HETEROCYCLES

■ Contents

■ β-Amino Alcohol Organocatalysts for Asymmetric Additions

Hiroto Nakano,* Isiaka Alade Owolabi, Madhu Chennapuram, Yuko Okuyama, Eunsang Kwon, Chigusa Seki, Michio Tokiwa, and Mitsuhiro Takeshita

*Division of Sustainable and Environmental Engineering, Graduate School of Engineering, Muroran Institute of Technology, 27-1 Mizumoto, Muroran, Hokkaido 050-8585, Japan

Abstract

A design of a chiral organocatalyst is very important for obtaining of a chiral product with a high optical purity in a catalytic asymmetric reaction. Recently, we developed a series of chiral β-amino alcohol organocatalysts A that showed high level of catalytic activity in some asymmetric reactions. These β-amino alcohols are stable in air, and have two advantageous features, easy preparation and exhibiting high stereoselectivity in an enantioselective reaction. This review summarizes our recent works involving the Diels-Alder (DA) reactions of 1,2-dihydropyridines, anthrones or 3-hydroxy-2-pyridones as dienes with dienophiles, the asymmetric 1,3-dipolar cycloaddition of nitrones with α,β-unsaturated aldehydes and the crossed aldol reaction of isatins with acetaldehyde, by the use of the simple primary β-amino alcohols as efficient chiral organocatalysts for the asymmetric reactions.

■ Cycloaddition Reactions of N-Alkyl-α,β-unsaturated Imines: Facile Preparation of Azaheterocycles for Synthesis and Biological Applications

Ambara R. Pradipta, Liliya Latypova, Dilyara Chulakova, Ivan Smirnov, Almira Kurbangalieva, and Katsunori Tanaka*

*Biofunctional Synthetic Chemistry Laboratory, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan

Abstract

In this review, we will describe the utilization of formal [4 + 4] cycloaddition reaction of N-alkyl-,-unsaturated imines derived from acrolein and biogenic alkylamines to synthesize 2,6,9-triazabicyclo[3.3.1]nonanes and 1,5-diazacyclooctanes. We also include here a new structural data of 1,5-diazacyclooctane determined by X-ray crystallography. Biological examination of 1,5-diazacyclooctanes revealed for the first-time its role in inhibition of amyloid- (A) 1-40 fibrillization. Eventually, we also found that when substituted or unsubstituted acrolein is reacted with chiral ethanolamine in the presence of formaldehyde, then hexahydropyrimidines or 1,3,5-triazacyclooctanes were produced in high yield and stereoselectivity through formal [4 + 2] or [4 + 2 + 2] cycloaddition reactions. Lastly, simple functional group manipulations of the cycloaddition products can be used to synthesize chiral 1,3-diamines, which could not be simply accessed by other methods.

■ Synthesis of Novel 1,3-Dioxa-5-thiazatriquinane and 1-Oxa-3,5-dithiazatriquinane Derivatives and Their Pharmacologies

Ryuichiro Ohshita, Noriki Kutsumura, Yasuyuki Nagumo, Naoshi Yamamoto, Tsuyoshi Saitoh, Shigeto Hirayama, Hideaki Fujii, and Hiroshi Nagase*

*International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan

Abstract

Novel triplet compounds with the 1,3-dioxa-5-thiazatriquinane and 1-oxa-3,5-dithiazatriquinane skeletons have been synthesized via the enantiomerically pure oxazoline intermediates. Their assay results showed that the substitution of sulfur atoms for the oxygen atoms increased the affinities for the opioid receptors and affected to the expression of the agonistic/antagonistic activities.

■ Ruthenium-Catalyzed [2 + 2] Cyclization of 1,7-Allenynes in Ionic Liquid and Catalyst Recycling

Nozomi Saito,* Momoko Koyama, and Yoshihiro Sato

*Faculty of Pharmaceutical Sciences, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan

Abstract

Ruthenium-catalyzed [2 + 2] cyclization of 1,7-allenynes in ionic liquid ([BDMI]PF6) as a reaction medium proceeded to give the corresponding bicyclo[4.2.0]octa-1(8),5-diene derivative in high yield. Furthermore, the recovered catalyst immobilized in the ionic liquid could be recycled up to 10 times.

