HETEROCYCLES
An International Journal for Reviews and Communications in Heterocyclic ChemistryWeb Edition ISSN: 1881-0942
Published online by The Japan Institute of Heterocyclic Chemistry
Special Issue
John Daly's Special Issues,Vol. 79, No. 1, 2009
Published online: 21st November, 2008
■ Assembly of Substituted Homophthalimides via CuI-Catalyzed Coupling of 2-Bromobenzamides with β-Keto Ester
Hexiang Wang, Kun Gao, Yongwen Jiang, and Dawei Ma*
*State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, 354 Finglin Road, Shanghai 200032, China
Abstract
CuI catalyzed coupling of 2-bromobenzamides and β-keto esters takes place at 90 °C in i-PrOH to afford substituted homophthalimides in good yields. This transformation undergoes a cascade coupling/intramolecular condensation process, which allows assembly of a wide range of substituted homophthalimides by varying 2-bromobenzamides and β-keto esters.
Published online: 25th November, 2008
■ 5,5’-Bipyridyl-2,4,6,2’,4’,6’-hexaone Derivatives (Hydurilic Acids): Syntheses, Mechanism of C-C-Bond Formation and Properties of the Dimeric Barbituric Acid Derivatives
Christa E. Müller,* Carolin Roegler, and Jörg Hockemeyer
*Pharmaceutical Institute Poppelsdorf, University of Bonn, Kreuzbergweg 26, D-53115 Bonn, Germany
Abstract
A series of hydurilic acid derivatives (5,5’-bipyrimidinyl-2,4,6,2’,4’,6’-hexaones) including several new derivatives was synthesized from 5,6-diaminouracils. Mechanisms for their formation are proposed and discussed. Furthermore, a new method for the preparation of pyrimidine-2,4,5,6-tetraone-5-oxime derivatives (violuric acids) was found starting from 5-amino-6-nitrosouracils.
Published online: 3rd December, 2008
■ Stereocontrolled Total Synthesis of (±)-FR901483
Shigeru Ieda, Yusuke Asoh, Teppei Fujimoto, Haruka Kitaoka, Toshiyuki Kan, and Tohru Fukuyama*
*Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Abstract
The total synthesis of potent immunosuppressant FR901483 (1) is reported. The remarkable feature of our convergent synthesis is the p-methoxybenzyl and methylamino groups are stereoselectively incorporated within the tri-cyclic core skeleton. The skeleton itself is constructed by an intramolecular aldol reaction on a symmetrical keto-aldehyde (14), which is readily derived by an eight-step sequence from nitromethane and methyl acrylate.
Published online: 10th December, 2008
■ Intermolecular Carbon Radical Addition to Cyclic Nitrone
Masafumi Ueda, Hideto Miyabe, Nami Nonoguchi, Okiko Miyata, Osamu Tamura, and Takeaki Naito*
*Kobe Pharmaceutical University, Motoyamakita, Higashinada, Kobe 658-8558, Japan
Abstract
The intermolecular radical addition to chiral glyoxylic nitrone was studied. The ethyl radical addition to nitrone by using triethylborane proceeded smoothly to give the desired ethylated product with moderate diastereoselectivities accompanying with the ethylated nitrone and the diethylated product. The radical reaction of nitrone took place even in aqueous media. The investigation of optimal reaction conditions and the reaction pathway were described.
Published online: 31st October, 2008
■ Synthetic Studies on Natural Isocoumarins and Isocarbostyril Derivatives Having an Alkyl Substituent at the 3-Position: Total Synthesis of Scoparines A and B, and Ruprechstyril
Marcellino Rudyanto, Koichi Kobayashi, and Toshio Honda*
*Faculty of Pharmaceutical Sciences, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan
Abstract
Two isocoumarins, scoparines A and B, having n-propyl group at the 3-position, and a new isocarbostyril, ruprechstyril, bearing n-pentyl substituent at the 3-position were synthesized via Sonogashira coupling of the corresponding aromatic halides and alkynes, followed by regioselective 6-endo-dig cyclization.
