HETEROCYCLES

■ Contents

■ Congratulations to Professor Albert Eschenmoser on his 85th Birthday

Bernhard Kräutler*

*Institut für Organische Chemie, Universität Innsbruck, Innrain 52, A-6020 Innsbruck , Austria

■ Preface to Special Issue of HETEROCYCLES - Honoring the 85th Birthday of Prof. Dr. Albert Eschenmoser

Scott E. Denmark* and Erik J. Sorensen

*245 Roger Adams Laboratory Box 18-5 , Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, U.S.A.

Abstract

“….In my opinion, there is a problem that is central to organic chemistry alone and in which biologists cannot help us. We all agree…that the emphasis in synthetic research is the synthesis of properties,” and not just compounds. Now, the most important property that we can attack by synthesis is the property of living. The problem, rigorously a problem of synthesis, is to study the laws, the rules, and the principles of self-organization of organic matter….”1

■ Autocatalysis and All That

Alan W. Schwartz*

*Evolutionary Biology, RUN, Lindenheuvel 12, 1217 JX Hilversum, The Netherlands

Abstract

“The search for the chemistry of life’s origin is a search for potentially primordial autocatalytic cycles.” (Eschenmoser, 2007a)

■ Curriculum Vitae - Albert Eschenmoser

Albert Eschenmoser*

*Laboratory of Organic Chemistry, Swiss Federal Institute of Technology (ETH), Universitatstrasse 16, CH-8092, Zurich, Switzerland

■ Survey of Scientific Work

Albert Eschenmoser*

*Laboratory of Organic Chemistry, Swiss Federal Institute of Technology (ETH), Universitatstrasse 16, CH-8092, Zurich, Switzerland

Abstract

Eschenmoser’s scientific oeuvre comprises experimental and theoretical contributions to the mechanism and stereochemistry of organo-chemical and biochemical reactions, to the concept and mechanistic elements of the “biogenetic isoprene rule”, and to problems related to chemical bonding and structure. One of the main themes of his research was the development of new reactions and methods for chemical synthesis in the context of the total synthesis of natural products. His work in the latter field culminated in the total synthesis of vitamin B12 and the development of a comprehensive synthetic chemistry of corrinoids and corphinoids relating to the chemical synthesis, biosynthesis, and etiology of the vitamin B12 structure. Most recent experimental and theoretical investigations aim at an etiology of nucleic acid structure in the wider context of a search for the chemistry of life’s origin.

■ Albert Eschenmoser - List of Scientific Publications

Albert Eschenmoser*

*Laboratory of Organic Chemistry, Swiss Federal Institute of Technology (ETH), Universitatstrasse 16, CH-8092, Zurich, Switzerland

■ Chemical Information Retrieval ⎯ A Short Discussion about the State of the Art, Progress, and Pitfalls

Engelbert Zass*

*HCI J57.5, Informationszentrum Chemie Biologie Pharmazie, ETH Zürich, Wolfgang-Pauli-Strasse 10,
CH-8093 Zuerich, Switzerland

Abstract

Examples of author, keyword, structure, and reaction searches related to the scientific achievements of A. Eschenmoser were analyzed to illustrate the power, but also the limitations of modern database systems like SciFinder, Reaxys, and Web of Knowledge.

■ Cornerstone Works for Catalytic 1,3-Dipolar Cycloaddition Reactions

Shuji Kanemasa*

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

Abstract

This review covers the following subjects: (1) The chemistry of N-metalated azomethine ylide as a new 1,3-dipole containing a metal atom is studied. This 1,3-dipole, generated from (N-alkylideneamino)alkanoates upon treatment with a Lewis acid and amine base, undergoes rapid 1,3-dipolar cycloadditions toward electron-deficient alkenes. Especially, α,β-unsaturated carbonyl substrates show high rate acceleration to give pyrrolidine-2,4-dicarboxylates in a highly regio- and endo-selective manner. (2) This 1,3-dipolar cycloaddition reaction of (N-alkylideneamino)acetate can be switched into anti-selective Michael addition reaction by modification of substrate structures as well as reaction conditions. (3) Two types of heterocyclic chiral auxiliaries are demonstrated for the asymmetric 1,3-dipolar cycloadditions. One types are attached at the b-position of α,β-unsaturated esters. The resulting chiral α,β-unsaturated esters are successfully applied to the stereoselective asymmetric cycloadditions of N-metalated azomethine ylides. The other types include 4-benzyl-2,2,5,5-tetramethyloxazolidine-3-acrylamides which are based on the conformational control of the acrylamide reaction site and that of steric shielding of 4-benzyl amoiety. These are applied to the absolutely asymmetric nitrile oxide cycloadditions. (4) The nitrone cycloadditions to electron-deficient alkenes is attained in the presence of a Lewis acid catalyst. This provides the first catalytic stereo control of 1,3-dipolar cycloadditions. (5) The extremly effective rate enhancement of nitrile oxide 1,3-dipolar cycloadditions to the magnesium alkoxides of allylic alcohols. Maximum rate enhancement observed is 16,000 fold rate acceleration of the uncatalyzed reaction. This method offers the first successful rate acceleration in nitrile oxide 1,3-dipolar cycloadditions. (6) Use of magnesium alkoxide of allylic alcohols is also highly effectve in nitrone 1,3-dipolar cycloadditons, resulting in high stereo- and regioselectivities. (7) Catalytic enantioselective 1,3-dipolar cycloadditions are achieved by use of nitrones, nitronates, diazomethane, and nitrile oxides in the presence of tolerant chiral catalysts based on our R,R-DBFOX/Ph ligand.

