HETEROCYCLES

■ Ivar Ugi: An Exceptional Scientist and Human being. In Memorial Ivar Ugi

Alexander Doemling

*Departments of Pharmaceutical Sciences and Chemistry, University of Pittsburgh, Pittsburgh, PA 12580, USA

■ Biography

Ivar Ugi*

*Organisch-Chemisches Institut, Technische Universität München, Lichtenbergstrasse 4, D-8046 Garching, Germany

■ Publication List of Prof. Dr. Ivar Karl Ugi

Ivar Ugi*

*Organisch-Chemisches Institut, Technische Universität München, Lichtenbergstrasse 4, D-8046 Garching, Germany

■ Cardiovascular Agents: Renin Inhibitors and Factor Xa Inhibitors

Aparna Kasani, Rajendra Subedi, Michael Stier, Daniel D. Holsworth, and Samarendra N. Maiti*

*Naeja Pharmaceuticals Inc, 4290-91A Street, Edmonton T6E 5V2, Canada

Abstract

Cardiovascular disease is a serious global health problem and the world’s leading cause of death, with an estimated 17 million people dying from it each year. Coronary heart disease (CHD) and stroke account for 20-50% of all deaths in most countries. These two diseases are the first and third cause of death in the industrialized world, and the first and second cause in many developing countries, respectively. Hypertension is a major contributing factor to cardiovascular disease. A number of therapies like diuretics, alpha and beta-blockers, ACE inhibitors and angiotensin receptor blockers (ARBs) are available for the treatment of hypertension. Despite these therapies 35% patients do not achieve blood pressure control goals. In recent years there has been tremendous effort focused on the development of renin inhibitors as a new class of antihypertensive drugs. These inhibitors offer a novel approach to control hypertension by acting further upstream in the RAAS pathway. Thrombosis is also responsible for heart attacks and stroke. To treat thrombosis, two groups of antithrombotic drugs such as thrombolytic and anticoagulant agents, are available. Despite available treatments, there remains a critical need for a safe and orally active anticoagulants. Recently, factor Xa inhibitors have been found to be a promising approach to prevent blood coagulation. This review will highlight the recent developments of renin inhibitors as antihypertensive agents and factor Xa inhibitors as anticoagulants.

■ Functionalized Acetylenes as Versatile Building-Blocks for the Multicomponent Assembling of Polysubstituted Furans and Pyrroles

Geneviève Balme,* Didier Bouyssi, and Nuno Monteiro

*ICBMS, Institut de Chimie et Biochimie Moléculaires et Supramoléculaires, Université Lyon, CPE, 43 Boulevard du 11 Novembre 1918, 69622 Villeurbanne, France

Abstract

This review highlights the versatility of functionalized alkynes in the multicomponent construction of polysubstituted furan and pyrrole derivatives.

■ Recent Advances in the Development and Applications of Post-Ugi Transformations

Irini Akritopoulou-Zanze* and Stevan W. Djuric

*Abbott Laboratories, Medicinal Chemistry Technologies, 100 Abbott Park Road, Abbott Park, IL 60044, USA.

Abstract

The Ugi reaction is one of the most prominent multiple component coupling reactions (MCRs) due to the large number of applications it has found in organic synthesis. In this review we summarize recent advances in the field of Ugi-post condensation reactions covering the literature for the past two years.

■ From Multi-Component-Reactions (MCRs) towards Multi-Function-Component-Reactions (MFCRs)

Heiner Eckert

*Department of Chemistry, Technical University of Munich, Lichtenbergstr. 4, 85747 Garching, Germany

Abstract

This review presents an overview on MCR chemistry by disclosing the logic of developments in recent progressive movements in MCR chemistry. An outlook points out what pathways will be followed up in the future.

■ Synthesis of Fluorescent Solamin for Visualization of Cell Distribution

Naoyoshi Maezaki, Daisuke Urabe, Masahiro Yano, Hiroaki Tominaga, Takekuni Morioka, Naoto Kojima, and Tetsuaki Tanaka*

*Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan

Abstract

Asymmetric synthesis of fluorescent solamin was accomplished by using highly stereoselective asymmetric alkynylation and Williamson etherification as the key steps, wherein the fluorescent acetogenin with all functionality was firstly synthesized.