Published online: 31st October, 2008
■ Naucleamide F, a New Monoterpene Indole Alkaloid from Nauclea latifolia
Yuka Kakuguchi, Haruaki Ishiyama, Takaaki Kubota, 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 monoterpene indole alkaloid, naucleamide F (1), has been isolated from the bark and wood of Nauclea latifolia, and the structure and stereochemistry were elucidated on the basis of the spectral data. Naucleamide F (1) is a new monoterpene indole alkaloid consisting of a tetrahydro-β-carboline ring fused to a pyridone ring, and a 1,3,5-trioxepane ring fused to a dihydropyran ring and a glucose unit.
Published online: 10th November, 2008
■ Studies toward Intramolecular Cycloaddition of o-Quinodimethane with an Oxazole Moiety
Yuji Matsuya,* Hongbo Qin, and Hideo Nemoto
*Faculty of Pharmaceutical Sciences, Toyama University, 2630 Sugitani, Toyama, Toyama 930-0194, Japan
Abstract
Thermal reaction of benzocyclobutene derivatives having an oxazole moiety was investigated. Intramolecular [4+2] cycloaddition of o-quinodimethane, generated by thermolysis of the benzocyclobutene, with the oxazole did not proceed, and instead, [1,5]-sigmatropic rearrangement occurred dominantly.
Published online: 14th November, 2008
■ Use of Diketopiperazines for Determining Absolute Configurations of α-Substituted Serines by 1H-NMR Spectroscopy
Shigeki Sano,* Michiyasu Nakao, Masanori Takeyasu, Syuji Kitaike, Yasuko Yoshioka, and Yoshimitsu Nagao
*Molecular Medicinal Chemistry, Faculty of Pharmaceutical Sciences, The University of Tokushima, Sho-machi, Tokushima 770-8505, Japan
Abstract
A chiral α-substituted serine of interest was transformed into both of the corresponding diastereomers of diketopiperazines utilizing L- and D-phenylalanine methyl ester hydrochloride. The absolute configuration of the original chiral α-substituted serine was determined by 1H-NMR analyses of the resulting diastereomers.
Published online: 14th November, 2008
■ Synthesis of the Bicyclo[3.3.1]nonane Core of Huperzine A and Novel Pyridine-Fused Tricycles by Cyclisation of Pyridine-Based Radicals
Jarrod Ward and Vittorio Caprio*
*Department of Chemistry, University of Auckland, 23 Symonds Street, Auckland, New Zealand
Abstract
The cyclisation of 3-pyridyl radicals and (2-pyridyl)methyl radicals, generated from (pyridyl)cyclohexenols 5 to 8, has been examined as part of a model study directed towards the synthesis of huperzine A. The 3-pyridyl radical, generated from 3-bromopyridine 5, undergoes 5-exo-trig cyclisation to give hexahydroindenopyridine 10. Related pyridine-fused tricycle 12 is formed by 5-exo-trig cyclization of the (2-pyridyl)methyl radical derived from selenide 7b, while the radicals generated from selenides 8b and 19 undergo 6-exo-trig cyclisation to give the bicyclo[3.3.1]nonane core of huperzine A.
Published online: 20th November, 2008
■ Total Synthesis of (–)-Flustramine B via One-Pot Intramolecular Ullmann Coupling and Claisen Rearrangement
Tomohiro Hirano, Kanako Iwakiri, Hiroshi Miyamoto, Atsuo Nakazaki, and Susumu Kobayashi*
*Faculty of Pharmaceutical Sciences, Science University of Tokyo, 2641 Yamazaki, Noda, Chiba 278-8510, Japan
Abstract
Total synthesis of (–)-flustramine B was achieved via one-pot intramolecular Ullmann coupling and Claisen rearrangement. A striking feature of this method of synthesis is that the sequential intramolecular Ullmann coupling and Claisen rearrangement reactions proceeds with concomitant deprotection of the methoxymethyl (MOM) group to afford spirocyclic oxindole with perfect asymmetric transmission in good overall yield.