■ The Chemistry of Azaazulenes

Noritaka Abe* and Takahiro Gunji

*Department of Industrial Chemistry, Faculty of Science and Technology, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan

Abstract

This review describes the synthetic methods and reactions of azaazulenes including some of their dihydro-, oxo-derivatives and hetero-fused derivatives published during 2000 to early in 2010. The biological and physical properties of azaazulenes are also described.

■ Nucleophilic Phosphine-Catalyzed Iodocyclization of Isoprenoids Bearing an Oxygen Terminal Group

Akira Sakakura, Gakujun Shomi, Atsushi Ukai, and Kazuaki Ishihara*

*Graduate School of Engineering, Nagoya University, Chikusa, Nagoya, Aichi 464-8601,

Abstract

The nucleophilic phosphine-catalyzed diastereoselective iodocyclization of linear isoprenoids bearing an oxygen terminal group was investigated. TBDMS ether of homogeraniol and TBDMS ester of homogeranic acid were successfully converted to the corresponding iodopolycyclic products in the presence of a catalytic amount of triphenylphosphine with complete diastereoselectivity.

■ Spirocyclization of an N-Acyliminium Ion with Substituted Pyridine: Stereoselective Synthesis of Tetracyclic Spirolactams Possessing the Pyridone Nucleus

Hideki Abe, Kei-ichi Takaya, Kazuhiro Watanabe, Sakae Aoyagi,* Chihiro Kibayashi, and Tadashi Katoh*

*Department of Synthetic Organic Chemistry, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan

Abstract

An efficient method for the stereoselective synthesis of tetracyclic spirolactams was developed based on a spirocyclization of an N-acyliminium ion with 2-methoxypyridine as the aromatic π-nucleophile.

■ A Flexible Route to 4-Substituted β-Lactams

Béatrice Quiclet-Sire* and Samir Z. Zard*

*CNRS UMR 7652, Laboratoire de Synthèse Organique Associé, Ecole Polytechnique, F-91128 Palaiseau, France

Abstract

A variety of 4-substituted β-lactams can be readily prepared by the radical addition-transfer of 4-S-xanthyl-azetidinones to unactivated olefins. For this radical chain process to operate efficiently it is necessary to place an acyl group on the nitrogen of the azetidinone ring.

■ Amidation of Hyaluronic Acid with a Methotrexate-Derived Amine: Optimization of the Key Reaction for the Synthesis of a Candidate Drug for the Trearment of Osteoarthritis

Akie Homma,* Takenori Ishizawa, Haruhiko Sato,* Akira Okamachi, Takashi Emura, Tatsuya Kato, Tetsu Matsuura, Shigeo Sato, Masahisa Ikemi, Hironoshin Kitagawa, Tadashi Morikawa, Hitoshi Ikeya, and Koichi Takahashi

*API Process Department, Chugai Pharmaceutical Company, Ltd., 5-5-1, Ukima, Kita-ku, Tokyo 115-0051, Japan

Abstract

Optimal amidation conditions between hyaluronic acid (HA) and a methotrexate (MTX)-derived amine that gave rise to a HA-MTX conjugate having a molecular weight of ~2000 kDa have been established based on a model experiment using a tryptophan-derived amine in aqueous THF. This method is robust and provides a conjugate with properties of primary importance for efficacy—MW and amine binding ratio—that satisfy the criteria for a HA-MTX conjugate to be a good candidate.

