HETEROCYCLES

■ Contents

■ Strategy for the Synthesis of C-Aryl Glucosides as Sodium Glucose Cotransporter 2 Inhibitors

Masatoshi Murakata and Masahiro Nagase*

*Chugai Pharmaceutical Company, Ltd., 5-5-1, Ukima, Kita-ku, Tokyo , Japan

Abstract

Sodium glucose cotransporter 2 (SGLT2) inhibitors are currently the focus of attention in the treatment of diabetes. Since the discovery of the first SGLT inhibitor phlorizin, a natural O‑aryl glucoside, extensive efforts in the search for selective SGLT2 inhibitors have continued and several C‑aryl glucosides have been launched onto the market. This review presents routes and strategies collected from both drug discovery chemistry and industrial process chemistry for the synthesis of nine pioneering C-aryl glucoside SGLT2 inhibitors (dapagliflozin, canagliflozin, ipragliflozin, empagliflozin, luseogliflozin, tofogliflozin, ertugliflozin, bexagliflozin, and sotagliflozin). The synthetic strategies employed for the construction of the carbon backbone of these inhibitors are classified into four types, and details of various synthetic routes and methods are described.

■ A Review on the Biological Activity of β-Carboline Derivatives

Mohamed Osama Mousa, Mina Emad Adly, Amr Mohamed Mahmoud, and Hala Bakr El-Nassan*

*Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, 33 Kaser El Ainin Street 11562, Egypt

Abstract

β-Carboline ring is one of the most important scaffolds in drug discovery owing to its abundance in nature and its various biological activity. A large number of β-carboline alkaloids were isolated from plants, mammals, marine organisms, fungi and bacteria. Various biological activities have been identified for synthetic β-carboline compounds like anticancer, antimicrobial, antileishmanial, antimalarial, anti-Alzheimer, anti-inflammatory, analgesic and vasorelaxant activity. The present review describes the method of synthesis of β-carboline and highlights the recent progress achieved in the last decade in the development of biologically active β-carboline derivatives.

■ Simple Brønsted Acid Catalyzed Three-Component Reactions for Efficient Alkylation of Indolizines with Aromatic Aldehydes and Hantzsch Esters

Jiang Geng, Jinyi Shi, Jin Wang, Jiaxian Li, Lin Jiao, and Dongdong Guo*

*Department of Basic Courses, Shanxi Agricultural University, Taigu, 030801, P. R. China

Abstract

An efficient three-component reaction has been developed for functionalization of indolizines with aromatic aldehydes and Hantzsch esters. Simple Brønsted acids were successfully employed as catalysts to form reactive cationic intermediate which could be efficiently trapped by Hantzsch ester. Different types of substituted indolizines could be efficiently obtained with good yields.

■ Effects of Degree of Polymerization of B-Type Procyanidins on Amyloid Aggregation

Taisei Tanaka, Hirono Fukushima, Vipul V. Betkekar, Ken Ohmori, Keisuke Suzuki, Yusaku Miyamae, and Hideyuki Shigemori*

*Institute of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8572, Japan

Abstract

Amyloid polypeptides are considered to be intensely involved in the pathogenesis of Alzheimer's disease (AD) and type 2 diabetes (T2D), both of which are increasing in incidence worldwide. AD is believed to be caused by the cytotoxicity of amyloid-β (Aβ) aggregates, while T2D is considered to be due to the cytotoxicity of human islet amyloid polypeptide (hIAPP) aggregates. Therefore, the inhibition of Aβ and hIAPP aggregate formation can be effective in the prevention of both diseases. Previously, we established that catechol-bearing polyphenolic compounds exhibit remarkable amyloid aggregation inhibitory activities. In this study, we examined the amyloid aggregation inhibitory activities of B-type procyanidins, which have multiple catechol moieties and different degrees of polymerization. We found that all of the tested B-type procyanidins bearing catechol moieties displayed amyloid aggregation inhibitory activity. Furthermore, the higher the degree of polymerization of B-type procyanidins, the stronger the inhibition of amyloid aggregation.

