HETEROCYCLES

■ Contents

■ Recent Advances in the Syntheses of Decalin Type Natural Products

Hiroyuki Akita*

*Department of Pharmaceutical Sciences, Nihon Pharmaceutical University, 10281 Komuro, Ina-machi, Kitaadachi-gun, Saitama, 362-0806, Japan

Abstract

This review summarizes the practical synthesis of both enantiomers of chiral intermediate for the syntheses of the natural products possessing the bicyclo[4.4.0]ring system with 4,4,10-trimethyl groups and their application to the total syntheses of the related natural products. Chiral induction was carried out based on enzymatic resolution or optical resolution using chiral auxiliary.

■ Functionalization of Porphyrins through C-C Bond Formation Reactions with Functional Group-Bearing Organometallic Reagents

Toshikatsu Takanami*

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

Abstract

Interest in the chemistry of porphyrins and related tetrapyrrolic macrocycles has increased greatly in recent years because of the importance of these compounds in many areas of chemistry, biology, and material sciences. Consequently, the development of efficient synthetic strategies and intermediates for the preparation of porphyrin derivatives with a variety of peripheral substituents has become an active field of research. Functionalized porphyrins, which contain chemically reactive functional groups such as esters, amides, nitriles, and formyl groups on the porphyrin core and as peripheral substituents, are potential precursors for more complicated porphyrin derivatives. However, current methods for synthesizing functionalized porphyrins generally suffer from limitations, including tedious multi-step preparation, laborious chromatographic purification, and low yields. This review describes our recent efforts to address some of these challenges using the following strategies: (1) a palladium-catalyzed Negishi cross-coupling reaction of halogenated porphyrins with functional group-bearing organozinc reagents, and (2) the silyl¬methylation of porphyrins with silylmethyl¬lithium and magnesium reagents, where the silylmethyl groups can be used as protected analogs of various chemically reactive functionalities, such as formyl and hydroxy¬methyl groups.

■ Novel Photosensitized Cyclization Reactions of Ethyl 3-Amino-3-phenyl-2-propenoate Derivatives to Highly Substituted Pyrroles

Yohsuke Ishida, Yuhki Yoshida, Tetsutaro Igarashi, and Tadamitsu Sakurai*

*Department of Material and Life Chemistry, Faculty of Engineering, Kanagawa University, 3-27-1 Rokkakubashi, Kanagawa-ku, Yokohama 221-8686, Japan

Abstract

Irradiation of nitrogen-saturated acetonitrile solutions containing ethyl 3-amino-3-phenyl-2-propenoate derivatives with the (Z)-configuration [(Z)-1] and 10-methylacridinium perchlorate (MAP) at wavelengths longer than 340 nm afforded the corresponding pyrrole derivatives in good to high yields without exhibiting a profound effect related to the substituents. An analysis of the Stern–Volmer plots for the fluorescence quenching of MAP by (Z)-1 showed that this sensitizer fluorescence is efficiently quenched, and hence electron transfer is confirmed to be involved in the primary process of the MAP-sensitized cyclization reactions of 1.

■ Synthesis, Characterization and Suppression of Impurities during Optimization of Dabigatran Etexilate

Yu Chen,* Jun Liang, Huansheng Chen, and Li Yuan

*R&D Department, Shanghai AoBo Bio-pharmaceutical Technology Co., Ltd., Room 601, No. 1011, Halei Road, Zhangjiang High-Tech Park, Shanghai, 201203, China

Abstract

The synthetic methods for two impurities of dabigatran etexilate are firstly described, and both of two impurities are characterized by NMR and MS spectral data. The suppression of impurities as well as the optimization process of dabigatran etexilate is also disclosed.

■ Synthesis of Novel Coumarin Derivatives and in vitro Biological Evaluation as Potential PTP 1B Inhibitors

Cheng Sun, Chune Peng, Jian Wang, Quan Wang, Wei Liu, Honggang Zhou,* and Cheng Yang

*College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300071, China

Abstract

The aim of protein tyrosine phosphatase 1B (PTP 1B) inhibitors is to develop effective drug for diabetes and obesity. Coumarin becomes as a good skeleton, and is often applied in drug design and synthesis. In this paper, we have synthesized a series of novel coumarin derivatives to be as potential PTP 1B inhibitors. The inhibition rate of compound 9 was more than 80%, and the IC50 value was 49.2 μM, which would be considered for further study.