■ Decarboxylative C-C Bond Cleavage Reactions via Oxapalladacycles

Masanari Kimura,* Tomohiko Kohno, Kei Toyoda, and Takamichi Mori

*Department of Applied Chemistry, Faculty of Engineering, Nagasaki University, 1-14, Bunkyo-machi, Nagasaki 852-8521, Japan

Abstract

In the presence of Pd(0) catalyst and triethylborane, 3-hydroxy-4-pentenoic acids undergo C-C bond cleavage reactions via oxapalladacyclopentanones to provide conjugated dienes with evolution of carbon dioxide.

■ Boromycin Derivatives: Synthesis and Antimalarial Activity in vitro and in vivo

Ayumi Tsutsui, Yujiro Furuya, Tomoyasu Hirose, Riyon Kim, Rokurou Masuma, Atsuko Matsumoto, Yoko Takahashi, Aki Ishiyama, Miyuki Namatame, Kazuhiko Otoguro, Satoshi Ōmura,* and Toshiaki Sunazuka*

*Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8642, Japan

Abstract

Derivatives of boromycin, which has significant antimalarial properties both in vitro and in vivo, were examined for similar the efficacy against both drug-resistance strain and drug-sensitive strain of malaria and as a means to elucidate structure-activity relationships. More potent in vitro compounds tended to lose their properties in vivo when administered orally. Some novel 16-O-acyl derivatives were found to be more potent and selective antimalarial compounds compared to boromycin. Furthermore, alkyne-bearing 16-O-alkylacyl compounds retained reasonably good efficacy in vivo when given per os.

■ A Novel Synthesis of a 1,3-Disubstituted 1,3-Dihydro-2H-imidazo[4,5-b]pyridin-2-one. Application to GW808990 a CRF1 Receptor Antagonist

Jerome F. Hayes* and Matthew E. Popkin

*GlaxoSmithKline Research & Development Ltd., Old Powder Mills, Old Powdermill Lane, Leigh, Nr Tonbridge, Kent, TN11 9AN, U.K.

Abstract

A novel synthesis of a 1,3-disubstituted 1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one has been achieved by condensation of iminohydantoin 3 with t-butyl acetoacetate in diglyme at 160 °C. Hydrogenation of the product in the presence of 4-heptanone followed by a Buchwald-Hartwig amination afforded GW808990, a CRF1 receptor antagonist.

■ Synthesis of 2,3,4-Tri-Substituted 3,4-Dihydroquinazolines via Tandem Nucleophilic Addition/Epoxy Ring-Opening Cyclization Methodology Using N-(2-Oxiranylphenyl)carbodiimides with Nucleophiles

Takao Saito,* Tatsuya Ote, Masahiro Shiotani, Hiroko Kataoka, Takashi Otani, and Noriki Kutsumura

*Department of Chemistry, Faculty of Science, Tokyo University of Science, Kagurazaka 1-3, Shinjuku-ku, Tokyo 162-8601, Japan

Abstract

N-(2-Oxiranylphenyl)carbodiimides, which were synthesized via an aza-Wittig reaction of the corresponding functionalized iminophosphoranes with aromatic and aliphatic isocyanates, underwent O-, S-, C-, or N-nucleophilic addition onto a cumulene, followed by an epoxy ring-opening cyclization with the newly formed NH-nucleophile in a one-pot reaction to furnish 2,3-disubstituted 4-(hydroxymethyl)-3,4-dihydroquinazolines in a highly stereospecific manner.

■ An Enantioselective Synthesis of the Resorcylic Acid Lactone L-783,277 via Addition of an Acetylide Anion to a Tethered Weinreb Amide

Andrew Lin, Anthony C. Willis, and Martin G. Banwell*

*Research School of Chemistry, Institute of Advanced Studies, The Australian National University, Canberra, ACT 0200, Australia

Abstract

Abstract – Treatment of the terminal acetylene 12, readily obtained from the previously reported acid 10, with LiHMDS resulted in a novel macrocyclization reaction to give the cycloalkyne 13. Subjection of compound 13 to hydrogenation under Lindlar-type conditions afforded the Z-configured enone 14 that could be converted into the resorcylic acid lactone 4 upon treatment with BCl3 in CH2Cl2 at –78°C.

■ Enantioselective Synthesis of the C(2)-C(11) Cyclopropylfuran Segment of Pinnatin A

Masayoshi Tsubuki,* Terunobu Abekura, Kazunori Takahashi, and Toshio Honda*

*Research Centre of Medicinal Sciences, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan

Abstract

Synthesis of the C(2)-C(11) segment, cyclopropylfuran derivative, of pinnatin A was accomplished by Suzuki cross-coupling between chiral cyclopropylboronic acid and bromofuran as a key step. Addition of silver (I) oxide was found to promote the Suzuki cross-coupling reactions.