■ Do Upper Limits to the Multiple Spiro Acetalization of the Cyclohexane Ring Exist?

Peter R. Selvaraj and Leo A. Paquette*

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

Abstract

An attempt to transform the pyranoside (5) into the bifacial ligand (3) is described. The first subtarget is acetal (13) whose conversion into tris acetal (17) is made possible by remote C-H activation. Regrettably, triol (20) does not lend itself to comparable triple cyclization.

■ High-Throughput Synthesis of Substituted Hydrazine Derivatives

Michio Kurosu,* 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

Regioselective alkylations of the hydrazine derivatives are achieved by using the (2,6-dichloro-4-methoxyphenyl)(2,4-dichlorophenyl)methoxycarboxyl resin. High-throughput synthesis of monosubstituted and 1,1-disubstituted hydrazine building blocks is described.

■ New End-On Thiolactone Scaffold by an Isocyanide-Based Multicomponent Reaction

Barbara Beck, Stuti Srivastava, and Alexander Dömling*

*Departments of Pharmaceutical Sciences and Chemistry, University of Pittsburgh, Pittsburgh, PA 12580, USA

Abstract

The three component reaction of homocysteine, an oxocomponent and an isocyanide smoothly and stereoselectively yields N-substituted 2-(2-oxotetrahydrothiophen-3-ylamino)acetamides. In this communication we present our preliminary results on six compounds derived from this unprecedented reaction.

■ Synthesis of 3-O-Acylated Epicatechin Derivatives via Sequential One-Pot Multi-Step Reactions

Makoto Kitade, Hiroshi Tanaka, and Takashi Takahashi*

*Department of Applied Chemistry, Graduate School of Science and Engineering, Tokyo Institute of Technology 2-12-1 Ookayama, Meguro, Tokyo 152-8552, Japan

Abstract

An effective approach for the synthesis of epicatechin derivatives based on sequential one-pot multi-step reactions is described. Reductive etherification of the disulfanyl derivative was promoted with a catalytic amount of TfOH, providing the cis-substituted benzopyran derivative in a stereoselective manner.

■ Gold-Catalyzed Cyclization Reaction of Alkynyl O-tert-Butylcarbamates

Hideto Miyabe,* Yuichi Sami, Takeaki Naito, and Yoshiji Takemoto*

*Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan

Abstract

Gold-catalyzed cyclization of alkynyl O-tert-butylcarbamates having N-benzyloxy group provided the 6-endo cyclized products selectively. Cascade reaction of O-tert-butylcarbamates having an enyne moiety was also examined.

■ Diastereoselective Approach to an HIV Protease Inhibitor Intermediate Using a Cation-Exchange Resin Mediated Mannich-Type Reaction

Makoto Shimizu,* Yukinori Hayashi, Ryosuke Hamanaka, and Iwao Hachiya

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

Abstract

Mannich-type reaction of ketene silyl acetals with a chiral imine proceeded smoothly to give β-amino esters in good yields with high diasetereoselectivity under the influence of a cation-exchange resin, and the subsequent functional group transformations gave an HIV protease inhibitor intermediate.

■ Quassinoid Support Studies: Increasing Stereocontrol in a Perhydronaphthalene Synthesis by Restricting Conformational Degrees of Freedom

David J. Hart* and Dexi Yang

*Department of Chemistry, The Ohio State University, 100 W. 18t^h Ave., Columbus, Ohio USA

Abstract

Free radical cyclization of 15 provides trans-perhydronaphthalene (16) in high yield and with much better stereoselectivity than conformationally less constrained analogs.

■ The Diastereoselective Synthesis of Difluoro-β-lactam Using Reformatsky-Honda Reaction

Atsushi Tarui, Keigo Kondo, Hiroko Taira, Kazuyuki Sato, Masaaki Omote, Itsumaro Kumadaki, and Akira Ando*

*Faculty of Pharmaceutical Sciences, Setsunan University, 45-1, Nagaotoge-cho, Hirakata, Osaka, 573-0101, Japan

Abstract

The high diastereoselective synthesis of chiral difluoro-β-lactams (3) was attained by treatment of ethyl bromodifluoroacetate (1), 2-hydroxy-1-phenylethyl group substituted imines (2) and diethylzinc in the presence of rhodium-catalyst. The absolute configuration of 3 was determined by X-ray analysis of 3,5-dinitrobenzoate (6) derived from 3.