■ Synthetic Models Related to Methoxalen – CYP2A6 Interactions. Dimethoxybenzofuran Derivatives as Potent and Selective Inhibitors of CYP2A6

Yuki Yamaguchi, Ichie Akimoto, Kyoko Motegi, Teruki Yoshimura, Keiji Wada, Naozumi Nishizono, and Kazuaki Oda*

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

Abstract

The human CYP2A6 enzyme metabolizes several xenobiotics including nicotine, the addictive component in tobacco. Reduced activity of CYP2A6, either for genetic reasons or by administering inhibitors of CYP2A6, reduces tobacco smoking. The reported compound methoxalen had a potent inhibitory effect on activity of CYP2A6 with an IC50 value of 1.27 μM. We selected methoxalen as a lead compound and prepared various dimethoxybenzofuran derivatives that have inhibitory effects on activity of human cytochrome P450 (CYP) 2A6. Synthetic benzofuran derivatives (3,6-dimethoxybenzofuran: IC50=1.92 μM and 3,7-dimethoxybenzofuran: IC50=2.00 μM) also exhibited comparable activities against CYP2A6 and were selective inhibitors of CYP2A6. These compounds can be used as lead compounds in the development of drugs for smoking reduction therapy.

■ One-Pot Synthesis of 2,3-Diarylthieno[2,3-b]-, -[2,3-c]- or -[3,2-c]pyridines from the Respective Aryl(chloropyridinyl)methanones

Kazuhiro Kobayashi,* Taira Ohmichi, Wataru Miyatani, Kazuhiro Nakagawa, and Shohei Yuba

*Division of Applied Chemistry, Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University, 4-101 Koyama-minami, Tottori 680-8552, Japan

Abstract

The title three types of 2,3-diarylthienopyridines can be conveniently prepared from the respective aryl(chloropyridinyl)methanones in one-pot. The starting ketones react with sodium sulfide nonahydrate to generate aryl[(sodiosulfanyl)pyridinyl]methanones, which are treated successively with 4-(BrCH2)C6H4EWGs and sodium hydride to give rise to the desired products in generally good yields.

■ Efficient Synthesis of N-Methylamides and Amines via 4-(Alkylamino)benzyl-N-methylamine as a New Protecting Group

Sang-Hak Lee, Yu Mu, Gun-Woo Kim, Jin-Seok Kim, Seok-Hwi Park, Tian Jin, Kee-Young Lee, and Won-Hun Ham*

*School of Pharmacy, Sungkyunkwan University, 2066, Seobu-Ro, Jangan-Gu, Suwon-Si, Gyeong gi-Do 440-746, Korea

Abstract

4-(Alkylamino)benzyl-N-methylamine is a good protecting group for the synthesis of N-methylamides and amines. The N-debenzylation of N-methylamides and amines can be carried out selectively and efficiently under condition using trifluoroacetic acid (TFA).

■ Three-Step Synthesis of Triazolobenzodiazepinones via Sonogashira/Huisgen Protocol

Giorgio Molteni*

*Department of Organic and Industrial Chemistry, University of Milano, Via Golgi 19, 20133 Milano, Italy

Abstract

The sequential Sonogashira coupling/intramolecular azide cycloaddition (Huisgen cycloaddition) protocol was performed onto N-(2-iodophenyl)-2-azidoacetamide as the acyclic precursor giving tricyclic 1,2,3-triazolo[5,1-d][1,4]benzodiazepin-2-ones. These target products were thus obtained through a three-step synthesis in variable yields depending upon the substituent placed onto the acetylenic counterpart. The influence of catalyst concentration, reaction temperature and reaction medium upon cycloadduct yields were also studied.

■ Facile Access to Novel 3-Acylimidazo[1,2-a]pyrimidines under Microwave Irradiation

Mohamed R. Shaaban*

*Department of Chemistry, Faculty of Science, Cairo University, Giza 12013, Egypt

Abstract

Treatment of mono-, bis- and tris(ω-bromoacetophenone) derivatives with N,N-dimethylformamidine derivative of 2-aminopyrimidine, afforded the novel 3-aroyl or heteroyl derivatives of imidazo[1,2-a]pyrimidine, bis(imidazo[1,2-a]pyrimidine) and tris(imidazo[1,2-a]pyrimidine) derivatives, respectively, under both conventional and microwave conditions.