■ Mannich-Type Reaction of N,O-Acetals with Ketones Mediated by a Combination of TiCl4 and PhSiCl3

Satoshi Kamogawa, Takashi Ikeda, Masami Kuriyama, Yoshihiro Matsumura, and Osamu Onomura*

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

Abstract

A combination of TiCl4 and PhSiCl3 efficiently conducts the Mannich-type reaction of N,O-acetals with ketones to afford α-substituted cyclic amine derivatives in good yields. This method was applicable to preparation of azabicyclo compounds by the intramolecular Mannich-type reaction.

■ Amphidinolide C3, a New Cytotoxic 25-Membered Macrolide from Marine Dinoflagellate Amphidinium sp

Takaaki Kubota, Akiko Suzuki, Mika Yamada, Shigeyuki Baba, and Jun'ichi Kobayashi*

*Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita 12 Nishi 6, Kita-ku, Sapporo, Hokkaido 060-0812, Japan

Abstract

A new cytotoxic 25-membered macrolide, amphidinolide C3 (1), has been isolated from marine dinoflagellate Amphidinium sp. (Y-56 strain), and the structure of 1 was elucidated on the basis of spectroscopic data and chemical means.

■ Iodoarene-Mediated Cyclization of N-Methoxy-2-arylethanesulfonamides with Oxone

Yoshihide Ishiwata, Yuhsuke Suzuki, and Hideo Togo*

*Graduate School of Sciences, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan

Abstract

Iodoarene-mediated cyclization of N-methoxy-2-arylethanesulfonamides with Oxone® was carried out to form the corresponding N-methoxy-3,4-dihydro-2,1-benzothiazine-2,2-dioxides in moderate to good yields in acetonitrile. In this reaction, reactive hypervalent iodine species, i.e., [(hydroxy)(tosyloxy)iodo]arenes, were formed in situ and reacted with N-methoxy-2-arylethanesulfonamides to form the corresponding N-methoxy-3,4-dihydro-2,1-benzothiazine-2,2-dioxides in an electrophilic manner on the aromatic ring. Ion-supported PhI could be also used for the same cyclization of N-methoxy-2- arylethanesulfonamides with Oxone® to provide N-methoxy-3,4-dihydro- 2,1-benzothiazine-2,2-dioxides in good to moderte yields. However, ion-supported PhI could not be reused for the same reaction. The same iodoarene-mediated cyclization of N-methoxy-3-phenylpropanamide and N-methoxy-4-phenylbutanamide with Oxone® was also carried out to form the corresponding N-methoxybenzolactams in moderate yields.

■ Synthesis of 1,2,3,4,5,7-Hexahydro-6H-azocino[4,3-b]indol-6-ones as Intermediates for the Synthesis of Apparicine

Jason G. Kettle, David Roberts, and John A. Joule*

*The School of Chemistry, The University of Manchester, Oxford Road, Manchester, M13 9PL, U.K.

Abstract

1-Phenylsulfonylindole is converted in eight steps into 2-(2-iodo-(Z)-but-2-en-1-yl)-6-methyl-1,2,3,4-tetrahydroazocino[4,3-b]indole, previously converted in one step into the indole alkaloid apparicine. The syntheses of other hexahydroazocino[4,3-b]indole potential precursors to the alkaloid are also described.

■ Sunabedine, a Novel Toxic Bromotyrosine-derivative Alkaloid from Okinawan Sponge, Order Verongida

Norihito Maru, Tomoyuki Koyama, Osamu Ohno, Kaoru Yamada, and Daisuke Uemura*

*Department of Biosciences and Informatics, Faculty of Science and Technology, Keio University, Hiyoshi, Kohoku-ku Yokohama 223-8522, Japan

Abstract

Sunabedine (1), a new bromotyrosine-derivative alkaloid, was isolated from the Okinawan sponge, order Verongida. The structure of 1 was determined by spectroscopic analyses. 1 showed the cytotoxicity against B16 mouse melanoma cells and toxicity against brine shrimp.

