HETEROCYCLES

■ Contents

■ Preface

Takeshi Nakai*

*Graduate School of Science and Engineering, Waseda University, 3-4-1 Okubo, Shinjuku-ku, Tokyo 169-8555, Japan

■ Biographical Summary

Ryoji Noyori*

*The Institute of Physical and Chemical Research, Wako-shi, Saitama 351-0198, Japan

■ Publications of Ryoji Noyori

Ryoji Noyori*

*The Institute of Physical and Chemical Research, Wako-shi, Saitama 351-0198, Japan

■ Azinylferrocenes: Synthesis and Properties

Irina A. Utepova, Oleg N. Chupakhin,* and Valery N. Charushin

*Department of Organic Chemistry, Urals State Technical University, 19, Mira Str., Ekaterinburg, Russia

Abstract

The present review gives an account of the various synthetic routes to azinyl ferrocenes. Magnetic, catalytic, redox, physiologically active and other properties of these derivatives are considered.

■ Heteoropoly Acids: Green Chemical Catalysts in Organic Synthesis

Tadaharu Ueda* and Hiyoshizo Kotsuki*

*Department of Applied Chemistry, Faculty of Science, Kochi University, Akebono-cho, Kochi 780-8520, Japan

Abstract

Heteropoly acids have been used in various fields of organic synthesis mainly due to their characteristic features: they are cost-effective reagents that are strongly acidic, environmentally friendly, and highly efficient. This review addresses the significant advances in organic synthesis using heteropoly acids or their salts mainly from papers published in this century. These include (1) Friedel-Crafts reactions, (2) Prins reactions, (3) Mannich reactions, (4) Biginelli reactions, (5) other types of condensation, (6) protection and deprotection, and (7) miscellaneous reactions such as epoxide ring-opening reactions.

■ Marchantiophyta (Liverworts): Rich Sources of Macrocyclic Bis(bibenzyls)

Yoshinori Asakawa,* Masao Toyota, Toshihiro Hashimoto, Motoo Tori, Fumihiro Nagashima, and Liva Harinantenaina

*Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima 770-8514 Japan

Abstract

The Marchantiophyta (liverworts) produce which show interesting biological activity such as antimicrobial, antifungal, antiobesity and muscle relaxing activity etc. and are of very valuable for the chemosystematic and evolutional study of the Marchantiophyta and pteridophytes. The isolation, identification, structural elucidation and total synthesis of these characteristic natural products and their biological activity are reviewed.

■ Photodimerization of a Pyrido[2,1-a]isoindol-6(4H)-one

Leo A. Paquette,* Robert D. Dura, and Judith C. Gallucci

*Evans Chemical Laboratories, The Ohio State University, Columbus, OH 43210, USA

Abstract

When subjected to acetone-sensitized irradiation, the title compound undergoes near-quantitative self-coupling to give an uncommon [4+2] dimer, whose reaction with several oxidants demonstrated the enamide double bond of the photoproduct to be the more reactive.

■ Copper-Catalyzed N-Arylation Reaction of 2-Azabicyclo[2.2.1]hept-5-en-3-one with Arylboronic Acids under Microwave Irradiation

Takumi Abe, Hiroyuki Takeda, Koji Yamada, and Minoru Ishikura*

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

Abstract

Copper-catalyzed N-arylation reaction of 2-azabicyclo[2.2.1]hept-5-en-3-one (ABH) with arylboronic acids was successively performed in the presence of KOH and trimethylamine-N-oxide under microwave irradiation.

■ LXR Antagonists with a 5-Substituted Phenanthridin-6-one Skeleton: Synthesis and LXR Transrepression Activities of Conformationally Restricted Carba-T0901317 Analogs

Atsushi Aoyama, Hiroshi Aoyama, Kosuke Dodo, Makoto Makishima, Yuichi Hashimoto, and Hiroyuki Miyachi*

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

Abstract

Conformationally restricted heterocyclic analogs of carba-T0901317, a liver X receptor (LXR) antagonist, were prepared via the palladium catalized cyclization reaction as a key step. In vitro transactivation assay revealed that the structural modification altered the nature of the activity from LXR-agonistic to LXR-antagonistic.