■ 4,6-Bis(imidazolio)pyrimidine as a New Anion Receptor

Kiyoshi Sato,* Shin-ichiro Takeuchi, Sadao Arai, Motowo Yamaguchi, and Takamichi Yamagishi

*Division of Applied Chemistry, Faculty of Urban Environmental Sciences, Tokyo Metropolitan University, 1-1 Minami-ohsawa, Hachioji, Tokyo 192-0397, Japan

Abstract

New aryl-oligomer type anion receptors bearing two imidazolium units linked by 6-membered ring aryl spacers at meta-positions have been synthesized. Complexation behavior of the receptors with halide ions (Cl^-, Br^-, and I^-) in DMSO-d₆ was investigated by ¹H NMR titrations and semi-empirical calculations (MOPAC AM1). Along with the imidazolium C-H protons, the ortho C-H proton of the central aryl unit forms additional hydrogen bond interaction with guest anion. The receptor with pyrimidine unit exhibited significantly improved anion binding properties.

■ Total Synthesis of (±)-Komaroviquinone

George Majetich,* Yang Li, and Ge Zou

*Department of Chemistry, The University of Georgia, Athens, Georgia 30602, U.S.A.

Abstract

(±)-Komaroviquinone (1) was synthesized from 3,4,5-trimethoxybenzoic acid in twenty-two steps. The key transformations in this synthesis are: (1) the construction of the cycloheptane ring via a Friedel-Crafts cyclialkylation; (2) a regiospecific benzylic oxidation; (3) a conformationally controlled introduction of the C(10) hydroxyl group and (4) intramolecular hemi-acetal formation.

■ Total Synthesis of (+)-Komaroviquinone

George Majetich,* Jianhua Yu, and Yang Li

*Department of Chemistry, The University of Georgia, Athens, Georgia 30602, U.S.A.

Abstract

(+)-Komaroviquinone (1) was synthesized from enone 8 in twelve steps. Three novel routes were developed to produce key intermediate dienone 11. Two additional noteworthy steps are a regiospecific bromohydrin formation to oxidize C(7) and a second regio- and stereospecific bromohydrin formation to introduce the β-C(10) alcohol.

■ A Novel Approach to 5,5’-Diisopropyl-3,3’-bi-2H-cyclohepta[b]furan-2-one

Noboru Morita,* Junya Higashi, Kazuyuki Okada, Taku Shoji, Kozo Toyota, Masataka Watanabe, Masafumi Yasunami, Shigeru Kikuchi, and Shunji Ito

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

Abstract

5-Isopropyl-2H-cyclohepta[b]furan-2-one (1) reacted with DMSD to give dimethyl(5-isopropyl-2-oxo-2H-cyclohepta[b]furan-3-yl)sulfonium trifluoromethanesulfonate (2), which was treated with Et₃N to give 5-isopropyl-3-methylthio-2H-cyclohepta[b]furan-2-one (3). Sulfide 3 was oxidized with mCPBA to give sulfoxide 4 and sulfone 5. The salt 6 which comes from the treatment of 4 with Tf₂O converted to an unexpected product, 5,5’-diisopropyl-3,3’-bi-2H-cyclohepta[b]furan-2-one (7), thermally.

■ Nucleophilic Asymmetric Epoxidation Catalyzed by Cyclic Guanidines

Tetsuya Kita, Bongki Shin, Yuichi Hashimoto, and Kazuo Nagasawa*

*Department of Biotechnology and Life Science, Tokyo University of Agriculture and Technology, Koganei, Tokyo 184-8588, Japan

Abstract

Asymmetric nucleophilic epoxidation of chalcone and its derivatives was studied using chiral cyclic guanidine compounds. Pentacyclic guanidine 1a, which has a characteristic closed-type cavity, catalyzed the reaction to give epoxides with 39-60% ee. The newly developed tricyclic guanidine 4 drastically accelerated the reaction, and induced the asymmetric induction of chalcones with almost the same level of 1a.