■ Synthesis of Novel 1-Hydroxyquinolones with High Anti-Toxoplasma Activity

Lutz F. Tietze* and Ling Ma

*Institute of Organic and Biomolecular Chemistry, Georg-August-University, Tammannstr. 2, D-37077 Göttingen, Germany

Abstract

All for the treatment of malaria and toxoplasmosis the novel hydroxyquinolones 2–5 were prepared by reaction of aniline and hydroxyaniline, respectively and the β-ketoesters 10a-c. As products the quinolones 8 and 15, respectively were obtained. Benzylation, oxidation and hydrogenation then led to the desired substances. Compound 2 has a similar anti-malaria activity as the approved drug Atovaquone.

■ Total Synthesis of Bioactive Indolo[3,2-j]phenanthridine Alkaloid, Calothrixin B

Shigeo Tohyama, Tominari Choshi,* Kohji Matsumoto, Akira Yamabuki, Yuhzo Hieda, Junko Nobuhiro, and Satoshi Hibino*

*Graduate School of Pharmacy and Pharmaceutical Sciences, Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Fukuyama, Hiroshima 729-0292, Japan

Abstract

The total synthesis of bioactive calothrixin B (2) was completed which two kinds of carbazoles using three approaches. The common strategy was based on an allene-mediated electrocyclic reaction of a 6π-electron system involving one or two indole [b]-bonds for the construction of an appropriate 4-oxygenated 2,3,4-trisubstituted carbazole 28 or a 6-oxygenated 5-methylindolo[2,3-a]carbazole 39, respectively. Oxidation of the methyl group of 28 followed by reduction of the nitro group of 21 afforded the pentacyclic phenol 5, which was oxidized with CAN to give calothrixin B (2). In a biomimetic pathway, the fully protected 5-formylindolo[2,3-a]carbazole 40 with a methoxymethyl group provided calothrixin B (2) through N-methoxymethyl-calothrixin B 43.

■ Isomerization of Diethyl 1-Alkynylphosphonates to 1,3-Dienylphosphonates Followed by Diels-Alder Reaction with Dead, Maleic Anhydride and Maleimide

Abdullatif Azab, Abed Al Aziz Quntar, Tamar Antebi, and Morris Srebnik*

*Institute of Drug Research, School of Pharmacy, The Hebrew University of Jerusalem, P. O. Box 12065, Jerusalem 91120, Israel

Abstract

Isomerization of diethyl 1-alkynylphosphonates, 1, with Pd[(PPh)3]4 in refluxing 1,4-dioxane provides 1,3-dienylphosphonates, 2, in satisfactory to excellent isolated yield (45-83%). The reaction is tolerant of chlorides and cyclic substituents. Cycloaddition reaction of 2 with DEAD provided the corresponding diethyl 3-(diethoxyphosphoryl)-6-alkyl-3,6-dihydropyridazine- 1,2-dicarboxylates, 3, in 85% isolated yield. The cycloaddition products can be obtained in a one-pot reaction directly from the isomerized 1-alkynylphosphonates with no loss in yields. Similarly, 1,3-dioxo-1,3,3a,4,7,7a- hexahydroisobenzofuran-4-ylphosphonate, and 1,3-dioxo-2,3,3a,4,7,7a-hexahydro-1H-isoindol-4-ylphosphonate 4 were obtained by reacting 1,3-dienylphosphonates with maleic anhydride and maleimide respectively.

■ Simple and Efficient One Pot Synthetic Protocol to Construct Morpholin-2-ones

Gorakh S. Yellol, Debendra K. Mohapatra, Mukund K. Gurjar,* and Chung-Ming Sun*

*Department of Applied Chemistry, National Chiao Tung University, Hsinchu 300-10, Taiwan, R.O.C.

Abstract

A new one pot synthetic method to construct 3-substituted morpholine-2-one derivatives is presented. Amino acids refluxed with 1,2-dibromoethane and potassium carbonate in acetonitrile followed by treatment with benzyl bromide in same pot furnished the 3-substituted N-benzyl-morpholine-2-ones in good yields. The simplicity of the reaction conditions and versatility of resulted scaffold to generate wide variety of molecules makes this method more attractive for synthetic organic chemists.

■ Tin-Tellurium Exchange Reaction in Tin-Containing Heterocycles: A New Entry for the Preparation of Tellurium Heterocycles

Haruki Sashida,* Mamoru Kaname, and Kazuo Ohyanagi

*Faculty of Pharmaceutical Sciences, Hokuriku University, 3-Ho, Kanagawa machi, Kanazawa 920-1181, Japan

Abstract

An alternative, simple and practical preparation of benzo[b]tellurophene, 1H-isotellurochromene, and 1-benzo- and 3-benzotellurepines by taking advantage of the tin-tellurium replacement reaction from the corresponding five-, six- and seven-membered tin-containing heterocycles was achieved.