Published online: 2nd December, 2008
■ The Dakin-West Reaction of N-Acylprolines in the Presence of Inorganic Bases: Unexpected Formation of Enol Esters
Momoko Saeki, Yuri Hagimoto, Hidemitsu Uno, and Masami Kawase*
*Matsuyama University, 4-2 Bunkyo-cho, Matsuyama, Ehime 790-8578, Japan
Abstract
A novel transformation of N-acylprolines (1) to enol esters (2) was realized by utilizing chlorodifluoroacetic or trifluoroacetic anhydrides in the presence of inorganic bases, in which probable intermediates were mesoionic 1,3-oxazolium-5-olates. The structure of the enol ester (2a) was determined by single crystal X-ray analysis.
Published online: 25th November, 2008
■ Syntheses and Absolute Configuration Assignments of Mono- and Di-substituted Chiral Quinoline Alkaloids Obtained by Asymmetric Oxidation
Derek R. Boyd,* Narain D. Sharma, Stephen A. Barr, and Pui L. Loke
*School of Chemistry and Chemical Engineering, The Queen's University of Belfast, David Keir Kuilding, Belfast, BT9 5AG, U.K.
Abstract
Mono- and di-substituted quinoline, 2-quinolone, dihydrofuroquinoline and dihydropyranoquinoline alkaloids have been synthesised with enantiomeric excess values of > 90%, via asymmetric epoxidation, or asymmetric dihydroxylation of the corresponding alkene precursors. The absolute configurations of isobalfourodine, ψ-balfourodine, ψ-isobalfourodine, isobalfourodinium methiodide, balfourolone, hydroxylunidine, orixine, nororixine, isopteleflorine, O-acetylisopteleflorine, O-methylhydroxylunium methiodide and hydroxylunine have been rigorously determined by a combination of circular dichroism spectroscopy, ozonolysis, and stereochemical correlation. Of these, the absolute configurations of six alkaloids were previously unknown and six were assigned incorrect configurations in the literature.
Published online: 3rd December, 2008
■ Development of Cyclic Hydrazine and Hydrazide Type Organocatalyst ⎯ Mechanistic Aspects of Cyclic Hydrazine/Hydrazide-Catalyzed Diels-Αlder Reactions
Ichiro Suzuki,* Ai Hirata, and Kei Takeda
*Divison of Medicinal Chemisry, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan
Abstract
Some hydrazines and hydrazides were prepared and screened for their catalytic efficiencies in Diels-Alder reactions. 1H-NMR studies and ab initio calculations revealed that catalytic efficiencies of these catalysts are greatly dependent on the release of the catalysts from the Diels-Alder adducts.
Published online: 10th December, 2008
■ Effect of Aryl Substituents on Intramolecular Cyclization of 2,2’-Biphenoquinones
Naoto Hayashi,* Akifumi Kanda, Taku Kamoto, Hiroyuki Higuchi, and Takeyuki Akita*
*Department of Chemistry, Faculty of Science, Toyama University, Gofuku 3190, Toyama 930, Japan
Abstract
Effect of aryl substituents on intramolecular cyclizations of 3,3',5,5'-tetraaryl-2,2'-biphenoquinones (Ar = phenyl (1a) and 4-methoxyphenyl (1b)) has been studied. In benzene, 1a gave 2,4,6,8-tetraphenyldibenzofuran-1-ol (10) gradually as a main product, indicating the phenyl substituents preferred to stabilize the intermediate by delocalization of the negative charge rather than that of the positive one. In contrast, the reaction of 1b occurred spontaneously in order to give a complex mixture, which should be due to 4-methoxyphenyl substituent at the 3 position.
