HETEROCYCLES

■ Contents

■ Asymmetric Synthesis of Cyclopropylamine Derivatives

Han Wang, Xiaokun Zhou, and Yongjun Mao*

*Department of Medicinal Chemistry, Shanghai University of Engineering Science, 333 Longteng Rd., Songjiang, Shanghai, 201620, China

Abstract

Cyclopropylamines are important synthetic intermediates and their enantiopure forms are also useful as chiral resolving agents. The present review outlines the recent developments on the asymmetric synthesis of cyclopropylamine derivatives. The transformations based on carbene or carbenoid species, asymmetric catalysis, ylide formation, Simmons-Smith, Kulinkovich and Mitsunobu reaction, conjugate addition, Favorskii-type rearrangement and intramolecular cyclopropanations are elaborated.

■ Pyroglutamic Acid Derivatives: Building Blocks for Drug Discovery

Azzurra Stefanucci, Ettore Novellino, Roberto Costante, and Adriano Mollica*

*Dipartimento di Farmacia, Università di Chieti-Pescara “G. d’Annunzio”, Via dei Vestini 31, 66100, Chieti, Italy

Abstract

Substituted prolines namely amino acid proline chimeras, have received a great synthetic efforts with the aim to develop a full library of compounds to be used in bioactive peptides drug discovery. Conversely pyroglutamic acid derivatives, strictly related to proline chimeras have been used only marginally in peptide modifications, probably due the lack of handled asymmetric syntheses. In this work we reviewed the “state of the art” on the synthetic approaches to pyroglutamic acid derivatives bearing a side chain related to that of natural amino acids.

■ Synthesis of Novel Thiazole and 1,3,4-Thiadiazole Derivatives Incorporating Phenylsulfonyl Moiety

Ahmed E. M. Mekky, Ahmed F. Darweesh, Amani A. Salman, and Ahmad M. Farag*

*Department of Chemistry, Faculty of Science, Cairo University, Giza 12613, Egypt

Abstract

Reaction of 1-(benzothiazol-2-yl)-2-phenylsulfonyl-1-ethanone (1) and 1-(1-methyl-1H-benzimidazol-2-yl)-2-(phenylsulfonyl)-1-ethanone (2) with phenyl isothiocyanate afforded the corresponding potassium salts 3 and 4, respectively. The potassium salts 3 and 4 were converted into the corresponding (Z)-1-(benzothiazol-2-yl)-3-mercapto-3-(phenylamino)-2-(phenylsulfonyl) propenone (5) and (Z)-1-(1-methylbenzimidazole-2-yl)-3-mercapto-3-(phenylamino)-2-(phenylsulfonyl)propenone (6), respectively upon acidification with HCl. The latter products were used as versatile building blocks for novel 1,3,4-thiadiazole derivatives via their reactions with the appropriate hydrazonyl halides. They have been also utilized for the synthesis of thiazole ring systems incorporating phenylsulfonyl moiety.

■ Synthesis and Characterization of N-Substituted (S)-1,2,3,4-Tetrahydroisoquinoline-3-carboxamides and Thioamides as Organocatalysts for Asymmetric Aldol Reaction

Ladislav Androvič, Pavel Drabina,* Illia Panov, Lydie Harmand, Zdeňka Padělková, and Miloš Sedlák

*Institute of Organic Chemistry and Technology, University of Pardubice, Studentská 573, Pardubice, 532 10, Czech Republic

Abstract

In this paper, the preparation and characterization of eight optically pure N-functionalized (S)-1,2,3,4-tetrahydroisoquinoline-3-carboxamides and thioamides is described. The prepared amides and thioamides were tested as organocatalysts of aldol reaction of 4-nitrobenzaldehyde and acetone. The highest ee of formation of 4-hydroxy-4-(4-nitrophenyl)butan-2-one was obtained with (S)-N-[(1R)-1-phenylethyl]-1,2,3,4-tetrahydroisoquinoline-3-thiocarboxamide (77% ee). The observed deceleration of the aldol reaction catalyzed in this way, as compared with that catalyzed with (S)-proline, was attributed to the formation of little reactive cyclic intermediate, which was isolated and characterized.