■ Synthetic Study of Thermolides: Stereoselective Construction of the C10-C21 Fragment

Hikaru Yoshimura, Jun Ishihara, and Susumi Hatakeyama*

*Medical Innovation Center, Nagasaki University, 1-14, Bunkyo-machi, Nagasaki 852-8521, Japan

Abstract

The C10-C21 fragment of nematocidal thermolides, macrocyclic PKS-NRPS hybrid metabolites isolated from a thermophilic fungus, was prepared in a highly stereoselective manner. The stereocontrol was accomplished by taking advantage of a cinchona alkaloid-catalyzed Morita-Baylis-Hillman reaction followed by diastereoselective hydrogenation and a cinchona alkaloid-catalyzed asymmetric β-lactone formation.

■ Dramatic Enantioselectivity Reversal in the Propargylation of Aldehyde with Alkynyllithium Catalyzed by Dilithium Binaphtholate Derivatives

Makoto Nakajima,* Rika Watanabe, Kazuki Osakama, Midori Sakamoto, Daijiro Takemoto, and Kenji Kukita

*Department of Pharmaceutical Sciences, Graduate School of Life Sciences, Kumamoto University, 5-1 Oe-hon-machi, Kumamoto 862-0973, Japan

Abstract

A slight structural modification of a chiral catalyst caused a dramatic reversal in the enantioselectivity of an aldehyde propargylation using alkynyllithium.

■ First Asymmetric Total Synthesis of (-)-Isostemonamine and Kinetic Analysis of Its Isomerizations

Takayuki Iwata, Taishi Tomiyama, Satoshi Fujita, and Mitsuru Shindo*

*Institute for Materials Chemistry and Engineering (IMCE), Kyushu University, 6-1, Kasuga-koen, Kasuga, Fukuoka 816-8580, Japan

Abstract

The first asymmetric total synthesis of (−)-isostemonamine is reported herein. The key reactions include the regioselective oxidation of the diketone, which is reported to be an intermediate in our synthesis of (−)-stemonamine. The chiral high-performance liquid chromatography (HPLC) analysis of the racemization and epimerization of (−)-isostemonamine revealed that isostemonamine isomerizes significantly faster than stemonamine.

■ Efficient One-Pot Synthesis of Substituted Oxazoles from 3-Trimethylsilylpropargylic Alcohols and Amides by Gold-Catalyzed Substitution Followed by Cycloisomerization

Nobuyoshi Morita,* Aoi Sano, Ayako Sone, Shino Aonuma, Arisa Matsunaga, Yoshimitsu Hashimoto, and Osamu Tamura*

*Laboratory of Organic Chemistry, Pharmaceutical Sciences, Showa Pharmaceutical University, 3-3165, Higashi-tamagawagakuen, Machida, Tokyo 194-8543, Japan

Abstract

3-Trimethylsilylpropargylic alcohols 1, on treatment with amides 2 in the presence of catalytic amounts of cationic gold(III), underwent propargylic substitution followed by cycloisomerization. The key of the cycloisomerization, in which the key feature is the β-cation-stabilizing effect of the silicon atom of 3-trimethylsilyl-propargylic alcohols 1.

■ β-Selective D-Psicofuranosylation of Pyrimidine Bases and Thiols

Atsushi Ueda,* Yuri Nishimura, Yui Makura, Masakazu Tanaka, and Jun'ichi Uenishi

*Department of Molecular Medicinal Sciences, Graduate School of Biomedical Sciences, Nagasaki University, 1-14, Bunkyo-machi, Nagasaki 852-8521, Japan

Abstract

N-Glycosidation of D-psicofuranosyl donor 1 with pyrimidine bases took place β-selectively in a β/α-ratio of 8:1 ~ 7:1. For S-glycosidation, 3,4-O-(3-pentylidene)-protected D-psicofuranosyl donor 15 was effective to increase β-selectivity up to 7:1.

■ Palladium-Catalyzed Asymmetric Haloiminolactonization of α-Allylmalonamides

Masami Kuriyama, Kosuke Yamamoto, Keiko Ishimaru, Noriyuki Fujimura, Daishiro Minato, and Osamu Onomura*

*Department of Natural Product Chemistry, Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan

Abstract

A catalyst composed of 10 mol% of Pd(OAc)2 and (R,R)-PhBox was proven to be effective in the asymmetric haloiminolactonization of α-allylmalonamides with N-halosuccinimides, giving the dihalogenated cyclic products with good diastereomeric ratio (up to 89/11) and enantiomeric excess (up to 72% ee).

