HETEROCYCLES

■ Contents

■ Total Synthesis of Strychnine

Miwako Mori*

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

Abstract

Strychnine is one of the most famous and complex natural products in its size. Woodward succeeded in the total synthesis of (-)-strychnine in 1954, but there were no other reports of the total synthesis of strychnine for about 40 years. In 1992, Magnus succeeded in the total synthesis of (-)-strychnine and then due to the dramatic progress of synthetic organic chemistry and organometallic chemistry, many researchers tried to synthesize (±)- and (-)-strychnine by their original methods. We developed a novel synthetic method of a chiral cyclohexenyl amine derivative having an aryl group at the 2-posotion by palladium catalyst for the synthesis of (-)-mesembrine. Furthemore, (+)-crinamine, (-)-haemanthidine, and (+)-pretazettine could be synthesized by the same procedure. Modifying this method, the total synthesis of (-)-strychnine was achieved. The chiral cyclohexenyl amine derivative having the sylyloxymethyl group at the 2-position was synthesized using the palladium catalyst. From this comopound, construction of the ABE-rings of (-)-strychnine was carried out. The C-ring was constructed using palladium-catalyzed allylic oxidation. The G-ring and then the F-ring were constructed by intramolecular Heck reaction. All cyclizations for synthesis of (+)-isostrychnine were performed using palladium catalysts. (+)-Isostrychnine was converted into (-)-strychnine by the known method. The progress of the synthesis of a chiral cyclohexenyl amine derivative having the substituent at the 2-position was described.

■ Stereoselective Intramolecular Cyclization of Isopentenyl Benzamide via π-Allylpalladium Complex Catalyzed by Pd(0)

Jae-Eun Joo, Yu Mu, Yiu-Suk Lee, Yong-Shou Tian, Gyu-Jin Lee, and Won-Hun Ham*

*Department of Chemistry, Sung Kyun Kwan University, Suwon 440-746, Korea

Abstract

An efficient procedure was developed to synthesize oxazoline as key intermediate in the total synthesis of (+)-lactacystin using palladium(0)-catalyzed intramolecular cyclization of isopentenyl benzamide via a π–allylpalladium complex. A convenient and efficient method was developed for the synthesis of the optically pure α-amino-β-hydroxy acid.

■ From 2,3-, 2,6-, 3,4- and 4,6-Dichloroquinolines to Isomeric Chloroquinolinesulfonyl Chlorides

Krzysztof Marciniec* and Andrzej Maślankiewicz

*Department of Organic Chemistry, The Medical University of Silesia, Jagielloñska Str. 4, 41-200 Sosnowiec, Poland

Abstract

The action of sodium methanethiolate (in boiling DMF) on x,y-dichloroquinolines (1) (x=3 or 6, y=2 or 4) occured via chlorine ipso-substitution followed by methanethiolato-S-demethylation to yield x,y-quinolinedithiolates 2A which were: i) subjected to S-methylation, ii) oxidatively chlorinated to y-chloro-x-quinolinesulfonyl chlorides (5). Oxidative chlorination of y,y'-bis(x-chloroquinolinyl) disulfides (7) led to x-chloro-y-quinolinesulfonyl chlorides (8) accompanied by x,y-dichloroquinolines (1). Both quinolinesulfonyl chlorides 5 and 8 were efficiently converted to the corresponding quinolinesulfonamides 6 and 9.

■ One-Pot Aryl-1,4-thiomorpholine 1,1-Dioxide Synthesis via Double 1,4-Addition of in situ Reduced Nitroarenes to Divinyl Sulfones

Joon Hee Han, Jaehwan Choi, Young Moo Jun, Byung Min Lee, and Byeong Hyo Kim*

*Department of Chemistry, Kwangwoon University, 447-1, Wolgye-Dong Nowon-ku, Seoul, 139-701, Korea

Abstract

One-pot reduction-triggered double aza-Michael type 1,4-addition reactions of various nitroarenes to divinyl sulfones were investigated. In the presence of indium/AcOH in MeOH or in sat. aq NH4Cl/MeOH, nitroarenes and divinyl sulfones were cyclized to give 1,4-thiomorpholine 1,1-dioxides.

■ Cyclization of 5-Cyano-6-cyanoimino-3,4-dihydropyridin-2(1H)-ones with Amines

Núria Mont, Francisco Carrión, José I. Borrell,* and Jordi Teixidó

*Molecular Engineering Group, IQS, Ramon Llull University, Via Augusta 390, E-08017 Barcelona, Spain

Abstract

The cyclization of 5-cyano-6-cyanoimino-3,4-dihydropyridin- 2(1H)-ones with amines, leading to pyrido[2,3-d]pyrimidines, is studied. Four factors play an important role on the direction of cyclization: (1) the planarity of the reaction area; (2) the cyclization proceeds by the nucleophilic attack of an amidine onto an electrophilic group which can be either a cyano group or an alkylamidine; (3) the basicity of the amine plays an important role, the ionization of the substrate making more difficult the formation of the aforementioned amidine which is needed for the cyclization; and (4) the nucleophilic attack and the tautomerization of the cyclization product are processes which can occur practically simultaneously, so that the electronic movement involved in the tautomerization process coincides with the one which happens in the nucleophilic attack, both processes promoting each other.