■ Synthesis of Sunitinib-Metastin Conjugate, a Novel Esterase-Sensitive Prodrug System Based on Lactonization Reaction

Yuki Takahashi, Sunao Shoji, Takuya Morishige, Aya Katsumata, Fumihiro Tsurifune, Mitsuhiro Tsutsumi, Yoshiharu Honda, Tomoyo Hasuda, Yukio Hitotsuyanagi, Toshiro Terachi, Toyoaki Uchida, and Koichi Takeya*

*Department of Natural Products and Medicinal Chemistry, School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan

Abstract

We describe a strategy for preparing sunitinib−metastin conjugate, a prodrug composed of the anticancer agent sunitinib for renal cell carcinoma and the carrier protein metastin, which are conjugated to each other by a linker. We designed a modified L-homoserine linker, which is composed of an acyl group that acts as the masking group for hydrolysis with an esterase, as well as a carbon chain of appropriate length between sunitinib and metastin. The sunitinib−metastin conjugate was converted into a hydrolyte by hydrolysis of the acyl group with an esterase, and sunitinib was released by intramolecular lactonization. Sunitinib−metastin conjugate, an esterase-sensitive amide prodrug that has a modified L-homoserine linker that participates in the intramolecular lactonization, was synthesized.

■ 9-Alkylacridine Synthesis Using 2,2-Dimethoxypropane as Water Scavenger

George Bratulescu*

*Department of Chemistry, University of Craiova, 13 A.I. Cuza, 200396 Craiova, Romania

Abstract

A rapid and high yielding green method was developed for acridine derivative synthesis in solvent free medium. The commercial reagents are easily converted into products by using of microwaves in a heterogeneous medium in presence of zinc chloride and 2,2-dimethoxypropane. Principal advantages of the procedure are short time, low energy consumption, and easy work-upStart here.) All manuscripts must be accompanied by an abstract.

■ A New and Practical Synthesis of 7-(3-Chloropropoxy)-6-methoxy-4-oxo-1,4-dihydroquinoline-3-carbonitrile

Yongjun Mao, Jianfeng Qin, Haijun He, Gang Liu, Bingyi Gao, and Han Wang*

*Department of Medicinal Chemistry, Shanghai University of Engineering Science, 333 Longteng Rd., Songjiang, Shanghai, 201620, China

Abstract

New and improved synthetic route of bosutinib intermediate 7-(3-chloropropoxy)-6-methoxy-4-oxo-1,4-dihydroquinoline-3-carbonitrile (3) is described on a hectogram scale. An intramolecular cyclization of 3-(2-aminophenyl)-3-oxopropanenitrile 11 with DMF-DMA to form the 4-oxo-1,4-dihydroquinoline-3-carbonitrile ring is adopted as the key step. Product 3 is obtained with 29.8% yield over eight steps and 98.6% purity (HPLC), which make it as a process of cost effective, environmental friendly and feasible for scale-up operation.

■ Multicomponent and Regioselective Synthesis of Dihydropyrazolo[1,5-a]pyrimidines from Aromatic Aldehydes, Meldrum’s Acid, and Aminopyrazole CAN508

Lukáš Jedinák, Vladimír Kryštof, Zdeněk Trávníček, and Petr Cankař*

*Department of Organic Chemistry, Palacký University, 17. listopadu 12, 77146 Olomouc, Czech Republic

Abstract

A regioselective synthesis of dihydropyrazolo[1,5-a]pyrimidines is reported. The multicomponent reaction of readily available arylaldehydes, Meldrum´s acid, and aminopyrazole CAN508 afforded fused pyrazolopyrimidines in high yields. The reaction proceeded regioselectively via initial Michael addition of the exocyclic amino group to arylidene Meldrum´s acid intermediate followed by a ring closure at the endocyclic nitrogen of aminopyrazole. The regioselectivity of the reaction was determined by X-ray crystallography.

■ Synthesis of 2-Hydroxymethyl-2,3-dihydrobenzofurans

Meng-Yang Chang,* Shin-Ying Lin, and Chieh-Kai Chan

*Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, TaiwanNo. 100, Shih-Chuan 1st Rd., San Ming District, Kaohsiung 80708, Taiwan, R.O.C.

