HETEROCYCLES

■ From Natual Products to Curatives: Refrections on Arnold Brossi’s Career and Contributions

Bernhard Witkop* and Yoshio Ban

*National Institute of Health, 9000 Rockville Pike, Bethesda, MD 20892-0815, U.S.A.

■ Preface to the Special Issue of HETEROCYCLES in Honour of Dr. Arnold R. Brossi

Alan Battersby*

*Department of Chemistry, University of Cambridge, Cambridge, CB2 1EW, U.K.

■ Preface to the Special Issue of HETEROCYCLES in Honour of Dr. Arnold Brossi

Nelson J. Leonard

*Division of Chemistry 164-30, California Institute of Technology, Pasadena, CA 91125, U.S.A.

■ Synthesis and [3+2]Cycloaddition Reaction of 3-[(Trimethylsilylmethylamino)(methylthio)]-methylene-2-coumaranone and -1-methyloxindole: Synthetic Equivalent of Heterocyclic Alkylideneazomethine Ylide as a Novel 1,3-Dipolar Reagent

Yoshinori Tominaga,* Satoshi Takada, and Shinya Kohra

*Faculty of Pharmaceutical Sciences, Nagasaki University, 1-14, Bunkyo-machi, Nagasaki 852-8521, Japan

Abstract

3-[(TrimethyIsilylmethylamino)(methylthio)methylene-2-coumaranone(4a) and -1-methyloxindole (4b), readily prepared by reaction of the corresponding bis(methylthio)methylene-heterocyclic compounds (2a, b) with trimethylsilylmethylamine (3), were found to be syntehtic equivalent of heterocyclic alkylideneazomethine ylides. Reaction of 4a, b with reactive heterodipolarophiles such as aldehydes and ketones in the presence of secium fluoride gave 1,3-dipolar cycloadducts, 3-(2-oxazolidenylidene)-2-coumaranone and -1-methyloxindole derivatives(8a-j, 9a-b), via the 1,3-elimination of (methylthio)trimethylsilane.

■ An Efficient Synthesis of Chloroethylclonidine

Wei-Yi Zhang, Venkatesalu Bakthavachalam, Yigong Gao, William L. White, and John L. Neumeyer*

*Research Biochemicals International, Inc., One Strathmore Road Natick, MA 01760, U.S.A.

Abstract

An efficient pathway for the preparation of chloroethylclonidine dihydrochloride (1) is described.

■ A Practical and General Synthesis of (+)-Carboxyalkyldeoxoartemisinis

Mankil Jung,* Antonio C. C. Freitas, James D. McChesney, and Hala N. ElSohly

*Research Institute of Pharmaceutical Sciences, Department of Medicinal Chemistry and Pharmacognosy, School of Pharmacy, University of Mississippi, University, Mississippi 38677, U. S. A.

Abstract

Dye-sensitized photoxygenation of olefinic alcohols of dihydroartemisinates (4a-c) and direct oxidation of olefinic deoxoartemisinins (5a-c) have led to the preparation of carboxyalkyldeoxoartemisinins (6a-c), which are water-soluble and chemically more stable antimalarial agents.

■ Lithiation of 3-Dimethylaminomethyl- and 3-Dimethylaminoethyl-1-methoxylndole Derivatives

Kyoko Nakagawa and Masanori Somei*

*Faculty of Pharmaceutical Scicences, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-0934, Japan

Abstract

Lithiation of 3-dimethylaminomethyl- and 3-dimethylaminoethyl-1-methoxyindole occurred regioselectively at the 2-position. 2-Substituted 3-dimethylaminomethyl-1-methoxyindoles were lithiated at the 4-position.

■ A Synthesis of Pyrrolomorphinans

Peter Schwarz and Helmut Schmidhammer*

*Institute of Pharmaceutical Chemistry, University of Innsbruck, Innrain 52a, A-6020 Innsbruck, Austria

Abstract

Pyrrolomorphinans (4, 10, and 13) have been prepared from the corresponding nitro ketones employing the tributylphosphine-diphenyl sulfide deoxygenating system. The nitro ketones (7, 9, and 12) were obtained either from hydrocodone (6) with lithium diisopropylamide and the corresponding nitroalkene, or from hydrocodonepyrrolidine enamine (11) by treatment with 2-nitropropene.

