HETEROCYCLES

■ Contents

■ Developments toward the Production of Diverse Natural-Product-Like Compounds: Diversity-Oriented Synthesis and Diversity-Enhanced Extracts

Haruhisa Kikuchi* and Yoshiteru Oshima*

*Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aza-Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan

Abstract

Natural products and their derivatives have proven very useful in the search for biologically active compounds and in the development of new drugs because of their structural diversity. However, new approaches that may increase the chemical diversity of such natural products must be developed in order to retain the future usefulness of these compounds. Diversity-oriented synthesis (DOS) has recently emerged as an efficient methodology for constructing complex and diverse compounds from simple and similar precursors. Through the combination of natural product chemistry and DOS, we therefore propose a new approach, diversity-enhanced extracts, for increasing the diversity of natural-product-like compounds. This review describes recent developments toward the production of diverse natural-product-like compounds by DOS based on natural products and direct chemical derivatization of natural extracts, including diversity-enhanced extracts.

■ Silica Gel-Assisted Preparation of (Bromo)(Chloro)(Iodo)benzo[b]thiophenes Bearing Halogen Atoms at the 2-, 4-, and 7-Positions

Shinichi Mikami, Hiroki Tanaka, Hiroki Kishi, Shuhei Yoshida, and Kozo Toyota*

*Department of Chemistry, Graduate School of Science, Tohoku University, Aoba, Sendai, Miyagi 980-8578, Japan

Abstract

Six types of (bromo)(chloro)(iodo)benzo[b]thiophenes bearing halogen atoms at the 2-, 4-, and 7-positions were prepared from the corresponding 2-(1-adamantylsulfanyl)-1,4-dihalo-3-(haloethynyl)benzene derivatives, by treatment with silica gel under thermal conditions. 4,7-Dihalobenzo[b]thiophenes, bearing two different halogen atoms (chlorine, bromine, or iodine), were also prepared from 2-(1-adamantylsulfanyl)- 3-(ethynyl)-1,4-dihalobenzene derivatives.

■ Synthesis of 4-Aryl and Unsymmetrical 4,6-Diarylpyrimidines by the Suzuki-Miyaura Cross-Coupling Reaction

Sahaj Gupta, Jennifer A. Melanson, M Selim Hossain, Louis Vaillancourt, Gerald J. Tanoury,* William A. Nugent, and Victor Snieckus*

*Department of Chemistry, Queen's University, 90 Bader Lane, Kingston, Ontario K7L 3N6, Canada

Abstract

A two-step procedure for the synthesis of 4-arylpyrimidines from inexpensive 4,6-dichloropyrimidine via a Suzuki-Miyaura/hydrodechlorination reaction sequence is described. The reaction resulted in the predominant formation of mono-arylated product. The cross-coupling of 4-chloro-6-substituted pyrimidines with various aryl/heteroarylboronic acids also furnished 4,6-disubstituted pyrimidines in acceptable yields.

■ An Efficient Synthesis of 4-Mono- and 4,4-Di-substituted 3,4-Dihydro-2H-1-benzothiopyran 1,1-Dioxides by LDA-Mediated Cyclization of o-(Methylsulfonyl)styrenes

Kazuhiro Kobayashi* and Takuma Ueyama

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

Abstract

A new and efficient method for the preparation of 3,4-dihydro-2H-1-benzothiopyran 1,1-dioxide derivatives has been developed. α-Substituted o-(methylsulfonyl)styrenes, which can be derived from α-substituted o-bromostyrenes by an easily operated two-step sequence, are cyclized on treatment with lithium diisopropylamide (LDA) to give, after aqueous workup, the corresponding 4-monosubstituted 3,4-dihydro-2H-1-benzothiopyran 1,1-dioxides. Addition of electrophiles prior to aqueous workup provides 4,4-disubstituted derivatives.

■ Three New 5,6-Dihydro-α-pyrones Isolated from Cryptocarya nitens

Koki Mori, Aiko Shimogomi, Naohito Abe, Manami Haba, Tomoaki Yoshimura, Joko Ridho Witono, Dedy Darnaedi, Toshiyuki Tanaka, Jin Murata, and Masayoshi Oyama*

*Laboratory of Pharmacognosy, Gifu Pharmaceutical University, 1-25-4 Daigaku-Nishi, Gifu 501-1196, Japan

Abstract

Three new 5,6-dihydro-α-pyrone derivatives, named cryptonitenones A–C (1–3), were isolated from the leaves of Cryptocarya nitens Koord. & Valeton. Their absolute structures were determined by means of the NMR and CD spectroscopic analyses. In addition, their deacetyl precursor, cryptomoscatone E3, was obtained from the twigs of the plant.