■ Asymmetric Synthesis of the ABCD Ring System of Daphnilactone B via a Tandem, Double Intramolecular, [4+2] / [3+2]Cycloaddition Strategy

Scott E. Denmark,* Son T. Nguyen, and Ramil Y. Baiazitov

*Department of Chemistry, Roger Adams Laboratory, University of Illinois, Urbana, Illinois 61801, USA

Abstract

An asymmetric synthesis of the ABCD ring system of daphnilactone B is described. The synthesis features a tandem, double intramolecular, [4+2]/[3+2] cycloaddition of a highly functionalized, enantiomerically enriched nitroalkene to generate a pentacyclic nitroso acetal. The cycloaddition establishes six contiguous stereogenic centers including the critical CD ring junction that bears two quaternary stereogenic centers. Hydrogenolysis of the nitroso acetal followed by amide reduction and cyclization provided the AB rings. The methyl substituent on the A ring was installed in the correct configuration via hydrogenation of an exocyclic olefin in the final step.

■ Synthesis of Functionalized β-Cyclodextrins by “Click Chemistry”

Chenfeng Ke, Cheng Yang, Zixin Yang, Weijia Wu, Tadashi Mori,* Yoshihisa Inoue,* and Yu Liu*

*Department of Applied Chemistry, Osaka University, 2-1 Yamada-oka, Suita 565-0871, Japan

Abstract

Two new β-cyclodextrins (β-CDs) modified with chromophore were synthesized in high yields through Huisgen 1,3-dipolar cycloaddition. The amount of Cu catalyst was demonstrated to be a key factor that determines the yield of the 1,3-dipolar cycloaddition when applied to CD derivatization. While a catalytic amount of Cu-catalyst is commonly required in conventional click chemistry, more than a half equivalent of Cu catalyst was desirable for obtaining the modified CDs in satisfactory yields.

■ Proton Dissociation-Induced Tautomerization of 4-Substituted 7-Hydroxycoumarin and Its Bridged Dimer in the Ground Stage

Hirohide Umeto, Kanna Kobayashi, Tetsutaro Igarashi, and Tadamitsu Sakurai*

*Department of Material and Life Chemistry, Faculty of Engineering, Kanagawa University, Kanagawa-ku, Yokohama 221-8686, Japan

Abstract

An investigation was undertaken to elucidate solvent effects on the intramolecular interaction between the 7-hydroxycoumarin chromophores in the title bridged dimer in the presence of tertiary amine. Analysis of equilibrium constants for the proton dissociation and proton dissociation-induced tautomerization of the title coumarin derivatives confirmed that both the hydroxycoumarin anion and the tautomer anion derived from the bridged dimer in methanol and acetonitrile are stabilized through the intramolecular hydrogen bonding interaction while dimethyl sulfoxide enables these anions to behave independently by its strong solvation effect.

■ Reversible Encapsulation of Terminal Alkenes and Alkynes

Dariush Ajami and Julius Rebek, Jr.*

*The Skaggs Institute for Chemical Biology and Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, U.S.A.

Abstract

Molecular encapsulation is a modern form of recognition in which a host completely surrounds a guest molecule. Unlike earlier covalent systems, reversible assembly allows the study of these complexes at equilibrium under ambient conditions. We show here that self-assembled capsules held together by hydrogen bonds surround a series of alkenes and alkynes that fill the space properly. These guests are frequently found in contorted conformations that reduce their length in order to fit inside and then make appropriate contacts with the capsule.

■ Regioselective Introduction of Electrophiles into Piperidine Derivatives at the 4-Position

Osamu Onomura,* Noriyuki Fujimura, Takahisa Oda, Yoshihiro Matsumura, and Yosuke Demizu

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

Abstract

Regioselective introduction of various electrophiles (aldehydes, ketones, and imines) into piperidine skeleton at the 4-position was achieved with a catalytic amount of Pd(OAc)₂/PPh₃ in the presence of excess Et₂Zn. In addition, enantioselective introduction of benzaldehyde into piperidine derivatives was accomplished by using chiral phosphine ligand with moderate enantioselectivity.