■ Synthesis of Iodinated Thiazolo[2,3-a]isoquinolinium Salts and Their Crystal Structures with/without Halogen Bond

Shoji Matsumoto,* Ryuta Sumida, Sia Er Tan, and Motohiro Akazome

*Department of Applied Chemistry and Biotechnology, Graduate School of Engineering, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan

Abstract

We investigated the cyclization reaction of 2-(2-(phenylethynyl)- phenyl)thiazoles with I2. A six-membered ring was formed to produce the corresponding thiazolo[2,3-a]isoquinolin-7-ium salts. The counter anions (I− and I3−) varied based on the structure of the thiazole moiety. We also revealed the single-crystal X-ray structures of those thiazolo[2,3-a]isoquinolin-7- ium salts. We discovered that various structures with and without halogen bonds existed, although they were the prospective structures to make “charge-assisted halogen bonds”.

■ A Practical Synthesis of Glycinamide Ribonucleotide

Debarpita Ray, Penny J. Beuning,* Mary Jo Ondrechen,* and George A. O'Doherty*

*Department of Chemistry and Chemical Biology, Northeastern University, 360 Huntington Avenue, Boston, MA 02115-5096, U.S.A.

Abstract

A practical nine-step synthesis of an alpha-/beta-anomeric mixture of glycinamide ribonucleotide (GAR) has been developed. The synthesis was accomplished in eight steps from D-ribose and occurred in 9.5% overall yield. The route as devised provided material on the multi-milligram scale

■ Construction of Azaisoflavone Derivatives by Hypervalent Iodine Reagent-Mediated Oxidative Rearrangement of 2’-Nitrochalcone

Akira Nakamura, Reo Takane, Junki Tanaka, Junya Morimoto, and Tomohiro Maegawa*

*School of Pharmaceutical Sciences, Kindai University, 3-4-1 Kowakae, Higashi-Osaka, Osaka 577-8502, Japan

Abstract

Fabrication of a synthetic azaisoflavone skeleton from 2’-nitrochalcone was done using oxidative rearrangement with a hypervalent iodine reagent. A key intermediate compound, aminoacetal, was prepared from readily available 2’-nitrochalcone via a PhI(OH)OTs-mediated rearrangement, followed by reduction of the nitro group. A variety of azaisoflavones were obtained in moderate to high yields by treatment of the intermediate compound under acidic conditions.

■ Heterogeneous Copper–Catalyzed Synthesis of S–Arylated 2-Aminothiophenols via Ring Opening of Benzothiazoles and C–S Coupling using Aryl Halides

Tomohiro Ichikawa, Tomohiro Matsuo, Takumu Tachikawa, Yoshinari Sawama, Yasunari Monguchi, and Hironao Sajiki*

*Laboratory of Organic Chemistry, Department of Pharmaceutical Sciences, Gifu Pharmaceutical University, 1-25-4 Daigakunishi, Gifu 501-1196, Japan

Abstract

Chelate resins, which are polystyrene-divinylbenezene-based polymers bearing iminodiacetic acids or polyamines as ligands, supported copper catalysts (Cu/CR11 or Cu/CR20) in effectively catalyzing the ring cleaving S-arylation of benzothiazole with aryl iodides or aryl bromides in the presence of lithium tert-butoxide in aqueous 2-propanol.

■ Activation of Grubbs–Hoveyda Second-Generation Catalysts Employing Aromatic Ligands Bearing a Widespread Aryl Substituent

Yuki Kobayashi, Rina Igarashi, Yuta Ishikawa, Sae Inukai, Kento Shimowaki, Yuya Sugiyama, Takayuki Shioiri, and Masato Matsugi*

*Department of Applied Biological Chemistry, Faculty of Agriculture, Meijo University, 1-501 Shiogamaguchi, Tempaku-ku, Nagoya, Japan

Abstract

In this study, an activation strategy for Grubbs–Hoveyda second-generation-type catalysts by utilizing the intramolecular steric strain on the ligands is described. The variant, which is expected to exhibit intramolecular steric strain, containing extensively spread aromatic and alkoxy groups in the ligand structure was prepared and examined. The combination of tricyclic anthracenyl and isopropoxy groups are observed to exhibit the highest catalytic activity among these synthetic catalysts. The activated catalyst was successfully used in a ring-closing metathesis reaction depicting a catalyst loading of the order of 20 mol ppm in dry benzene. The X-ray crystallographic analysis suggests the existence of an intramolecular CH/π interaction between the sp2 carbon of the anthracenyl group and the methyne hydrogen of the isopropoxy group.