■ An Efficient Synthesis of 1,2,3,4-Tetrasubsttituted Pyrroles via Intramolecular Azomethine Ylide [3+2] Dipolar Cycloaddition

Masahiro Toyota, Youichi Nishikawa, and Keiichiro Fukumoto*

*Pharnaceutical Institute, Tohoku University, Aramaki, Aoba-ku, sendai 980-8578, Japan

Abstract

A sequence of reactions, involving intramolecular azomethine ylide [3+2] dipolar cycloaddition, was used to efficiently construct 1,2,3,4-tetrasubstituted pyrroles.

■ Total Synthesis of (±)-Diplophyllin Using Intramolecular Cyclization of ω-Formyl-β-alkoxycarbonylallysilane

Kiyoshi Nishitani, Jun Suzuki, Hideyasu Ishibashi, Yoshiko Saitoh, Shoko Kariya, and Koji Yamakawa*

*Faculty of Pharmaceutical Sciences, Science University of Tokyo, 12, Ichigaya Funagawara-machi, Shinjuku-ku, Tokyo 162-0826, Japan

Abstract

ω-Formyl-β-ethoxycarbonylallylsilane derivative (15) was prepared from methyloctalone in several steps. Intramolecular cyclization of the allylsilane (15) was effected by BF₃-OEt₂ to give hydroxy esters (17 and 18) in good stereoselectivity at C-7. The hydroxy ester (17) was converted into (±)-diplophyllin (I) with p-TsOH in an excellent yield.

■ Efficient Synthesis of Hydroxyphthalides

Yoshimitsu Ogawa, Masao Murano, and Takeshi Wakamatsu*

*Central Research Laboratory, Tsumura & Co., 3586 Yoshiwara, Ami-machi, Inashiki-gun, Ibaraki, 300-11, Japan

Abstract

Naturally occurring hydroxyphthalides were synthesized via migration of double bond regio- and stereoselectively. Isomerization of E-isomer to Z-isomer easily occurred under acidic or basic conditions.

■ A Novel Approach to Functionalized Policyclic Systems; Synthesis of Tetracycli Compounds by Sequential Diels-Alder Reactions of 2-Acylated 4H,6H-Thieno[3,4-c]furan 5,5-Dioxide

Katsuhiro Konno, Satoshi Sagara, Takaaki Hayashi, and Hiroaki Takayama*

*Faculty of Pharmaceutical Sciences, Teikyo University, 1091-1 Suarashi, Sagamiko-machi, Tsukui-gun, Kanagawa 199-0195, Japan

Abstract

The 7-oxa-2,3-dimethylenenorbornene derivative (3), synthesized previously from 4H,6H-thieno[3,4-c]furan 5,5-dioxide (1) through its 2-acylated derivative (2), reacted with a variety of dienophiles to give the adducts (4), the functionalized tetracyclic compounds, in good to excellent yield.

■ A Formal Synthesis of Dihydrocompactin

Shigeru Nagashima, Teruhiko Taishi, and Ken Kanematsu*

*Institute of Synthetic Organic Chemistry, Faculty of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan

Abstract

A formal synthesis of dihydrocompactin is reported. A key intermediate, tricyclic lactone (1b), was prepared by an efficient method of lactone synthesis, based on an intramolecular cycloaddition reaction of allenyl ether.

■ General Stereoselective Route to (E)-3-Hydroxy-1-alkenyl Chlorides and Phenyl Ethers

Seiichi Takano,* Yoshiaki Sugihara, and Kunio Ogasawara

*Pharnaceutical Institute, Tohoku University, Aramaki, Aoba-ku, sendai 980-8578, Japan

Abstract

Treatment of 2,3-epoxyalkyl chlorides with potassium tert-butoxide affords the corresponding (E)-1-chloro-3-hydroxyalkenes stereoselectively when dicyclohexano-18-crown-6 is present. On the other hand, 2,3-epoxyalkyl phenyl ethers furnish (E)-3-hydroxy-1-alkenyl phenyl ethers stereoselectively upon exposure to n-butyllithium in the presence of hexamethylphosphoric triamide.