Abstract

A one-pot protocol toward 2-hydromethyl-2,3-dihydrobenzofurans (1) starting with oxygenated o-allylbenzaldehydes (3) was described. The facile one-pot process was carried out the oxidation of o-allylbenzaldehydes (3) with Oxone in the co-solvent of acetone and DMF in the presence of aqueous EDTA solution and then intramolecular ring-closure of the resulting o-allylphenols (2) in acceptable yields.

■ A New Cyclic Triterpene Saponin from Phyteuma japonicum

Chung Sub Kim, Oh Wook Kwon, Sun Yeou Kim, Ki Hyun Kim, and Kang Ro Lee*

*Natural Products Laboratory, School of Pharmacy, Sungkyunkwan University, 300 Chunchun-dong, Jangan-ku, Suwon 440-746, Korea

Abstract

A new cyclic triterpene saponin, phyteujaposide (1) and eight known compounds (2-9) were isolated from the leaves of Phyteuma japonicum. The structure of the new compound (1) was elucidated by 1D and 2D data analysis, acid hydrolysis and GC-MS. Compounds 7 and 9 potently inhibited the NO production in LPS-activated BV-2 cells and compounds 5 and 6 showed a significant secretion induction of NGF in C6 glioma without cell toxicity.

■ Design, Synthesis and Antiproliferative Activity Evaluation of New 5-Azaisoindigo Derivatives

Ping Zhao, Yun Yan, Yanzhong Li, Aiying Zhang, Xiaoping Zhan, Zenglu Liu, Zhenmin Mao,* Shaoxiong Chen, and Liqun Wang

*School of Pharmacy, Shanghai Jiaotong University , No.800 Dongchuan Road, Minhang District, Shanghai 200240, China

Abstract

New 5-azaisoindigo derivatives were synthesized with two key intermediates 5-azaoxindole (7) and substituted indole-2,3-dione (10) in this paper. Intermediate 7 was prepared using 3-methylpridine (1) as the starting material via oxidation, nitration, condensation and cyclization, bromination and reduction reactions. Intermediate 10 was obtained by a convenient Sandmeyer’s method. The target compounds 5-azaisoindigo derivatives 11a-f were obtained by condensation of these two intermediates 7 and 10 in acidic condition. All target compounds were evaluated for their antiproliferative activity against seven cell lines by SRB assay. Compounds 11e and 11f showed significant antiproliferative activity against K562 cells (IC50: 8.9 µM and 13.6 µM, respectively).

■ A Simple Method for the Preparation of Pyrimido[4,5-d]pyrimidine-2,4(1H,3H)-dithione Derivatives

Kazuhiro Kobayashi,* Minami Kuroda, Noriyuki Tanaka, Yuki Yokoi, Akihiro Kobayashi, Hidetaka Hiyoshi, and Kazuto Umezu

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

Abstract

A facile and efficient two-step sequence for the preparation of 1,3-disubstituted pyrimido[4,5-d]pyrimidine-2,4(1H,3H)-dithiones starting with 4-chloro-6-methoxy-2-(methylsulfanyl)pyrimidine has been developed. Thus, the reaction of 4-chloro-5-lithio-6-methoxy-2-(methylsulfanyl)pyrmidine, generated by the treatment of the starting material with lithium diisopropylamide (LDA), with some aliphatic isothiocyanates gives N-alkyl-4-chloro-6-methoxy-2- (methylsulfanyl)pyrimidine-5-carbothioamides, which are then allowed to react with various isothiocyanates in the presence of sodium hydride to give the desired products. This method is applicable to the synthesis of 1,3-disubstituted 4-thioxo- 3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-ones using phenyl isocyanate in place of isothiocyanates.

■ Corrigendum to “Synthetic Exploitation of Halogenated Alkenes Containing Electron-Withdrawing Group (EWG): Access to Valuable 2,4-Dinitrothiophenes via Ring-Closing and Ring-Opening/Ring-Closing Protocols” : HETEROCYCLES, 2013, 87, 2589 : DOI: 10.3987/COM-13-12860

Amac Fatih Tuyun*

*Department of Chemical Engineering, Engineering and Architecture Faculty, Beykent University, 34396, Turkey