■ Substituent Effects in Regio- and Stereoselective Ring-Opening Reaction of Aziridines with Et3N·3HF for β-Fluoroamine Synthesis

Shigeru Sasaki,* Satono Watanabe, Kaori Shiino, Yuko Yanaka, Shiho Kaneko, Kana Miyamoto, Ayano Yasui, Hina Sakaino, Hiroyoshi Teramoto, Takayasu Yamauchi, and Kimio Higashiyama

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

Abstract

This paper discusses the reactivity of various 2-substituted aziridine derivatives. The reaction of chiral 2-aryl-substituted aziridines with triethylamine trihydrofluoride (Et3N·3HF) afforded chiral β-fluoroamines with high stereoselectivity. In contrast, the reaction of chiral 2-aliphatic-substituted aziridines with benzyl bromide, followed by treatment with Et3N·3HF, gave chiral β-fluoroamines with high stereoselectivity.

■ Metal-Free Synthesis of N-Containing Heterocycles from o-Substituted Aniline Derivatives via 2,4,6-Trihydroxybenzoic Acid-Catalyzed Oxidative Dehydrogenation of Benzylamines under Oxygen Atmosphere

Shun Kumazawa, Akinori Uematsu, Chun-ping Dong, Shintaro Kodama, Akihiro Nomoto, Michio Ueshima, and Akiya Ogawa*

*Department of Applied Chemistry, Graduate School of Engineering, Osaka Prefecture University, 1-1 Gakuencho, Sakai, Osaka 593-8531, Japan

Abstract

A series of N-heterocycles, i.e., benzimidazoles, benzoxazoles, and benzothiazoles, can be conveniently synthesized by the oxidative cyclization of benzylamines with o-substituted aniline derivatives, i.e., o-phenylenediamines, o-aminophenols, and o-aminothiophenols, using 2,4,6-trihydroxybenzoic acid as an organocatalyst under an oxygen atmosphere. This approach provides a mild and efficient tool towards benzimidazoles and benzothiazoles with good yields and a broad substrate scope. The developed synthesis of N-heterocycles might proceed via the oxidative dehydrogenation of benzylamines (ArCH2NH2), generating the corresponding imines (ArCH=NH) as key intermediates.

■ Unexpected Emergence of Luciferase-Inhibitory Activity During Structural Development Study of Phenyloxadiazole-Based Ppar Ligands

Ryuta Shioi, Yosuke Toyota, Tomomi Noguchi-Yachide, Minoru Ishikawa, Takao Yamaguchi, Makoto Makishima, Yuichi Hashimoto, and Kenji Ohgane*

*Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan

Abstract

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that regulate transcription of genes involved in lipid, glucose, and cholesterol homeostasis in a ligand-dependent manner. PPARs have long been a target of drug development, and evaluation of PPARs activity frequently involves reporter-gene assay, in which luciferase activity is utilized to visualize transcriptional activation by the receptors. Here, we report our experience of the unexpected emergence of luciferase-inhibitory activity during our search for PPAR antagonists. We believe information about negative experiences like this will help to make medicinal chemists more aware of potential pitfalls in SAR studies with luciferase-based assays.

■ Asymmetric Synthesis of O-Methylneferine

Katsumi Nishimura,* Shinji Horii, and Takao Tanahashi

*Organic Chemistry, Kobe Pharmaceutical University, 4-19-1 Motoyamakita-machi, Higashinada-ku, Kobe 658-8558, Japan

Abstract

Diastereoselective Pictet–Spengler reaction of 2-arylethylamine bearing an N-(R)-1-(1-naphthyl)ethylcarbamoyl group with arylacetaldehyde gave 1-benzyltetrahydroisoquinoline in good yield with moderate diastereoselectivity. The reaction was applied to asymmetric synthesis of O-methyl derivative of neferine, an alkaloid of the lotus embryo, Nelumbo nucifera Gaertner.