■ One-Pot Preparation of Ethyl 2(Z)-4-(Anilinoxy)pentenoate by α-Aminoxylation of Propanal Followed by Z-Selective HWE Reaction and the Study on Its Cyclization Reaction

Kaori Ando,* Mami Takao, Ikumi Oyama, and Kouki Furuta

*Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, Yanagido 1-1, Gifu 501-1193, Japan

Abstract

A one-pot sequence of α-aminoxylation of n-propanal catalyzed by L-proline followed by the Z-selective Horner-Wadsworth-Emmons reaction was developed. The highly functionalized chiral γ-anilinoxy-Z-α,β-unsaturated ester 6 was obtained in 57-58% yield with 98:2 Z-selectivity from n-propanal in one-pot procedure. The transformation of the anilinoxy group of 6 into a hydroxyl group can be carried out by treatment with catalytic amount of CuSO4 in methanol to give either the corresponding alcohol 8 or chiral γ-valerolactone 4a in moderate yield. Chiral 6-methyl-2-phenyl-2H-1,2-oxazin-3(6H)-one 7 was obtained in 75% yield from 6 by treatment with CSA.

■ (+)-12-epi-Fragilide G, a New Chlorinated Briarane from the Sea Whip Gorgonian Coral Junceella fragilis

Li-Guo Zheng, Yu-Chia Chang, Jih-Jung Chen, Zhi-Hong Wen,* Tsong-Long Hwang,* and Ping-Jyun Sung*

*National Museum of Marine Biology and Aquarium, Pingtung 944, Taiwan

Abstract

Chemical investigation on the EtOAc-soluble fraction from the MeOH/DCM extract of a gorgonian coral Junceella fragilis afforded a new chlorinated briarane-type diterpenoid, (+)-12-epi-fragilide G (1) and this compound was found to be the enantiomer of (–)-12-epi-fragilide G (2). The structure of 1 was established on the basis of spectroscopic methods. Briarane 1 was found to inhibit the protein expression of pro-inflammatory iNOS in a murine macrophage-like cell line, RAW 264.7, stimulated with LPS and briarane 2 displayed inhibitory an effect on the generation of superoxide anion by human neutrophils.

■ Synthesis of 3-Hydroxy-2,3-dihydro-1H-isoindole-1-thione Derivatives by the Reaction of 2,N-Dilithiobenzamides with Carboxylic Esters

Kazuhiro Kobayashi,* Daiki Fujiwara, Kazuma Nozaki, and Takashi Nogi

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

Abstract

An efficient one-pot method for the preparation of 2,3-disubstituted 3-hydroxy-2,3-dihydro-1H-isoindole-1-thiones from secondary benzothioamides and carboxylic esters has been developed. Thus, the reaction of the starting thioamides with two equivalents of butyllithium generates the corresponding 2,N-dilithiobenzothioamides, which are then allowed to react with carboxylic esters to give the desired products. The similar preparation of 4- and 5-aza-analogues from 2(or 3)-bromopyridine-3(or 4)-carbothioamides, respectively, is also described.

■ Cs2CO3-Promoted Vinylation of Phenols with Trichloroethylene: Facile Synthesis of (E)-1,2-Dichloro-1-phenoxyethenes

Kazunori Takahashi,* Naho Mamiya, Kei Fukushima, Masayoshi Tsubuki, and Toshio Honda

*Institute of Medicinal Chemistry, Hoshi University, Ebara 2-4-41, Shinagawa-ku, Tokyo 142-8501, Japan

Abstract

An efficient method for the synthesis of (E)-1,2-dichloro-1-phenoxyethenes 2 has been developed. The reaction of phenol derivatives 1 with trichloroethylene at ambient temperature by means of Cs2CO3-DMSO system furnished the corresponding aryl vinyl ethers 2 in excellent yields. On the other hand, the same reaction of phenol derivatives 1i, 1k and 1p possessing an electron-withdrawing group at the o- or p-position of the hydroxy group required a harsh reaction conditions to heat at 70 °C for the synthesis of the desired products 2i, 2k and 2p.

■ Two New C19-Diterpenoid Alkaloids from Aconitum franchetii var. villosulum 

Wenliang Xu, Lin Chen, Feng Gao, and Xianli Zhou*

*School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, Sichuan, China

Abstract

Two new C19-diterpenoid alkaloids, named villosudine A (1) and villosudine B (2), along with seven known diterpenoid alkaloids, were isolated from the root of Aconitum franchetii var. villosulum. Their structures were elucidated by extensive spectroscopic analyses including 1D, 2D NMR, and HR-ESI-MS. Compounds (1-7) were evaluated for their cytotoxicity against the MCF-7 and HepG2 human cancer cell lines.

■ New and Convergent Synthesis of Momelotinib Dihydrochloride

Zhiwei Zhao, Mingjie Liu, Yaowei Liu, Yuan Wang, Chuntao Wu, Yongjun Mao, Han Wang,* and Jingli Xu

*College of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, Shanghai 201620, China

Abstract

A new and convergent synthesis of Momelotinib dihydrochloride, a new anticancer drug, is described in this article. The key step is cyclization of 1-(4-morpholinophenyl)guanidine (12) with N-(cyanomethyl)-4-(3-(dimethylamino)acryloyl)benzamide (17) to give Momelotinib under mild condition in 77% yield. The title product is obtained in 52.5% yield over 4 steps and 99.1% purity (HPLC).