*Department of Chemistry, Vali-Asr University, Islamic Republic of Iran, 7713936417, Iran

Abstract

An easy, efficient and simple approach for the synthesis of some perfluoropyridine and pyrimidine derivatives by reaction of pentafluoropyridine and tetrafluoropyrimidine with mono and bidentate N-nucleophiles in the presence of potassium carbonate in water as a green solvent, at room temperature is reported. The structures of some products were unambiguously confirmed by X-ray crystallography.

■ Synthesis and Antibacterial Activity of Novel N-Carboxyalkyl-N-phenyl-2-aminothia(oxa)zole Derivatives

Rita Vaickelioniene, Kristina Mickeviciene, Kazimieras Anusevicius, Jurate Siugzdaite, Kristina Kantminiene, and Vytautas Mickevicius*

*Department of Organic Chemistry, Kaunas University of Technology, Radvilėnų pl. 19, Kaunas LT-50254, Lithuania

Abstract

N-Phenyl-N-thiocarbamoyl-α- and β-methyl-β-alanines were converted into a series of 1,3-thiazole derivatives by treatment with chloroacetaldehyde and haloketones. The reaction of N-phenyl-N-thiocarbamoyl-β-alanines and N-carbamoyl-N-phenyl-β-alanines with 2,3-dichloro-1,4-naphthoquinone and 2,3-dichloroquinoxaline provided naphthoquinone- and quinoxaline-fused thiazoles and oxazoles, respectively. A number of the synthesized compounds exhibited good antibacterial activity against Staphylococcus aureus and Salmonella enteritidis with MIC and MBC values (62.5 and 125 µg/mL, respectively) which are the same or even lower than those for the antibiotic oxytetracycline.

■ Synthesis of New Hydantoins Bearing Glutarimide or Succinimide Moiety and Their Evaluation for Cell Differentiation-inducing and Anti-angiogenic Activities

Jun-ichi Yamaguchi,* Tomomi Noguchi-Yachide, Yuka Sakaguchi, Chiaki Shibata, Shinnosuke Kanuma, Akiko Yoshizaki, Yuka Takizawa, and Yuichi Hashimoto

*Department of Applied Chemistry, Faculty of Engineering, Kanagawa Institute of Technology, Shimo-ogino, Atsugi-shi 243-02, Japan

Abstract

Several derivatives of hydantoin containing glutarimide or succinimide at the 3-position were synthesized. The new hydantoin derivatives had a structure similar to that of thalidomide, and so may possess activity similar to that of thalidomide and/or its analogs, such as effects on cell differentiation and angiogenesis. Some hydantoins showed enhancing effects on all-trans retinoic acid (ATRA)-induced cell differentiation of human leukemia cell line HL-60 and anti-angiogenic activity on human umbilical vein endothelial cells (HUVEC). These new hydantoin derivatives were more effective than thalidomide in cell differentiation-inducing activity on HL-60 and anti-angiogenic activity on HUVEC.

■ A Synthesis of Lamellarins via Regioselective Assembly of 1,2,3-Differentially Substituted 5,6-Dihydropyrrolo[2,1-a]Isoquinoline Core

Tsutomu Fukuda, Daichi Sato, and Masatomo Iwao*

*Division of Chemistry and Materials Science, Graduate School of Engineering, Nagasaki University, 1-14, Bunkyo-machi, Nagasaki 852-8521, Japan

Abstract

A modular synthesis of the marine natural products lamellarins has been developed. The key reactions utilized are C3-selective Vilsmeier-Haack formylation followed by iterative bromination/cross-coupling of the 5,6-dihydropyrrolo[2,1-a]isoquinoline core. The 1,2-diaryl-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carbaldehyde thus synthesized was readily converted to the lamellarin skeleton by mean of palladium-catalyzed oxidative lactonization.