Published online: 4th December, 2008
■ Synthesis of a Novel trans-3’,4’-BNA Monomer Bearing a 4,8-Dioxa-5-azabicyclo[5.3.0]decane Skeleton
Tetsuya Kodama, Kensaku Sugaya, Takeshi Baba, Takeshi Imanishi, and Satoshi Obika*
*Graduate School of Pharmaceutical Science, Osaka University, 1-6 Yamadaoka, Suita, Osaka 560-0871, Japan
Abstract
A novel trans-3’,4’-BNA monomer, in which sugar conformation was restricted to S-type by a trans-fused 3-oxa-4-azapentylene bridge between C3’ and C4’ position, was designed and synthesized. The trans-fused 7-membered cyclic structure within a 4,8-dioxa-5-azabicyclo[5.3.0]decane skeleton was prepared by means of intramolecular substitution reaction using potassium carbonate as a base. We found that all of protecting groups (benzyl, benzyloxymethyl, and benzyloxycarbonyl group) were able to be removed smoothly by DDQ oxidation followed by boron trichloride treatment without cleavage of N-O linkage to afford the desired trans-3’,4’-BNA monomer.
Published online: 26th November, 2008
■ N-Glycosylhydroxylamines as Masked Polyhydroxylated Chiral Nitrones in Cycloaddition Reactions: An Access to Pyrrolizidines
Marco Marradi, Massimo Corsi, Stefano Cicchi, Marco Bonanni, Francesca Cardona, and Andrea Goti*
*Department of Organic Chemistry “Ugo Schiff”, University of Florence, via della Lastruccia 13, I-50019 Sesto Fiorentino (FI), Italy
Abstract
N-glycosylhydroxylamines undergo 1,3-dipolar cycloadditions via their tautomeric open chain nitrones. Cycloadditions to maleic acid esters occur with high diastereoselectivity and the products can be converted into highly functionalized pyrrolizidines.
Published online: 27th November, 2008
■ Hydrophilic Diazirine Polymer for One-Step Photo-Fabrication of Proteins on Polypropylene Surface
Takenori Tomohiro, Norie Tachi, Yusuke Azuma, and Yasumaru Hatanaka*
*Faculty of Pharmaceutical Sciences, Toyama University, 2630 Sugitani, Toyama, Toyama 930-0194, Japan
Abstract
A facile photochemical fabrication of chemical and biological functionalities on polypropylene surface has been performed by using photoactivatable polymers containing diazirine photophore. The water-soluble polymers have been synthesized from polyamine or polycarboxylic acid by coupling with aryldiazirine derivatives. Upon irradiation, the photoactivatable polymer successfully immobilized proteins such as horseradish peroxidase, lysozyme, and pepsin on the inert surface of polypropylene film in one step. This soft polymer cushion supplied a hydrophilic environment around the enzyme and enhanced the enzyme activity. Specifically, the polymer (HDA-PEI) introduced a hydrophilic spacer between diazirine and polymer main chain significantly increased the activity.
Published online: 5th December, 2008
■ Antineoplastic Agents. 575. The Fungus Aspergillus phoenicis
George R. Pettit,* Jiang Du, Robin K. Pettit, John C. Knight, and Dennis L. Doubek
*Department Chemistry and Biochemistry, Arizona State University, Physical Sciences bldg. PSD118 1711 S. Rural Rd., Tempe, Arizona 85287, U.S.A.
Abstract
Cancer cell line bioassay-guided separation of an extract from the fungus Aspergillus phoenicis collected in Saskatchewan, Canada, resulted in the isolation of three new constituents designated asperlactone (1), aspergillol A (2), and aspergillol B (3), accompanied by four previously known constituents: asperic acid (4), hexylitaconic acid (5), methyl 2-hydroxyphenylacetate (6), and methyl 4-hydroxyphenylacetate (7). The structure of each was determined by analyses of high-resolution mass spectra and high-field NMR data. Asperic acid (4) was found to inhibit growth of the murine lymphocytic leukemia P388 (ED50 0.18 μg/mL) and a panel of human cancer cell lines (GI50 1.7–2.0 μg/mL; pancreas, breast, CNS, lung, colon, and prostate), while aspergillol A (2) showed moderate inhibition against the breast adenocarcinoma MCF-7 (GI50 7.2 μg/mL).