■ Formal Total Synthesis of (—)-Physostigmine

Kaori Asakawa, Naoyoshi Noguchi, and Masahisa Nakada*

*Department of Chemistry and Biochemistry, Faculty of Science and Engineering, Waseda University, 3-4-1 Ohkubo, Shinjuku-ku, Tokyo 169-8555, Japan

Abstract

The formal total synthesis of (-)-physostigmine via the chiral malonic acid mono-ester ((R)-2-(2-chlorophenyl)-2-methoxycarbonylpropanoic acid, 99% ee) newly prepared by the pig liver esterase (PLE) mediated asymmetric hydrolysis of the corresponding di-ester is described. The CuI-mediated intramolecular aryl amidation under modified Buchwald’s conditions is a key reaction to constructing the oxindoline core in the target.

■ Asymmetric Oxidation of Cyclic Sulfides Catalyzed by an Aluminum(salalen) Complex as the Catalyst

Kazuhiro Matsumoto, Tetsufumi Yamaguchi, and Tsutomu Katsuki*

*Department of Chemistry, Faculty of Science, Graduate School, Kyushu University, Hakozaki, Higashi-ku, Fukuoka 812-8581, Japan

Abstract

We report a catalytic asymmetric oxidation of cyclic sulfides that uses a combination of aluminum(salalen) complex 1 as the catalyst and aqueous hydrogen peroxide as the oxidant. Oxidations of six-membered cyclic sulfides, thiochroman-4-ones, furnish the corresponding sulfoxides in high yield with high enantioselectivity. Five-membered 2,3-dihydrobenzo[b]thiophene and seven-membered dibenzo[b,e]thiepin-11(6H)-one are also good substrates for the aluminum-catalyzed system.

■ Palladium-Catalyzed Asymmetric Intramolecular Metallo-Ene Reaction Using Monodentate Phosphines, 9-PBN and 9-NapBN

Osamu Hara, Hiroshi Fujino, Kazuishi Makino, and Yasumasa Hamada*

*Graduate School of Pharmaceutical Sciences, Chiba University, Yayoi-cho, Inage-ku, Chiba, 263-8522, Japan

Abstract

The palladium-catalyzed asymmetric intramolecular metallo-ene reaction of the type I substrate using 9-PBN and 9-NapBN smoothly takes place in the presence of B(OAc)₃ and/or NaBF₄ at room temperature to afford the products with up to 51%ee, the best value in this area.

■ Regioselective Double Nucleophilic Addition Reaction Leading to the Synthesis of β-Lactams

Atsushi Takahashi, Shiho Kawai, Iwao Hachiya, and Makoto Shimizu*

*Department of Chemistry for Materials, Graduate School of Engineering Mie University, Tsu, Mie 514-8507, Japan

Abstract

β-Lactams were prepared in a regio- and stereoselective manner using the double nucleophilic addition of ketene silyl acetals and ketene silyl thioacetals to α,β-unsaturated imines followed by base-promoted cyclization. An attempted approach to 2-aryl carbapenem is also described.

■ Synthesis and Mercurophilic Properties of Dithiocrown Ethers Having an Azulene Pendant

Kanji Kubo,* Akira Mori,* Tatsuya Nishimura, and Nobuo Kato

*School of Dentistry, Health Sciences University of Hokkaido, 1757 Kanazawa, Ishikari-Tobetsu, Hokkaido 061-0293 Japan

Abstract

Dithiocrown ether derivatives (3) having an azulene pendant were synthesized by regioselective reaction of 8,8-dicyanoheptafulvene derivatives with malononitrile in the presence of sodium ethoxide to examine their extraction and transport of Hg(II) ion through a liquid membrane. The transport was driven by acidic conditions and was capable of moving metal cations ‘up-hill’. Thus, it was possible to follow the transport of Hg(II) ion from the aqueous source phase to the organic layer and from the organic layer to the receiving phase. The carrier (3) displayed remarkable selectivity for Hg(II) ion.