■ A Concise Enantiocontrolled Route to (+)-Patulolide C

Seiichi Takano*, Taku Murakami, Kiyohiro Samizu, and Kunio Ogasawara

*Pharnaceutical Institute, Tohoku University, Aramaki, Aoba-ku, sendai 980-8578, Japan

Abstract

A naturally occurring anti fungal macrolide (+)-patulolide C has been synthesized enantioselectively via the C₂-symmetric bis-epoxide by incorporation of two molecular units of (R)-O-benzylglycidol.

■ 1-Chlorobenzotriazole-mediated Ring Closure of 1,3,5-Triarylformazans: Improved Syntheses of 2,3,5-Triaryl-2H-tetrazolium Salts

Alan R. Katritzky,* Sergey A, Belyakov, Jamshed N. Lam, H. Dupont Drust, and Dmitrii V. Karpenko

*Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville, FL 32611-2046, U.S.A.

Abstract

Oxidative ring closure of mono- and bis-triarylformazans mediated by easily available 1-chlorobenzotriazole leads to the corresponding 2,3,5-triaryl-2H-tetrazolium chlorides in yields of 70-97%.

■ The Dolastatins 16. Synthesis of Dolaphenine

George R. Pettit,* Fiona Hogan, Douglas D. Burkett, Sheo B. Singh, Darko Kantoci, Jayaram Srirangam, and Michael D. Williams

*Cancer Research Institute, Department of Chemistry, Arizona State University, Tempe, Arizona 85287-1604, U.S.A.

Abstract

Synthesis of dolaphenine (2), the thiazole-containing unit of the strongly antineoplastic peptide dolastatin 10 (1), has been summarized. While conversion (4→7 or 4→11) of phenylalanine to thiazolidines (7) or thiazolines (11) was routinely uneventful, a dependable procedure for dehydrogenation of these intermediates to dolaphenine (2, Doe) proved elusive. While several types of specially prepared manganese dioxide were found most effective for the dehydrogenation, yields of dolaphenine varied from almost nil to over 70%. Some of these reactions resulted in partial to complete racemization of the phenylalanine derived chiral carbon.

■ An Approach to Open Chain and Modified Heterocyclic Analogues of the Acetylcholine-sterase Inhibitor, Huperzine A, through a Bicyclo[3.3.1]nonane Intermediate

Alan P. Kozikowski, Giuseppe Campiani, and Werner Tückmantel*

*Mayo Foundation for Medical Education and Research, 4500 San Pablo Road, Jacksonville, FL 32224, USA

Abstract

The use of the bicyclo[3.3.1]nonane derived keto urethane (3) in a general synthesis of open chain and modified heterocyclic analogues of huperzine A was investigated and resulted in the preparation of the dimethylcarbamoyloxy analogue (27). Thiazole annulation by the Gewald procedure gave only the undesired regioisomer (36).

■ Synthesis of 7-Ethyl-1,2-dihydroquinolin-2-ones as Angiotensin II Receptor Antagonists

Norbert Beier, Erwin Labitzke, Werner W.K.R. Mederski,* Hans-Eckart Radunz, Karin Rauschenbach-Ruess, and Björn Schneider

*E. Merck, Preclinical Pharmaceutical Research Laboratories, 64271 Darmstadt, Germany

Abstract

A number of biphenyl substituted 1,2-dihydroquinolin-2-ones were synthesized by regiospecific alkylation of the corresponding 1H-derivatives. Again, these precursors were prepared in three steps by acetoacetylation of anilines, regiospecific C-alkylation of the resulting β-ketoanilides and subsequent condensation to the quinolinones. One of the target compounds, 2-[7-ethyI-4-methyl-2-oxo-1-[(2’-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-1,2-dihydroquinolin-3-yl]-N,N-dimethylacetamide (10e), is a potent angiotensin II receptor antagonist.