■ A Facile Synthesis of Thiaaza- and Thiadiaza-fluorene Derivatives Involving Benzothiazole-DMAD Zwitterion with Arylidenemalononitriles and N-Tosylimines

Vijay Nair,* Rema Devi B., Abhilash N. Pillai, and Rony Rajan Paul

*Organic Chemistry Section, Regional Research Laboratory (CSIR), Trivandrum-19, India

Abstract

An efficient protocol for the one-pot synthesis of thiaazafluorene and thiadiazafluorene derivatives are described.

■ Lewis Base Catalyzed Aza-Diels-Alder Type Reactions between Danishefsky’s Dienes in the Presence of Lewis Base Catalysts.
An Efficient Method for the Synthesis of Substituted 2,3-Dihydropyridin-4-ones

Takayuki Kitazawa, Yuji Maruyama, and Teruaki Mukaiyama*

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

Abstract

Aza-Diels-Alder type reactions of various imines with 1-methoxy-3- trimethylsilyloxy-1,3-butadiene (Danishefsky’s diene) derivatives catalyzed by Lewis bases such as lithium methoxide are described. The reaction proceeds via a stepwise pathway, i.e. first by an imino-aldol reaction followed by the acid mediated annulation to afford the corresponding 2,3-dihydropyridin-4-ones in high yields. An appropriate choice of the substituents on nitrogen plays important roles both in addition of the silyl enolates and in the subsequent annulation to form the desired cycloadducts.

■ Synthesis of Scyphostatin Analogs Possessing Various Saturated Fatty Acid Side-Chains

Kazuhiro Watanabe, Takamasa Oguchi, Toshiya Takizawa, Miki Furuuchi, Hideki Abe, and Tadashi Katoh*

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

Abstract

Scyphostatin analogs 2a-f possessing various saturated fatty acid side-chains (C₁₂-C₁₉) were efficiently synthesized in enantiomerically pure form starting from the known cyclohexene derivative 3. These analogs were designed to improve the stability of scyphostatin (1), a powerful and specific inhibitor of neutral sphingomyelinase (N-SMase) from a microorganism.

■ Synthesis of Unusual Tricyclic Ring Systems of Biological Interest

Debendra K. Mohapatra,* Pradip K. Maity, Mukund S. Chorghade, and Mukund K. Gurjar

*Division of Organic Chemistry: Technology, National Chemical Laboratory, Pune-411 008, India

Abstract

We describe a new synthesis of tricyclic scaffolds that incorporate a fusion of triazole with 1,4-benzodiazepine utilizing intramolecular “click” chemistry.

■ Substituent Effects on Ultraviolet Absorption Spectra of 5-Substituted N_b-Acetyl-1-methoxytryptamines Studied by Density Functional Theory Calculations

Kunihiro Tokumura,* Kenta Imai, Akio Hayashi, Tomonori Ida, and Masanori Somei*

*Division of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Japan

Abstract

Density functional theory (DFT) calculations were performed for twelve 5-substituted N_b-acetyl-1-methoxytryptamines (5-X: NO₂, SO₂CH₃, CN, CF₃, Cl, H, CH₃, OH, OCH₃, NHCOCH₃, NH₂, N(CH₃)₂) in methanol. The respective HOMO→LUMO and HOMO-1→LUMO singly excited configurations are mainly responsible for the lowest and the second singlet excited states (S₁ and S₂). Observed UV absorption spectra of 5-H, 5-NHAc, and 5-CH₃ derivatives are well predicted by simple time-dependent DFT calculations. Distinct substituent effects are found with respect to the energies of MOs responsible for S₁←S₀ and S₂←S₀ transitions. Both HOMO-1 and HOMO are destabilized by electron-donating groups, and stabilized by electron-withdrawing groups. LUMO+1 of 5-NO₂ derivative should be classified into normal LUMO, which are found for eleven other derivatives as well as indole. Normal LUMO is not significantly affected in energy by electron-donating groups, but stabilized by electron-withdrawing groups.