■ Facile Synthesis of 3-Methoxycarbonyl-2,2,5,5-tetra-methylpyrrolidine-1-oxyl and Derivatives

Bunpei Hatano,* Hiroki Araya, Yutaka Yoshimura, Haruna Sato, Tomohiro Ito, Tateaki Ogata, and Tatsuro Kijima

*Graduate School of Science and Engineering, Yamagata University, 3-16 Jonan 4-Chome, Yonezawa 992-8510, Japan

Abstract

We have achieved an efficient alternative synthesis of blood-brain-barrier permeable nitroxyl radicals 3-methoxycarbonyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl (1a) and 3-ethoxycarbonyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl (1b), which affords 1a and 1b in 65% isolated yields by four steps from 2,2,6.6-tetramethyl-4-piperidone (2), respectively. This protocol is applicable to the synthesis of 3-isopropoxy-2,2,5,5-tetramethylpyrrolidine-1-oxyl (1c) and 3-carbonyl-2,2,5,5-tetramethylpyrro-lidine-1-oxyl (6).

■ A Concise Synthesis of Fluorine-Containing Benzo[h]quinolines and Benzo[h]quinolones by Selective Pyridine and Pyridinone Rings Formation Reactions of N-Propargyl-2,4-bis(trifluoroacetyl)-1-naphthylamine with Various Active Methylene Compounds

Etsuji Okada,* Dai Shibata, Norikado Tsukushi, Masato Dohura, Norio Ota, Satoru Adachi, and Maurice Médebielle

*Department of Chemical Science and Engineering, Graduate School of Engineering, Kobe University, 1-1 Rokkodai-cho, Nada-ku, Kobe 657-8501, Japan

Abstract

N-Propargyl-2,4-bis(trifluoroacetyl)-1-naphthylamine (3) underwent nitrogen-containing heterocyclic ring-formation reactions with a variety of active methylene compounds in the presence of sodium alkoxides. This annulation reactions with dialkyl malonates were highly dependent on reaction temperature to give selectively the corresponding fluorine-containing benzo[h]quinolines (5) at high temperature and 1H-benzo[h]quinolin-2-ones (7 and 8) at low temperature. Furthermore, changing the electron-withdrawing groups of active methylene compounds led to alternation of the reactive site wherein the reagents attack first and to the formation of the different nitrogen-containing heterocyclic systems, pyridine (9), dihydropyridine (11 and 13) and pyridone (12)

■ Synthesis of a 6H-Chromeno[3,4-b]quinoline and a 6a,12a-Dehydro-7-azarotenoid

Andrew L. C. Morris and Yvette A. Jackson*

*Department of Chemistry, Mona Campus, University of the West Indies, Mona, Kingston 7, Jamaica

Abstract

The preparation of a 6H-chromeno[3,4-b]quinoline via a palladium-mediated coupling reaction, and the first synthesis of a nitrogenous dehydro-analogue of the naturally occurring rotenoids are reported.

■ Synthesis of 20-Epi-eldecalcitol [20-Epi-1α,25-dihydroxy-2β-(3-hydroxypropoxy)vitamin D3: 20-Epi-ED-71]

Madoka Yoshino, Kohei Eto, Keisuke Takahashi, Jun Ishihara, Susumi Hatakeyama, Yoshiyuki Ono, Hitoshi Saito, and Noboru Kubodera*

*Chugai Pharmaceutical Company, Ltd., 2-1-1, Nihonbashi-Muromachi, Chuo-ku, Tokyo 103-8324, Japan

Abstract

A convergent synthesis of biologically interesting 20-epi-eldecalcitol which possesses an inverted C-21 methyl substituent at the 20-position of the side chain of 1α,25-dihydroxy-2β-(3-hydroxypropoxy)vitamin D3 (eldecalcitol) is described.

■ Synthesis of Some New Pyridazinylspirohetarylindoles and Hetarylpyridazine Derivatives

Yassin Gabr,* Mohamed Abdel-Megid, Mohamed Abdel-Hamid Awas, and Naser Mohamed Abdel-Fatah

*Department of Chemistry, Faculty of Education, Ain Shams University, El-Maqreezy St, Roxy, Heliopolis, Cairo 11757, Egypt

Abstract

Condensation of 4-acetyl-5,6-diphenylpyridazine-3(2H)-one (1) with 1H-indol-2,3-dione afforded the biheterocyclic enone 2. Interaction of 2 with some bifunctional nitrogen nucleophiles and dimedone yielded some novel pyridazinyl spirohetarylindoles 3-6. The reaction of 3-chloropyridazine derivative 7 with some heterocyclic compounds having vicinal amino and cyano groups gave hetarylaminopyridazines 9 and 13. Treatment of acetylpyridazinone 1 with arylidenecyanoacetate and arylidenemalononitrile afforded pyridylpyridazines 16 and 19, respectively. The effect of some active methylene compounds and thioacetamide on biheterocyclic enone 22 was also studied.