■ Structure Determination of a Geometric Isomer of 2-Acetyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-(2-methylpropylidene)isoquinoline

Tozo Fujii,* Masashi Ohba, Naoko Fukui, and Tadamasa Date

*Faculty of Pharmaceutical Scicences, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-0934, Japan

Abstract

A geometric isomer (mp 112-113°C) of 2-acetyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-(2-methylpropylidene)isoquinoline (4), prepared previously from 3,4-dihydro-6,7-dimethoxy-1-(2-methylpropyl)isoquinoline (3) by acetylation with acetic anhydride and pyridine, has been shown to have the E configuration (4a) by means of ¹H nmr spectroscopic and X-ray crystallographic analyses.

■ A Two-step Synthesis of Imidazoles from Aldehydes via 4-Tosyloxazolines

David A. Horne, Kenichi Yakusijin, and George Büchi*

*Department of Chemistry, Room 18-390, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, U.S.A.

Abstract

Imidazoles with substituents in the 4- and 4,5-positions were prepared by heating 4-tosyloxazolines in saturated methanolic ammonia. Similar treatment of these oxazolines with monoalkylamines regioselectively affords 1,4-disubstituted imidazoles. When oxazolines bearing an ethyl group at the 4-position were heated with alkylamines, however, a regioisomeric mixture of di- or trisubstituted imidazoles was produced. These reactions proceed via an intermolecular condensation of α-amino ketones and amidines or intramolecular cyclization of α-amidino ketone intermediates, respectively.

■ A Convenient and Facile Synthesis of 5-Trifluoromethyl-1,2,4-triazine Derivatives

Yasuhiro Kamitori, Masaru Hojo, Ryoichi Masuda,* Masamichi Sukegawa, Kouji Hayashi, and Ken Kouzeki

*Department of Industrial Chemistry, Faculty of Engineering, Kobe University, Rokkodai-cho, Nada-ku, Kobe 657-8501, Japan

Abstract

3-Hydrazono-1,1,1-trifluoroalkan-2-ones (2) and 3-methylhydrazono-1,1,1-trifluoroalkan-2-ones (3) prepared from 1,1,1-trifiuoroalkane-2,3-diones (1) reacted with several aldehydes in the presence of aq. NH₄OH to afford 5-trifluoromethyl-2,3-dihydro-1,2,4-triazines (4 and 5) of which oxidation gave 5-trifluoromethyl-1,2,4-triazines (6) and 5-trifluoromethyl-2,5-dihydro-5-hydroxy-1,2,4-triazines (7). Thermal reaction of 5 afforded 1-amino-4-trifluoromethylimidazoles (8).

■ Synthetic Studies towards a trans-3,4-Diamine Derivative of Piperidine Mimicking Buspirone

Shikai Zhao, Arun Ghosh, Stan V. D'Andrea, Jeremiah P. Freeman, Philip F. VonVoigtlander, Donald B. Carter, Martin W. Smith, James. R. Blinn, and Jacob Szmuszkovicz*

*Department of Chemistry and Biochemistry, College of Science, University of Notre Dame, Notre Dame, IN 46556, U.S.A.

Abstract

Based on modeling experiment of buspirone we synthesized the sterically restricted analog, namely the piperidine 3,4-trans-amino amide (3). Preliminary biological evaluation is reported.

■ Effect of Tin(II) Triflate on Reactions of α-Ethoxycarbamates with Enolates

Tatsuo Nagasaka,* Shiro Nishida, Shu Sugihara, Toshio Kawahara, Koichi Adachi, and Fumiko Hamaguchi

*Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan

Abstract

Reactions of α-ethoxycarbamates (α-ethoxylated derivatives of N-ethoxycarbonylpyrrolidine, -piperidine, and -hexamethyleneimine) with various enolates (enol acetates, enol ethers, or tin(II) enolates of ketones) in the presence of tin(II) triflate are described.

■ Synthesis of 1,3-Dithietane-2,4-diylidenebis(cyanomethylphosphonates) and -phenyl-phosphinates and Their Reaction with Carboxylic Acid Hydrazides

Richard Neidlein,* Monica Jochheim, Claus Krieger, and Walter Kramer

*Pharmazeutisch-Chemishces Institut, Ruprecht-Karls-Universität Heidelberg, Im Neuenheimer Feld 364, D-69120 Heidelberg, Germany

Abstract

1,3-Dithietane-2,4-diylidenebis(cyanomethylphosphonates) and -phenylphosphinates react with carboxylic acid hydrazides to yield tautomeric derivatives of 1,3,4-oxadiazoles. One of the starting materials as well as one of the reaction products is examined by X-ray crystal structure analysis.