■ Binding Selectivity of 1- or 12-Substituted Indolactam Derivatives for Protein Kinase C Isozymes

Ryo C. Yanagita, Keiji Torii, Yu Nakagawa, and Kazuhiro Irie*

*Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan

Abstract

The selectivity with which 1- or 12-substituted analogues of indolactam-V (1) bind protein kinase C (PKC) isozymes was examined. Moderate selectivity for novel PKC isozymes over conventional PKC isozymes was observed in the case of indolactam-nV (13) and indolactam-L (14) without an α-branched side chain at position 12. The introduction of a bulky isopropyl group to position 1 of 1 drastically increased the selectivity for novel PKC isozymes.

■ Synthesis of Conformationally Constrained 2’-N,4’-C-Ethylene-Bridged Adenosine (aza-ENA-A)

Malgorzata Wenska, Dmytro Honcharenko, Wimal Pathmasiri, and Jyoti Chattopadhyaya*

*Department of Bioorganic Chemistry, Box 581, Biomedical Center, Uppsala University, SE-75123 Uppsala, Sweden

Abstract

The synthesis of conformationally constrained 2’-N,4’-C-ethylene-bridged adenosine (aza-ENA-A), in which the pentose-sugar is cis-fused with the piperidino skeleton at C2’ and C4’ centres of the sugar ring, is reported. The corresponding phosphoramidite building block will be used for incorporation into oligo-DNA and -RNA by solid phase synthesis to examine their nuclease stability as well as their application in blocking the translation of the target RNA using the antisense and siRNA approach. 2-Aza-6-oxabicyclo[3.2.1]octane skeleton is assembled through multi-step synthetic manipulation of appropriately protected D-arabinose based sugar precursor. The conversion of appropriate arabino precursor to ribo counterpart was achieved by direct nucleophilic displacement of “ara” positioned 2-(trifluoromethanesulfonyloxy) group in the sugar precursor 8. A high regio- and enhanced stereoselectivity with preferential formation of β anomer in glycosylation reaction was achieved using Vorbrüggen conditions in the absence of any 2-participating group. Coupling step was performed using 1-O-acetyl-3,5-di-O-benzyl-(2-deoxy-2-azido)-4-C-(p-toluoyloxyethyl)-D-ribofuranose (10) as a glycosyl donor and persilylated N⁶-benzoyladenine. Finally, the ring-closure giving the North-type conformationally constrained cis-fused bicyclic aza-ENA-A have been confirmed unambiguously by the long range ¹H-¹³C NMR correlation (HMBC), TOCSY, COSY and nOe experiments.

■ Syntheses of 2-Formyl-, 2,3-Diformyl- and 8-Formyl-1-azaazulenes

Kazuya Koizumi, Chikara Miyake, Tomoyuki Ariyoshi, Kenji Umeda, Noriko Yamauchi, Shoji Tagashira,* Yoshiko Murakami, Hiroyuki Fujii, and Noritaka Abe*

*Applied Molecular Bioscience, Graduate School of Medicine, and Department of Biology and Chemistry, Faculty of Science, Yamaguchi University, Yoshida, Yamaguchi 753-8512, Japan

Abstract

2-Styryl-1-azaazulenes were synthesized by two ways: a) Suzuki coupling of 2-bromo-1-azaazulenes with trans-2-phenylvinylboronic acid b) Condensation of 2-methyl-1-azaazulene, being synthesized by Negishi coupling of 2-bromo-1-azaazulene with dimethylzinc, with benzaldehyde. Oxidative cleavage of 2-styryl-1-azaazulenes with OsO₄-KIO₄ gave 2-formyl-1- azaazulenes. 8-Formyl-1-azaazulenes were synthesized by the reaction of 1- azaazulenes with 2-lithio-1,3-dithiane followed by the hydrolysis.

■ Taxezopidines O and P, New Taxoids from Taxus cuspidata

Haruaki Ishiyama, Yuka Kakuguchi, Eri Arita, and Jun’ichi Kobayashi*

*Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan

Abstract

Two new taxoids, taxezopidines O (1) and P (2), have been isolated from seeds of the Japanese yew Taxus cuspidata, and the structures and relative stereochemistry were elucidated on the basis of spectroscopic data. The absolute stereochemistry of a 3-N-methylamino-3-phenylpropanoyl group in 1 was determined by HPLC analysis for FDAA (1-fluoro-2,4-dinitrophenyl-5-L-alanine amide) derivative of hydrolysate of 1.