■ TFA-Protected α-Amino Acid N-Hydroxysuccinimide Ester: Application for Inter- and Intramolecular Acylation

Zetryana Puteri Tachrim, Kazuhiro Oida, Fumina Ohashi, Haruna Wakasa, Haruka Ikemoto, Natsumi Kurokawa, Yasuko Sakihama, Yasuyuki Hashidoko, Takeyuki Suzuki, and Makoto Hashimoto*

*Graduate School of Agriculture, Hokkaido University, Kita 9 Nishi 9, Kita-ku, Sapporo, Hokkaido 060-0589, Japan

Abstract

The utilization of N-trifluoroacetyl (TFA)-α-amino acid N-hydroxysuccinimide ester (OSu) derivatives, a promising acylating agent with high storage stability, is reported for Friedel–Crafts acylation into arenes and N-heterocycles. The reaction between TFA-Phe-OSu derivatives and arenes afforded inter- and intramolecular products. TFA-Tyr-OSu derivatives, which possess hydroxyl substituent in the aromatic moiety of phenylalanine, afforded only intermolecular product with benzene. The heterocyclic TFA-Pro-OSu also shows relatively high reactivity toward acylation.

■ Tandem Oxidation/Cyclization Reaction of 4-(Arylmethyl)oxy-2-diazobutyrate Derivatives

Hideaki Kondo, Shuji Nagano, Hiroyuki Yamakoshi, and Seiichi Nakamura*

*Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan

Abstract

A tandem oxidation/cyclization reaction of γ-(arylmethyl)oxy-α-diazobutyrate derivatives was investigated. While oxidative cleavage of the PMB ether was only observed upon treatment of an α-diazo-β-ketoester with DDQ, oxidation of α-diazo esters with an sp3 carbon at the β-position was accompanied by intramolecular attack of the diazo carbon atom and expulsion of the nitrogen gas to give 2,3-dihydrofurans in modest to good yields when an electron-withdrawing group was substituted at the β-position. Substrates bearing no electron-withdrawing β-substituent were found to give rearranged products, albeit in modest yields. A benzofuran derivative could also be obtained, although a hydroquinone adduct was formed as a byproduct.

■ Synthesis of 4,5-Disubstituted Pyrano[3,4-b]Pyrrol-7(1H)-ones via Sonogashira–Hagihara Cross-Coupling of N-Benzenesulfonyl-3-bromo-1H-pyrrole-2-carboxylate and Subsequent Iodine-mediated Cyclization

Tsutomu Fukuda,* Minoru Komure, Gen Onodera, Masanari Kimura, and Masatomo Iwao

*Division of Chemistry and Materials Science, Graduate School of Engineering, Nagasaki University, 1-14, Bunkyo-machi, Nagasaki 852-8521, Japan

Abstract

A method for the synthesis of 4,5-disubstituted pyrano[3,4-b]pyrrol-7-(1H)-ones has been developed in this study. The key reactions involved are the Sonogashira–Hagihara cross-coupling of methyl N-benzenesulfonyl-3-bromo-1H-pyrrole-2-carboxylate with terminal alkynes, followed by the iodine-mediated cyclization of 3-alkynylated N-benzenesulfonyl-1H-pyrrole-2-carboxylates. The thus-obtained 5-substituted 4-iodopyrano[3,4-b]pyrrol-7(1H)-ones could be converted to 4,5-disubstituted pyrano[3,4-b]pyrrol-7(1H)-ones via the Suzuki–Miyaura or Sonogashira–Hagihara cross-coupling reactions.

■ Arylation Reactions of Monocarba-closo-Dodecaborate at the Boron Vertices

Mai Otsuka, Gaku Akimoto, Atsuya Muranaka, Ryo Takita,* and Masanobu Uchiyama*

*Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan

Abstract

We have developed two methods for aryl group introduction at the boron vertices of monocarba-closo-dodecaborate under palladium catalysis. Details of reaction development, as well as mechanistic insights, are described.