■ One Step Introduction of 4,4-Bis(trifluoroacetyl)-1,3-butadiene System to Aromatic Rings Using Fluorine-Containing 3,4-Dihydro-2H-pyrans. A Facile Synthetic Method for 1,1,1,5,5,5-Hexafluoro-3-[(E)-3-arylallylidene]pentane-2,4-diones

Norio Ota, Etsuji Okada,* Atsushi Sonoda, Nobuyuki Muro, Dai Shibata, and Maurice Médebielle

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

Abstract

New 1,1,1,5,5,5-hexafluoro-3-[(E)-3-arylallylidene]pentane-2,4-diones were synthesized in moderate to high yields by the ring-opening reaction of 1-(2-ethoxy-4-isobutoxy-6-trifluoromethyl-3,4-dihydro-2H-pyran-5-yl)-2,2,2-trifluoroethanone with aromatic compounds in refluxing trifluoroacetic acid.

■ A New Synthesis of Dihydropyridin-2-ones from Brassard’s Diene and Imines

Teruaki Mukaiyama,* Yuji Maruyama, and Takayuki Kitazawa

*Center for Basic Research, The Kitasato Institute, 6-15-5 (TCI) Toshima, Kita-ku, Tokyo 114-0003, Japan

Abstract

A new method for the synthesis of dihydropyridin-2-ones from various N-2-nitrobenzenesulfonyl (nosyl) imines and 1,3-diethoxy-1-trimethylsiloxy-1,3-butadiene (Brassard’s diene) under weakly-basic conditions is described. This synthesis of dihydropyridin-2-ones involves the initial addition reaction of Brassard’s diene to imines to afford the adducts followed by a cyclization reaction that forms the corresponding 4-ethoxy-5,6-dihydro-1H-pyridin-2-ones in moderate to good yields after deprotection of its nosyl group from the adducts.

■ Diene-Transmissive Hetero-Diels-Alder Cycloaddition Using Cross-Conjugated Dioxatrienes: A Novel Synthesis of Tetrahydropyran-Fused Aza- and Thia-heterocycles

Takao Saito,* Satoru Kobayashi, Takashi Otani, Hideoki Iwanami, and Takayuki Soda

*Department of Chemistry, Faculty of Science, Tokyo University of Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan

Abstract

The diene-transmissive hetero-Diels-Alder methodology using cross-conjugated dioxatrienes [2-(R-methylene)propanedials] has been developed. The initial cycloaddition with electron-rich dienophiles, followed by the reactions of the resulting 1-oxadiene moiety of the monoadducts with amines and Lawesson’s reagent generated 1-azadienes and 1-thiadienes. The second hetero-Diels-Alder reaction of these reactive heterodienes with dienophiles (tosyl isocyanate, diphenylketene, enones, and maleinimide) produced pyran-fused aza- and thiaheterocycles, providing a new synthetic method for these heterocycles.

■ Synthesis of ¹¹C-Labeled Uracil Derivative for a PET Tracer Targeting Thymidine Phosphorylase

Masayuki Takahashi, Koh-ichi Seki, Ken-ichi Nishijima, Yuji Kuge, Nagara Tamaki, and Kazue Ohkura*

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

Abstract

The expression of thymidine phosphorylase (TP) is closely associated with angiogenesis in tumors. For developing a TP-expression-based positron emission tomography (PET) radiotracer for diagnosis and prognosis of cancer chemotherapy, we synthesized a novel ¹¹C-labeled oxoimidazolidinylmethyluracil ([¹¹C]-2a), which was designed on the basis of one of the most potent inhibitors, 5-bromo-6-[(2-iminoimidazolidinyl)-methyl]uracil hydrobromide (5BIMU), through a ring closure reaction of [¹¹C]phosgene with a developed diamine precursor (1a). After purification by HPLC, the total synthesis was accomplished in just 23 min after bombardment, and the yield was 1653 MBq at the end of synthesis (EOS).