Published online: 27th November, 2008
■ Petiolins D and E, Phloroglucinol Derivatives from Hypericum pseudopetiolatum var. kiusianum
Naonobu Tanaka, Takaaki Kubota, Haruaki Ishiyama, Yoshiki Kashiwada, Yoshihisa Takaishi, Junji Ito, Yuzuru Mikami, Motoo Shiro, 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 phloroglucinol derivative possessing citran skeleton, petiolin D (1), and a new chromone glucoside, petiolin E (2), were isolated from aerial parts of Hypericum pseudopetiolatum var. kiusianum. The structures of 1 and 2 were elucidated by spectroscopic data, and a single-crystal X-ray diffraction analysis of 1 revealed that 1 was a racemic mixture.
Published online: 8th December, 2008
■ A Synthetic Approach to Develop Peptide Inhibitors Selective for Brain-Type Sodium Channels on the Basis of Pompilidotoxin Structure
Sawana Yokote, Ritsuko Setoguchi, Eisuke Shimizu, Naoki Mishima, Kohichi Kawahara, Akihiko Kuniyasu, Tetsuya Shirasaki, Kazuo Takahama, Katsuhiro Konno, Nobufumi Kawai, Kaoru Yamaoka, Eiji Kinoshita, and Hitoshi Nakayama*
*Faculty of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-hon-machi, Kumamoto 862-0973, Japan
Abstract
To develop inhibitors that are selective for brain-type sodium channels, several peptides were synthesized on the basis of pompilidotoxin structure. A peptide having N-terminal 7 amino acids and its homologs in which Phe7 is substituted into more hydrophobic amino acids, selectively inhibit sodium current of brain-type sodium channels.
Published online: 9th December, 2008
■ Formal Synthesis of (5R,8R,8aS)-Indolizidine 209I via Enaminones Incorporating Weinreb Amides
Charles B. de Koning, Joseph P. Michael,* and Darren L. Riley
*School of Chemistry, University of the Witwatersrand, Private Bag 3, PO WITS
2050, South Africa
Abstract
A formal enantioselective synthesis of the amphibian alkaloid (5R,8R,8aS)-(–)-indolizidine 209I (6) is reported. Control of the absolute stereochemistry at C-5 resulted from application of the Davies procedure, which entails stereoselective conjugate addition of (R)-(+)-N-benzyl-1-phenylethylamine to tert-butyl (E)-hex-2-enoate. The resulting chiral adduct 26 was converted in eight steps into a pivotal enaminone incorporating a Weinreb amide, the inherent nucleophilicity of which was exploited in a cyclisation that yielded the key bicyclic intermediate (5R)-N-methoxy- N-methyl-5-propyl-1,2,3,5,6,7-hexahydroindolizine- 8-carboxamide (38). Stereoselective catalytic hydrogenation of the alkene bond, reaction of the Weinreb amide with ethylmagnesium bromide, and epimerisation of the resulting ketone completed the formal synthesis of the target alkaloid.
Published online: 11th December, 2008
■ A New Synthetic Route to the 1-Oxygenated Carbazole Alkaloids, Mukonine and Clausine E (Clauzoline I)
Shigeo Tohyama, Tominari Choshi, Shuhei Azuma, Haruto Fujioka, and Satoshi Hibino*
*Graduate School of Pharmacy and Pharmaceutical Sciences, Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Fukuyama, Hiroshima 729-0292, Japan
Abstract
A new synthesis of the 1-oxygenated 1,3-disubstituted carbazole alkaloids, mukonine (1a) and clausine (1f) is described. The construction of the carbazole framework is based on an allene-mediated electrocyclic reaction involving the indole 2,3-bond. The 1,3-disubstituted 1-oxygenated carbazoles 1a and 1f are derived from the 1,2,3-trisubstituted carbazole.