■ The First Synthesis of 3-O-Methylcyanidin and the Effect of 3-O-Substitution on Stability Under Acidic Conditions

Asmaa B. El-Meligy, Takehiro Ishihara, Kin-ichi Oyama, Ahmed M. El-Nahas, and Kumi Yoshida*

*Graduate School of Informatics, Nagoya University, Chikusa, Nagoya 464-8601, Japan

Abstract

The simplest and most common anthocyanin in nature is 3-O-glucosylcyanidin (1), and 3-O-glucosylation is believed to stabilize the chromophore. To clarify the effect of the glucose residue we compared the stability of 1 with its aglycone, cyanidin (2), and newly synthesized 3-O-methylcyanidin (3). In an aqueous solution at pH 1, 1 and 3 showed similar stabilities, and 2 was less stable than 1 and 3, indicating that 3-O-substituion does enhance stability. We also analyzed the co-pigmentation effect of flavocommelin (4) and rutin (5), on the color and stability of 3-O-substituted cyanidins and cyanidin. The bathochromic shift of λvismax and stability of the color by addition of 4 was greater than that of rutin (5). 4 might stack closer and stronger to the anthocyanidin chromophore than 5.

■ Synthetic Study of Anti-Obesity Iridoid Isolated from Tabebuia avellanedae

Mitsuaki Yamashita, Shinya Hayakawa, Shuhei Hata, Honoka Murakami, Youichi Fukuda, and Akira Iida*

*School of Agriculture, Kindai University, Nakamachi, Nara 631-8505, Japan

Abstract

Synthetic study toward iridoid 1 with anti-obese activity was performed by utilizing palladium-catalyzed cycloalkenylation reaction, Pd/C-catalyzed debenzylation reaction without hydrogenation and/or isomerization of alkene moiety, and the two-step, one-pot cyclization of diol as key steps.

■ Lithiation of 1-Alkoxyindole Derivatives

Kyoko Nakagawa (Goto), Tetsuya Kobayashi, Toshiya Kawasaki, and Masanori Somei*

*Noto Marine Laboratory, Institute of Nature and Environmental Technology, Faculty of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University, 56-7 Matsuhidai, Matsudo-shi, Chiba 270-2214, Japan

Abstract

Lithiation of 1-alkoxyindoles, 3-dimethylaminomethyl- and 3-dimethylaminoethyl-1-methoxyindole occurred regioselectively at the 2-position. The introduction of a sterically bulky group into the 2-position of 3-dimethylaminomethyl-1-methoxyindoles directed the lithiation to the 4-position.

■ Palladium-Catalyzed Homo-Coupling of Heteroarylsulfoniums via Borylation/Suzuki-Miyaura Coupling Sequence

Hiroko Minami, Keisuke Nogi, and Hideki Yorimitsu*

*Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8502, Japan

Abstract

Palladium-catalyzed homo-coupling of heteroaryldimethylsulfoniums proceeds in the presence of bis(pinacolato)diboron and a base to yield biheteroaryls. The homo-coupling involves palladium-catalyzed borylation and the subsequent Suzuki-Miyaura coupling. As the sulfoniums were able to be prepared in situ from the corresponding heteroaryl sulfides and methyl triflate, one-pot transformations of heteroaryl sulfides into the homo-coupling products were executed. Furthermore, a facile synthesis of a highly substituted 2,2'-bibenzofuran was accomplished with a combination of Pummerer-type synthesis of 2-benzofuryl sulfide and the present homo-coupling.

■ Synthetic Approach to Oxa-Cage Systems via Ring-Closing Metathesis

Sambasivarao Kotha,* Subba Rao Cheekatla, and Milind Meshram

*Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai - 400076, India

Abstract

Here, we report a new synthetic approach to oxa-cage systems by employing RCM as a key step. These cage systems were assembled starting with easily accessible starting materials by adopting a three-step sequence involving the Grignard addition, allylation followed by RCM.

■ Total Synthesis of Lissoclinolide by Acid-Induced Lactonization of an (E)-α-Bromo-γ,δ-Epoxy Acrylate Derivative

Kenichi Kobayashi,* Keisuke Kuwahara, Kosaku Tanaka III, Risako Kunimura, and Hiroshi Kogen*

*Graduate School of Pharmaceutical Sciences, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan

Abstract

The stereoselective total synthesis of lissoclinolide, a naturally occurring antibiotic and cytotoxic butenolide, was achieved in 10 steps including a highly E-selective Still–Gennari-type olefination and an acid-induced lactonization of an (E)-α-bromo-γ,δ-epoxy acrylate derivative. The key regioselective 5-exo lactonization could be regulated by using AcOH under kinetically controlled conditions.