■ Systematic Investigation of Fluorescence Properties of Symmetric and Asymmetric Diazolo[1,2-a:2′,1′-c]quinoxaline Derivatives

Shoji Matsumoto,* Keisuke Sakamoto, and Motohiro Akazome

*Department of Applied Chemistry and Biotechnology, Graduate School and Faculty of Engineering, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan

Abstract

The investigation of the synthesis and optical properties of symmetric and asymmetric diazolo[1,2-a:2′,1′-c]quinoxaline derivatives were systematically examined. The formation of an intramolecular carbon-carbon bond between two azole rings could be achieved by selection of the reaction depending on the type of azole. The absorption and fluorescence spectra revealed the following effects induced by structural changes: 1) introduction of a fused-benzene ring affects the peak shape and the increment of 0-0 transition in the absorption and fluorescence spectra. 2) A hypsochromic shift is induced by substitution of the CH moiety with a nitrogen atom. 3) Introduction of fused-benzene ring(s) is a promising strategy for improving the fluorescence quantum yield of these species. Furthermore, all of the compounds were fluorescent in the solid state, although no systematic trend was found. Investigation of the single crystal structures revealed a diversity of crystal packing arrangements, even in related structures.

■ Domino [3+2+1] Heteroannulation for Stereoselective Synthesis of Anti-Pyrazolo[3,4-d][1,3]oxazines

Yi Ning, Wei Fan, Wen-Juan Hao, Mu-Yan Sun, Bo Jiang,* Shu-Jiang Tu,* and Guigen Li*

*Department of Chemistry & Biochemistry, Texas Tech University, Lubbock, TX 79409-1061, U.S.A.

Abstract

A novel three-component domino reaction of arylglyoxals with pyrazol-5-amines in HOAc has been developed, providing an efficient and stereoselective access to polysubstituted anti-pyrazolo[3,4-d][1,3]oxazines in a intermolecular manner. Features of this strategy include mild conditions, convenient one-pot operation, and excellent stereoselectivity, which make highly attractive.

■ Reactivity of 2-(1-Methyl-1H-benzo[d]imidazol-2-yl)-2-nitrosoacetonitrile: A Facile One-Pot Synthesis of Benzimidazo[1,2-a]piperazine Derivatives

Samia M. Sayed, Mohamed A. Khalil, and Mohamed A. Raslan*

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

Abstract

Several new heterocyclic compounds such as benzimidazo[1,2-a]piperazine derivatives (5-7;9,10 and 14,15,17) have been synthesized by the reactions of the versatile 2-(1-methyl-1H-benzo[d]imidazol-2-yl)-2-nitroso-acetonitrile (2) with malononitrile derivatives (3a-e) and 2-cyanomethyl-benzimidazole derivatives (1b,c). Oxidation of iminopyrazino[1,2-a]benzimidazole-3-carbothioamide derivatives 9 via refluxing in aqueous H2O2 solution afforded iminopyrazino[1,2-a]benzimidazole-3-carboamide derivatives 10. Also, reaction of 9 with 1-aryl-2-bromoethanone derivatives (11a,b) in refluxing DMF, the Hantzsch-type thiazoles (12a,b) were obtained. All newly synthesized compounds were elucidated by considering the data of both elemental and spectral analysis.

■ Convenient Synthesis of Novel Phenylpyrimido[1,2-c]thienopyrimidinones as IL-6/STAT3 Inhibitors

Jae Hoo Park, So Young Hong, Jungah Kim, Hyuck Joo Lee, Hyun Ho Lee, Ka Young Kim, Seung Woong Lee, Hyun-Mee Oh, Mun-Chul Rho, Beom-Gyu Lee, and Yang-Heon Song*

*Department of Chemistry, Mokwon University, Daejeon, Doan-dong 800, 302-729, Korea

Abstract

New phenylpyrimido[1,2-c]thienopyrimidinones 4A and 4B were easily prepared in good yields by the one-pot reaction of formamidine derivatives 2 of 4-aminothienopyrimidine 1 with phenylacetyl chlorides. The application of this convenient and reliable method could be used for the synthesis of a variety of pyrimido[1,2-c]thienopyrimidinone derivatives of biological importance. Some of the compounds synthesized showed strong IL-6/STAT3 inhibition.

■ IBr-Catalyzed O-Glycosylation of D-Glucals: Facile Synthesis of 2,3-Unsaturated-O-glycosides

Rungnapha Saeeng, Onanong Siripru, and Uthaiwan Sirion*

*Department of Chemistry and Center for Innovation in Chemistry, Faculty of Science, Burapha University, Sangsook, Chonburi 20131, Thailand

Abstract

Iodine monobromide (IBr) is explored as an alternative catalyst for the selective synthesis of 2,3-unsaturated glycosides from tri-O-acetyl-D-glucal 1 with several alcohols through Ferrier rearrangement. This reaction was shown to be a simple, efficient and cost-effective method, affords twenty examples of corresponding glycoside products in high yields with good α-selectivity.