HETEROCYCLES

■ Contents

■ Total Biosynthesis of Fungal Indole Diterpenes Using Cell Factories

Atsushi Minami, Chengwei Liu, and Hideaki Oikawa*

*Division of Chemistry, Graduate School of Sceince, Hokkaido University, Kita 10 Nishi 8, Kita-ku, Sapporo, Hokkaido 060-0810, Japan

Abstract

Reconstitution of biosynthetic genes in a heterologous host is a newly emerging method for synthesis of fungal secondary metabolites. Application of this method to indole diterpenes is described. We have successfully elucidated all of the individual enzymatic steps and produced four representative indole diterpenes, paspaline, paxilline, aflatrem, and penitrem, at a yield of ~100 mg/L. These results confirmed that the Aspergillus oryzae expression system is highly reliable for elucidation of biosynthetic pathways, even those involving 17 enzymatic reactions.

■ Catalytic Cyclization of 2,3-Dibromopropionates with Benzyl Azides to Afford 1-Benzyl-1,2,3-triazole-4-carboxylate: The Use of a Nontoxic Bismuth Catalyst

Hong-bin Sun,* Dong Li, Weiping Xie, and Xinlin Deng

*Department of Chemistry, Northeastern University of China, Wenhua Road 3-11, Shenyang 110819, China

Abstract

We synthesized 1,2,3-triazoles via the cyclization of 2,3-dibromopropionates with benzyl azides. Bismuth chloride is an efficient catalyst, and the reaction is accelerated by weak bases such as sodium acetate. A variety of functional groups are compatible with this catalytic protocol, and it takes advantage of oxygen stable catalyst and substrates because the reactive dibromides are saturated.

■ Synthesis, Molecular Docking and Anti-Human Breast Cancer Activities of Novel Thiazolylacetonitriles and Thiazolylacrylonitriles and Their Derivatives Containing Benzenesulfonylpyrrolidine Moiety

Mahmoud S. Bashandy* and Shimaa M. Abd El-Gilil

*Department of Chemistry, Al-Azhar University, Nasr City, Cairo 002, Egypt

Abstract

This article describes the synthesis of some novel sulfonamides having the biologically active, thiazole 3, 8-10, 13, 19, 20, 24, 30, 31, 35-41, pyrazolo[5,1-c][1,2,4]triazine 5, 1H-1,2,4-triazole 6, thiazolo[3,2-a]pyridine 14, chromen-2-one 16, benzo[f]chromen-3-imine 17, benzo[f]chromen-3-one 18, triazolo[4,3-a]pyrimidine 22, pyrazolo[1,5-a]pyrimidine 23, isoxazole 26, 2,4-diaminopyrimidine 27, benzo[4,5]imidazo[1,2-a]pyridine 28, imidazolidine 32 and 1H-benzo[d]imidazolidene 33 moieties, starting with 2-(4-(4-(pyrrolidin-1-ylsulfonyl)phenyl)thiazol-2-yl)acetonitrile (2), which was prepared from cyclocondensation of phenacyl bromide derivative 1 with 2-cyanoethanethio-amide. The structures of the newly synthesized compounds were confirmed by elemental analysis, IR, 1H NMR, 13C NMR and Ms spectral data. All the compounds were tested in-vitro antihuman breast cancer cell line (MCF7). Compounds 18, 8, 41 and 28 with IC50 values of 48.01, 49.11, 49.27 and 49.78 µM, respectively, exhibited better activity than doxorubicin (DOX) as a reference drug with IC50 value of 68.6 µM. Molecular Operating Environment (MOE) performed virtual screening using molecular docking studies of the synthesized compounds. The results indicated that some synthesized compounds suitable inhibitor against dihydrofolate reductase (DHFR) enzyme (PDB ID: 4DFR) with further modification.

■ An Efficient and Convenient Synthesis of Acyl CoA: Monoacylglycerol Acyltransferase 2 Inhibitor, 2-[2-(4-tert-Butylphenyl)ethyl]-N-[4-(3-cyclopentylpropyl)-2-fluorophenyl]-1,2,3,4-tetrahydroisoquinoline-6-sulfonamide

Tsuyoshi Busujima* and Hiroaki Tanaka

*Medicinal Chemistry 3, Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho Kita-ku Saitama 331-9530, Japan

Abstract

An efficient and convenient synthesis of MGAT2 inhibitor, 2-[2-(4-tert-butylphenyl)ethyl]-N-[4-(3-cyclopentylpropyl)-2-fluorophenyl]-1,2,3,4-tetrahydroisoquinoline-6-sulfonamide (1), is reported. The optimized route consists of an effective chlorosulfonylation and debromination, resulting in an increase in the total yield from 6.8% to 45%, compared with our previous method. This synthetic approach enabled the synthesis of 1 to be scaled-up to a multi-gram scale.