■ L-Malic Acid as Chiral Auxiliary and Building Block in the Asymmetric Synthesis of (S)-(−)-Crispine A

Maria Chrzanowska*

*Faculty of Chemistry, Adam Mickiewicz University, ul. Uniwersytetu Poznańskiego 8, 61-614 Poznań, Poland

Abstract

The asymmetric synthesis of (S)-(–)-crispine A was performed using L-malic acid as chiral auxiliary and building block. Condensation of homoveratrylamine with L-malic acid led to imide which was further reduced and cyclized by N-acyliminium ion intermediate to pyrrolo[2,1-a]isoquinoline. Hydroxyl group at C-1 position was replaced by phenylthio one and removed by Raney nickel. Last step of the synthesis - reduction of lactam carbonyl group furnished (S)-(–)-crispine A with 99.99% ee. Additionally synthesis of racemic crispine A was performed staring from homoveratrylamine and succinic anhydride to furnish samples for enantiomeric excess determination by HPLC.

■ Triazene-Bridged Nitrogen-Rich Heterocyclic Energetic Compounds 4,4'-(Triaz-1-ene-1,3-diyl)bis(1,2,5-oxadiazol-3-amine) - Synthesis, Characterization and Properties

Jin Zhu, Qianxiong Chen, Suming Jing,* Keyao Li, Zhineng Wang, Yuanyuan Wang, and Jiahao Deng

*Department of Environmental and Safety Engineering, North University of China, Taiyuan, Shanxi, China

Abstract

4,4'-(Triaz-1-ene-1,3-diyl)bis(1,2,5-oxadiazol-3-amine) was designed and synthesized with 3,4-diaminofurazan and triazene bridges, which was fully characterized by NMR, IR, elemental analyses, and single crystal X-ray diffraction. The results of structural and physicochemical characterization of 4,4'-(triaz-1-ene-1,3-diyl)bis(1,2,5-oxadiazol-3-amine) showed that this compound exhibits particularly high formation heats (ΔHf=926.32 kJ mol-1) which is higher than that of all currently reported furazan-based energetic compounds, excellent detonation performance (D=8151 m s-1, P=28.55 GPa). In addition, this compound is insensitive to external mechanical stimuli (IS=40 J FS=289 N). Its crystal packing, intermolecular interaction and ESP play an important role in reducing sensitivity. Further, its thermal decomposition temperature is 172.6 °C. This work provides the inspiration for designing nitrogen rich energetic compounds, especially triazene bridges.

■ Syntheses and Catalytic Properties of 1-Naphthoate-Copper-Bipy Complex

Yi Zhu,* Wenjuan Zhu, Chibin Liu, Yanxin Wei, Mingjing Xia, and Xi Wang

*Department of Chemical and Pharmaceutical Engineering, Hefei Normal University, 230601

Abstract

In this paper, 1-naphthoic acid, 2,2-dipyridyl (Bipy) and cupric nitrate are used to synthesize a novel complex by hydrothermal method. The complex is characterized by means of IR and X-ray diffraction. The complex is applied in the hydroxylation of phenol and the degradation of Congo Red as catalysts. The influence of dosage of catalyst, reaction time, temperature, etc. is studied in both hydroxylation of phenol and the degradation of Congo Red. The best results of the phenol hydroxylation reaction are obtained by reacting 0.2 g phenol with 0.30 mL hydrogen peroxide (30%) at 80 ℃ for 180 min under the catalysis of 8 mg complex. The yield of benzenediol is 81.45%. The optimum degradation of Congo Red reaction is achieved by mixing 0.75 mg Congo Red with 4 mg complex, 0.30 mL hydrogen peroxide and reacting at 45 ℃, for 30 min.

■ Aqueous Synthesis of (R*,R*)-Bis(spiropyrazolone)cyclopropanes through Iodine-Promoted Cyclization of Aldehydes and Pyrazolin-5-ones

Qi-Yue Zhu, Xue Wang, Zeng-Yang He,* Ming-Jun Li, Hui Xu, and Ze Zhang*

*School of Chemical and Environmental Engineering, Anhui Polytechnic University, Wuhu 241000, P. R. China

Abstract

The molecular iodine promoted cyclization of aldehydes and pyrazolin-5-ones was accomplished in water using tetrabutylammonium iodide as a phase transfer catalyst, affording a variety of substituted (R*,R*)-bis(spiropyrazolone)cyclopropanes in good to excellent yields (76–96%). This aqueous reaction exhibits very high chemoselectivity, and the products were obtained by simple Büchner filtration without chromatographic isolation procedure.