■ Regiocontrolled Total Syntheses of the Tropoloisoquinoline Alkalnoids Imerubrine and Grandirubrine

Martin G. Banwell,* Ernest Hamel, Neil K. Ireland, and Maureen F. Mackay

*School of Chemistry, The University of Melbourne, Parkville, Victoria 3052, Australia

Abstract

The previously reported dihydroazafluoranthene (8) has been converted, over a number of steps, into the σ-homo-o-benzoquinone monoacetal (5). The structure of compound (5) was established by X-ray crystallographic methods and treatment of this material with trifluoroacetic acid resulted in formation of the tropoloisoquinoline alkaloid imerubrine (1). Alternatively, acetal (5) could be hydrolysed to the corresponding diketone (6) which proved to be unstable and isomerised to grandirubrine (2) on heating. Both tropoloisoquinolines (1) and (2) were tested for antitubulin activity, and weak inhibition of polymerisation was observed only with the former compound.

■ 8H-Anhydro-4-hydroxy-2-oxo-1,3-thiazinium Hydroxides as Mesoionic 1,4-Dipoles

Albert Padwa,* Steven J. Coats, and Lazaros Hadjarapoglou

*Department of Chemistry, Emory University, 1515 Pierce Drive Atlanta, Georgia 30322, U.S.A.

Abstract

The previously unknown 8H-anhydro-4-hydroxy-2-oxo-1,3-thiazinium hydroxides (1) were prepared and their 1,4-dipolar cycloaddition behavior was examined. In most cases, elimination of the proton in the 8-position of the mesoionic ring was observed to occur unless extremely reactive dipolarophiles were used. The S,N-ketene acetals were converted to the corresponding α-diazo ketones for further study.

■ (-)-Padocin: A Novel Epoxylignan from Haplophyllum Cappadocicum

Belkis Gözler, Bijen Kivçak, Gökay Arar, Tekant Gözler, and Manfred Hesse*

*Institute of Organic Chemistry, University of Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland

Abstract

Haplophyllum cappadocicum (Rutaceae) of Turkish origin yielded a novel lignan, incorporating an unusual 6,9’ fusion in a 9,9’-epoxylignan structure. Extensive 2D nmr experiments and catalytic hydrogenolysis are undertaken for the elucidation of structure with the relative configuration given in 1.

■ Synthesis and Anti-Acetylcholinesterase Activity of Thiaphysostigmine Derivatives

Masayuki An-naka, Kosuke Yasuda, Masaki Yamada, Akiyosi Kawai, Norio Takamura,* Shigehiko Sugasawa (the late), Yuzo Matsuoka, Hirosi Iwata, and Tomiko Fukushima

*Organic Chemistry Research Laboratory, Tanabe Seiyaku Co.Ltd., 2-2-50, Kawagishi, Toddda, Saitama 335-8505, Japan

Abstract

A series of thiaphysostigmine derivatives (2a, b and 3a, b), with a sulfur atom instead of N-methyl group in B ring or C ring of physostigmine (1), were synthesized, and their inhibitory effects on AChE and BuChE activity, and acute toxicity were evaluated.

■ Ortho-directed Metalation of 3-Heterosubstituted 4-Methyl-6-phenylpyridazines

Jean-Marie Sitamzé, André Mann,* and Camille-Georges Wermuth

*Laboratoire de Pharmacochimie Moleculaire, Centre de Neurochimie du CNRS, 5, rue Blaise Pascal, 67084 Strasbourg-Cedex, France

Abstract

Side-chain metalation of 4-methyl-6-phenyl pyridazines (2-4) with lithium diisopropylamide or 2,2,6,6-tetramethylpiperidide and subsequent alkylation with various electrophiles have been investigated. Depending on the substituent attached at the 3-position (Cl, OMe or NHCOtBu), the preparation of the alkylated pyridazines was more or less efficient.