■ Inter- and Intramolecular Diels-Alder Reaction of Ethenetricarboxylate Derivatives

Shoko Yamazaki,* Hirotaka Sugiura, Mamiko Niina, Yuji Mikata, and Akiya Ogawa

*Department of Chemistry, Nara University of Education, Takabatake-cho, Nara 630-8528, Japan

Abstract

Inter- and intramolecular [4+2] cycloaddition reactions of highly electron-deficient ethenetricarboxylates have been studied. Intermolecular Diels-Alder reaction of ethenetricarboxylate esters and cyclopentadiene proceeded at room temperature or -20 °C to give cycloadducts with 1:1.5-1.9 endo:exo ratio. Lewis acids such as EtAlCl2, Zn(OTf)2 and Cu(OTf)2 catalyzed reaction at room temperature or -40 °C gave cycloadducts with 3.1-5.4:1 endo:exo ratio. Reaction of N-benzyl- or N-allyl-2-furylmethylamine and 1,1-diethyl 2-hydrogen ethenetricarboxylate in the presence of EDCI/HOBt/Et3N at room temperature led directly to an intramolecular Diels-Alder adduct stereoselectively. The observed stereoselectivities were explained by the use of DFT calculations.

■ Synthesis and Biological Evaluation of Novel Coumarin Derivatives as Antiplatelet Agents

Peng Huang, Lei-Lei Gao, Zhuo Zhang, Jing-Ru Liu, and Li-Qin He*

*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

In order to develop anti-thrombotic agents with higher potency, a series of novel coumarin derivatives (5a-m) were designed, synthesized and biologically evaluated. Compound 5e displayed the strongest activity in inhibiting the adenosine diphosphate (ADP)-induced platelet aggregation in vitro, with 2.3-fold more effectiveness than clinically used antiplatelet drug aspirin (ASP). Thus, Compound 5e could deserve further investigations as antiplatelet agents.

■ Facile and Efficient Synthesis of 2-Aminoquinoline Derivatives Reduced by Zn/AcOH

Guolan Dou,* Deming Wang, and Daqing Shi

*School of Safety Engineering, China University of Mining & Technology, Xuzhou 221116, China

Abstract

In this paper, a simple and efficient method for one-pot synthesis of 2-aminoquinolines was accomplished in good yields via reductive cyclization of nitro and cyano groups mediated by zinc/acetic acid is reported.

■ Ring-Opening Reactions of Aziridines with Carboxylic Acids Catalyzed by DBU

Yanqin Guo, Yepeng Xie, Qin Yang, Songsong Xu, Zhihong Deng, Xuechun Mao, and Yiyuan Peng*

*College of Chemistry & Chemical Engineering, Jiangxi Normal University, Nanchang, Jiangxi 330022, China

Abstract

An efficient ring-opening of aziridines with various carboxylic acids catalyzed by an organocatalyst—DBU afforded the corresponding products in good to excellent yield under mild reaction conditions.

■ Preparation of (+)-Biotin: Process Development and Scale-up

Fei Xiong,* Jin Li, Gen Li, Bo Song, Yu-Xiao Zhou, Fen-Er Chen, and Dan Li

*Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, China

Abstract

A practical asymmetric total synthesis of (+)-biotin based upon the chiral bifunctional sulfamide 8-promoted enantioselective anhydride desymmetrization has been achieved via the key chiral intermediacy of (3aS,6aR)-1,3-bis(4-methoxybenzyl)tetrahydro-4H-thieno[3,4-d]imidazole-2,4(1H)-dione (4). In addition, the installation of the 4-carboxybutyl side chain at C-4 position of 4 was efficiently introduced by an improved C4+C1 strategy.

■ Synthesis of Novel Benzofuro-Fused Thiazolo[3,2-a]pyrimidinones via Pictet-Spengler Reaction

Dao-Lin Wang,* Dong Wang, Jian-Hua Qiang, and Lin Liu

*Liaoning Key Laboratory of Synthesis and Application of Functional Compound, College of Chemistry & Chemical Engineering, Bohai University, Jinzhou 121001, China

Abstract

An efficient method for the preparation of novel benzofuro[3’,2’:2,3]pyrido[4,5:d]thiazolo[3,2-a]pyrimidin-5-ones 5 is described. The key intermediate, 7-(3-amino-2-benzofuran)-5H-thiazolo[3,2-a]pyrimidin-5-one (3), was synthesized from 7-(chloromethyl)-5H-thiazolo[3,2-a]pyrimidin-5-one (1) with salicylonitrile (2) by Thorpe-Ziegler isomerization. Subsequent reaction of the intermediate amine with aromatic aldehydes via Pictet-Spengler reaction provided benzofuro-fused thiazolo[3,2-a]pyrimidines under sulfamic acid as catalyst in good yields.

■ Room-Temperature One-Pot Palladium-Catalyzed Synthesis of 3-Hydroxyisoindolin-1-ones from Phenylglyoxylic Acids

Menglei Yuan, Yu Sun, Hui Yan, Jinxiong Wu, Gaofeng Ma, Feng Li, Siyu Miao, Mengyao Hao, and Na Li*

*Department of Chemical Engineering & Process, North University of China, Changning Road 65, Shuozhou, Shanxi, 036000, China

Abstract

A room-temperature and efficient synthesis of 3-hydroxyisoindolin-1-ones by Pd-catalyzed C-H activation has been proposed. Wide ranges of benzamides and phenylglyoxylic acids indicated good functional group tolerance and wide potential application of this approach. Moreover, good yields of products further made it practical and attractive.