Published online: 7th January, 2009
■ Tandem Catalysis Strategy for Direct Glycosylation of 1-Hydroxy Sugars. Methoxyacetic Acid as an Effective Catalytic Mediator
Yasuo Yokoyama,* Takeshi Hanamoto, Shoko Suzuki, Kosuke Shimizu, Hiroshi Furuno, and Junji Inanaga*
*Akita National College of Technology, Iijima-bunkyomachi 1-1, Akita, Akita 011-0923, Japan
Abstract
1-Hydroxy sugars were dehydratively coupled with a variety of alcohols including thiophenol in the presence of a catalytic amount of ytterbium(III) triflate [Yb(OTf)3] and methoxyacetic acid to give the corresponding glycosides in good to excellent yields, and in some cases, with high stereoselectivities. The reaction proceeds through selective esterification of 1-hydroxy sugars with methoxyacetic acid in the presence of free alcohols as glycosyl acceptors. The mechanism of methoxyacetic acid-mediated tandem catalysis with Yb(OTf)3 is discussed.
Published online: 16th December, 2008
■ Synthesis of Macrocyclic Lactams from 2-(ω-Aminoalkyl)-2-benzoylamino-3-phenyl-N,N-dimethylpropanamides via Direct Amide Cyclization
Stephan P. Fritschi, Anthony Linden, and Heinz Heimgartner*
*Institute of Organic Chemistry, University of Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland
Abstract
The alkylation of 4-benzyl-2-phenyl-1,3-oxazol-5(4H)-one (11) with ω-azidoalkyl iodides (12) by deprotonation with LDA in THF/HMPT at –78 °C yielded mixtures of the 4,4-disubstituted 1,3-oxazol-5(4H)-ones (13) and the O-alkylated 1,3-oxazoles (14) in 65–50%, with 13 as the major product. The reaction of the latter with dimethylamine in acetonitrile at room temperature led to ω-azido-2-benzamido-2-benzylalkane amides (15), which were reduced to give the corresponding ω-amino derivatives (16). On treatment with HCl gas or BF3 in boiling toluene, the macrocyclic 2-benzamido lactams (18) were formed in up to 27% yield via the intermediate formation of 1,3-oxazol-5(4H)-ones (17). The structures of the 14- and 15-membered lactams have been established by X-ray crystallography.
Published online: 12th December, 2008
■ Maitotoxin-Photoactive Probe Binds to Membrane Proteins in Blood Cells
Keiichi Konoki,* Masaki Hashimoto, Kaori Honda, Kazuo Tachibana, Rie Tamate, Futoshi Hasegawa, Tohru Oishi, and Michio Murata*
*Department of Chemistry, Faculty of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Abstract
The photoactive and biotinylating ligand was prepared from MTX and maleimide-conjugated Hatanaka reagent with use of Diels-Alder reaction. Blood cells were subjected to affinity labelling experiments using the ligand thus obtained. The labelled band on SDS-PAGE was replaced not by MTX but by brevetoxin B (PbTx2), which suggested the presence of binding proteins in blood cells. Screening of polyether compounds for MTX inhibitory activity using Ca2+ flux assays in C6 cells disclosed that a synthetic fragment of the hydrophilic portion of MTX inhibited the MTX activity.
Published online: 8th January, 2009
■ An Energy Transfer Chemiluminescent Reaction of Lophine Peroxides
Masaru Kimura,* Kaoru Akaki, Yasunobu Mishima, Hiroyuki Araki, and Takeshi Fukai
*No. 185, Qianshan Middle Road, Hi-Tech Zone, Anshan, Liaoning, China
Abstract
A linear correlation existed between the absorption energy of activators (Eo-o's) and the sensitized chemiluminescence (CL) yields (φSCL's) for the CL reaction of lophine peroxides (2a and 2b), whereas a linear correlation did not exist between their oxidation potentials (Eox's) and φSCL's. Based on the finding, an energy transfer mechanism is likely rather than an electron transfer mechanism like the CIEEL mechanism.