■ 15N NMR Spectroscopy of Annulated Δ2-Pyrazolines and Δ2-1,2,4-Triazolines

Teresa Recca, Lara De Benassuti, and Giorgio Molteni*

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

Abstract

Enantiopure Δ2-pyrazolines and Δ2-1,2,4-triazolines fused to the 1,4-benzodiazepine moiety, as well as Δ2-pyrazolines annulated to the 1,5-benzoxazocine moiety (racemic) or inserted in a bis-1,3-pyrazolophane skeleton (enantiopure) were investigated through 15N NMR spectroscopy in natural abundance. Nitrogen chemical shifts were determined by (1D)-INEPT experiments, while proton-nitrogen scalar coupling were obtained through 2D-J-HMBC experiments

■ S-Methylation of N-Containing Heterocyclic Thiols with Conjugated Acids of Methoxy Groups

Masao Shimizu,* Teruaki Shimazaki, Yoshihiro Kon, and Takeo Konakahara

*Research Institute for Innovation in Sustainable Chemistry, National Institute of Advanced Industrial Science and Technology, 1-1-1 Higashi, Tsukuba, Ibaraki 305-8565 Tsukuba, Japan

Abstract

2-Mercaptopyridine-3-carboxylic acid reacts with methanol under acidic conditions to afford the corresponding S-methylated methyl ester, methyl 2-methylthiopyridine-2-carboxylate. Such S-methylation occurred for various N-containing heterocyclic thiols with acidic methanol. The reaction proceeded by the attack of mercapto groups on the conjugated acid of methanol. Therefore, the sulfur atom of pyridine-2-thiol was also methylated with acidic methyl ethers or methyl esters.

■ Synthesis of Optically Active γ-Valerolactone and γ-Nonanolactone via Optical Resolution Using Chiral Amine Derived from Amino Acid

Kenichi Yumoto, Morifumi Hasegawa, and Hiroaki Toshima*

*Department of Bioresource Science, College of Agriculture, Ibaraki University, ,

Abstract

Optically active γ-valerolactone and γ-nonanolactone have been synthesized via optical resolution using a newly developed chiral amine derived from L-phenylalanine. Both racemic γ-lactones were transformed to corresponding diastereomeric amides by amidation with the optical resolution agent. Fractional crystallization of diastereomeric amides, recrystallization of each diastereomer, and subsequent hydrolysis gave optically active γ-valerolactone and γ-nonanolactone with sufficient enantiomeric excess and isolated yield. The optical resolution agent was recovered after hydrolysis.

■ Synthesis of 1-(1-Arylsulfanylalkyl)indoles and 2,2-Bis[1-(1-arylsulfanylalkyl)indol-3-yl]propanes by Acid-Catalyzed Reactions of Indoles with Aryl Vinyl Sulfides

Kazuhiro Kobayashi,* Yuu Shirai, Shuhei Fukamachi, and Hisatoshi Konishi

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

Abstract

We report a facile synthesis of 1-(1-arylsulfanylalkyl)indoles and 2,2-bis[1-(1-arylsulfanylalkyl)indol-3-yl]propanes under mild conditions. Thus, treatment of 3-substituted indoles with aryl vinyl sulfides in dichloromethane at room temperature in the presence of a catalytic amount of (±)-camphor-10-sulfonic acid yields the former indole derivatives in moderate to fair yields. 3-Nonsubstituted indoles could be transformed into the latter indole derivatives in satisfactory yields on treatment with excess aryl vinyl sulfides in the presence of a catalytic amount of the acid under similar conditions.

■ Cephastigiamide A, and Antiplasmodial Activity of Cephalotaxus Alkaloids from Cephalotaxus harringtonia Forma Fastigiata

Hiroshi Morita,* Yuta Nagakura, Takahiro Hosoya, Wiwied Ekasari, Aty Widyawaruyanti, Kanami Mori-Yasumoto, Setsuko Sekita, and Yusuke Hirasawa

*Faculty of Pharmaceutical Sciences, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan

Abstract

A new Cephalotaxus alkaloid, cephastigiamide A (1), has been isolated from the leaves of Cephalotaxus harringtonia forma fastigiata and the structure was elucidated by 2D NMR analysis and chemical degradation. Harringtonine, deoxyharringtonine, and homodeoxyharringtonine showed pronounced antiplasmodial activity against Plasmodium falciparum 3D7 but not against Leishmania major. Structure-activity relationship for antiplasmodial activity of isolated Cephalotaxus alkaloids was also discussed.