■ Enantiomeric Synthesis of 2-C-Methyl-D-erythritol 2,4-Cyclodiphosphate

Prabagaran Narayanasamy* and Dean C. Crick*

*Department of Microbiology, Immunology, and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, 1682 Campus Delivery, Fort Collins, CO 80523-1682, USA

Abstract

Enantiomerically pure 2-C-methyl-D-erythritol 2,4-cyclodiphosphate 1 (ME-CPP) is synthesized from 1,2-O-isopropylidene-α-D-xylofuranose with facile phosphorylation in good yield. Subsequently, the synthesized enantiomerically pure 1 can be used as a substrate in IspG assays to identify inhibitors that may be developed into antibacterial drug leads.

■ Ultrasound-Assisted N-Arylation of Indoles without any Catalyst

Hui Xu,* Lei Lv, Ling-ling Fan, and Xiao-qiang He

*Lab of Pharmaceutical Synthesis, College of Sciences, Northwest A&F University, Yangling 712100, P. R. China

Abstract

An efficient method for the ultrasound-assisted N-arylation of indoles with haloarenes in an air atmosphere mediated by Cs₂CO₃ without any catalyst is reported. N-arylindoles are obtained in moderate to good yields while indoles cross-coupling with activated aryl halides (X = F or Cl).

■ Studies on Synthesis of OSW-1 Analogue with Thiazole Ring at Side Chain Employing Wittig Rearrangement

Masayoshi Tsubuki,* Sohichiro Matsuo, and Toshio Honda*

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

Abstract

OSW-1 analogue with thiazole at the side chain was synthesized employing a tandem Williamson etherification - [2,3]-Wittig rearrangement, which provided a one-pot producer for the formation of (20S)-22-hydroxy steroids 6 and 7 from the known allylic alcohol 4 and 2-bromomethylthiazole as a key step. Glycosylation of steroid aglycone 17 with donors was investigated under various conditions.

■ Cycloaddition of 2-Pyridones Having an Electron-Withdrawing Group

Masato Hoshino, Hisao Matsuzaki, and Reiko Fujita*

*Tohoku Pharmaceutical University, 4-4-1, Komatsushima, Aoba-ku, Sendai, Miyagi 981-8558, Japan

Abstract

Cycloaddition of 1-methyl-2(1H)-pyridones bearing an electron-withdrawing group at 3-5 positions acting as the diene with N-phenylmaleimide was carried out under atmospheric and high pressure conditions to give the corres-ponding isoquinuclidines. Stereoselectivity of the cycloaddition of 1-methyl-2(1H)-pyridones was investigated using molecular orbital calculations.

■ Total Synthesis of Spiruchostatin A — A Potent Histone Deacetylase Inhibitor

Toshiya Takizawa, Kazuhiro Watanabe, Koichi Narita, Kyosuke Kudo, Takamasa Oguchi, Hideki Abe, and Tadashi Katoh*

*Laboratory of Medicinal Synthetic Chemistry, Department of Chemical Pharmaceutical Science, Tohoku Pharmaceutical University, Komatsushima, Aoba-ku, Sendai 981-8558, Japan

Abstract

Total synthesis of spiruchostatin A (1), a potent histone deacetylase inhibitor, was achieved; the method features (i) Julia-Kocienski olefination of sulfone 10 and aldehyde 11 to install the requisite (E)-olefin unit present in segment 6, (ii) amide coupling of segment 5 with segment 6 to produce the key seco-acid 4, and (iii) macrolactonization of 4 employing Shiina reagent to efficiently construct the desired 15-membered macrocyclic compound 32.

■ Synthesis of Highly Oxygenated Biphenyl Derivative in an Optically Active Form through Palladium-Mediated Intramolecular Biaryl Coupling Reaction

Hitoshi Abe,* Masatsugu Arai, Keisuke Nishioka, Tatsuya Kida, Kazuma Shioe, Yasuo Takeuchi, and Takashi Harayama*

*Advanced Science Research Center, Okayama University, Okayama 700-8530, Japan

Abstract

Optically active 6,6’-dihydroxymethyl-2,2’-3,3’-4,4’-hexamethoxybiphenyl (1) was prepared via the Pd-mediated biaryl coupling reaction of a phenyl benzoate derivative and the following enantioselective lactone opening reaction.