Published online: 26th January, 2009
■ Synthesis and Spectroscopic Comparison of the Eight Methyl-2,3’-bipyridyls and Identification of a Hoplonemertine Alkaloid as 3-Methyl-2,3’-bipyridyl
William R. Kem,* James Rocca, H. Martin Garraffo, Thomas F. Spande, John W. Daly, and Ferenc Sóti
*Department of Pharmacology and Therapeutics, College of Medicine, University of Florida, 1600 SW Archer Rd., Gainesville, FL 32610-0267, U.S.A.
Abstract
The pyridyl ring is frequently found in natural products and drugs. While bipyridyls have served as useful scaffolds for development of industrial and pesticidal chemicals, their biological properties are still not well understood. Only 2,3’-bipyridyl, of the six isomeric bipyridyls, has been reported as a natural product in tobacco plants and in a hoplonemertine marine worm, Amphiporus angulatus (Aa), which uses its pyridyl alkaloid-rich venom to paralyze its crustacean prey and chemically defend itself against predators. Here we report for the first time the synthesis and spectroscopic properties of all eight possible methyl 2,3’-bipyridyl isomers and use this data to identify a trace alkaloidal constituent of Aa as 3-methyl-2,3’-bipyridyl. This is only the second reported instance of a methyl-bipyridyl being found as a natural product, the first being the tobacco alkaloid 5-methyl-2,3’-bipyridyl.
Published online: 22nd December, 2008
■ Catalytic Asymmetric Synthesis of Both Enantiomers of Pyrrolizidines 223H’, 239K’, 265H’, and 267H’ Found in Madagascan Frogs (Mantella) and Their Affinities for Nicotinic Acetylcholine Receptor
Yukako Saito, Seiki Takahashi, Nehad Azer, Amira T. Eldefrawi, Mohyee E. Eldefrawi, and Hiroki Takahata*
*Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan
Abstract
The asymmetric synthesis of pyrrolizidines 223H’, 239K’, 265H’, and 267H’ has been achieved starting from 1,5-hexadiene via a common synthetic intermediate 5. The affinity of both enanthiomers of 1–4 for nicotinic acetylcholine receptor was evaluated.
Published online: 19th February, 2009
■ Probes for Narcotic Receptor Mediated Phenomena. 38. An Expeditious Synthesis of rac-cis-4a-Ethyl-2-methyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ol and rac-cis-2-Methyl-4a-phenethyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ol
Malliga R. Iyer, Jeffrey R. Deschamps, Arthur E. Jacobson, and Kenner C. Rice*
*Laboratory of Medicinal Chemistry,
National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bldg 8, Rm B122, Bethesda, Maryland 20892-0815, U.S.A.
Abstract
A high-yielding five-step synthesis of cis-benzofuropyridin-6-ols provided an improved route to compounds with low to subnanomolar affinity at opioid receptors and high antinociceptive potency. This synthesis provided the known rac-cis-4a-ethyl-2-methyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ol (1a) in high yield, and the novel rac-cis-2-methyl-4a-phenethyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ol (1b). It was achieved using NBS to prepare the key intermediate 7. Di-demethylation followed by subsequent displacement of the bromine by the phenolic ion in hot Et3N gave the desired 1a. The structure of 1a was confirmed by X-ray crystallography.
Published online: 9th October, 2008
■ Design, Synthesis, and Biological Effect of (1-Oxo-1,2,3,4-Tetrahydro- β-Carbolin-9-yl)-acetic Acids as Inhibitor of Aldose Reductase 2
Naoki Toyooka,* Daisuke Takeda, Yuka Minoshima, Atsushi Kato, and Isao Adachi
*Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Sugitani 2630, Toyama 930-0194, Japan
Abstract
Design and synthesis of (1-oxo-1,2,3,4-tetrahydro-β-carbolin-9-yl)acetic acids (4a-e) have been described. The acids (4a-e) synthesized here showed good to moderate inhibitory effects (IC50 = 21.7 ~ 45.3 μM) for the aldose reductase 2 (ALR2).