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
Kiyoshi Tomioka's Special Issues, Vol. 97, No. 2, 2018
Published online: 4th June, 2018
■ Synthetic Studies toward Isoschizogamine: Construction of Pentacyclic Core Structure
Kenji Sugimoto, Hiroaki Fujiwara, Akihiro Takada, Dong-Gil Kim, Hirofumi Ueda, and Hidetoshi Tokuyama*
*Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai, 980-8578, Japan
Abstract
Development of a concise construction of the pentacyclic core skeleton of isoschizogamine was described. Tetracyclic A,B,D,F-rings structure was assembled by intramolecular aza-Diels–Alder reaction via an ortho-iminoquinone methide intermediate. The C-ring was formed by oxidation of the benzylic position with a combination of Cr(CO)6 and t-BuO2H, followed by the introduction of an aminoethyl side chain, C–H oxidation of the lactam ring with CrO3 and n-Bu4NI, and final cyclization to construct the cyclic aminal moiety.
Published online: 24th April, 2018
■ Preparation of Chiral Right-Half Models of Antitumor Bistetrahydroisoquinolinequinone Natural Products
Yuuki Senbonmatsu, Shinya Kimura, Megumi Akiba, Shingo Ando, and Naoki Saito*
*Department of Medicinal Chemistry, Pharmaceutical Chemistry, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan
Abstract
The preparation of chiral right-half model compounds of bistetrahydroisoquinolinequinone natural products having a lactam carbonyl group (-)-1 or an aminonitrile group (+)-2 from (-)-14 was presented. The crucial steps of this synthesis include the N-methylation of compound (-)-12 and ring closure to generate (-)-19a without any epimerization at C-2.
Published online: 27th April, 2018
■ Synthesis of 2-Amino-1-cyanoazulenes: Substituent Effect on 2H-Cyclohepta[b]furan-2-ones toward the Reaction with Malononitrile
Taku Shoji,* Shuhei Sugiyama, Kota Miura, Akira Ohta, Ryuta Sekiguchi, Shunji Ito, Shigeki Mori, and Tetsuo Okujima
*Department of Chemistry, Faculty of Science, Shinshu University, Asahi 3-1-1, Matsumoto, Nagano 390-8621, Japan
Abstract
3-Substituted 2-amino-1-cyanoazulene derivatives were prepared by the reaction of 2H-cyclohepta[b]furan-2-ones with malononitrile in the presence of triethylamine as a base. The great influence of the substituent at their 3-position on the reactivity to form the 2-aminoazulene derivatives was revealed. The intramolecular charge transfer (ICT) characters of 2-amino-1-cyano-3-vinylazulenes were investigated by UV/Vis spectroscopy and theoretical calculations. The structure of compounds 13b and 14b was clarified by single crystal X-ray analysis.
Published online: 12th June, 2018
■ Preparation of meso-Silylporphyrins via Nickel-Catalyzed Coupling of meso-Brominated Ni(II) Porphyrins with Silylzinc Reagents
Satoshi Hayashi,* Taiga Endo, and Toshikatsu Takanami*
*Pharmaceutical Sciences, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan
Abstract
In this paper, we developed a technique for the nickel-catalyzed coupling of meso-brominated Ni(II) porphyrins with silylzinc reagents in order to prepare meso-silyl-substituted Ni(II) porphyrins. Porphyrin silylation occurs under mild conditions and exhibits both excellent substrate generality and functional group compatibility.
Published online: 5th June, 2018
■ Notable Difference between Tetrabutylammonium Fluoride and Organic Superbases as Triggers for the Chemiluminescent Decomposition of Bicyclic Dioxetanes Bearing a 4-(N-Phenylbenzimidazol-2-yl)-3-hydroxyphenyl Moiety
Nobuko Watanabe, Koh Kumagai, Rei Ohtuka, Ayu Wakatsuki, Hisako K. Ijuin, Yoshio Kabe, and Masakatsu Matsumoto*
*Department of Chemistry, Faculty of Science, Kanagawa University, 2946 Tsuchiya, Hiratsuka 259-1293, Japan
Abstract
Chemiluminescent decomposition of bicyclic dioxetanes 3a−3c bearing a 4-(N-phenylbenzimidazol-2-yl)-3-hydroxyphenyl moiety was effectively induced by organic superbases, BTPP [(tert-butylimino)tris-(pyrrolidino)phosphorene], TBD (1,5,7-triazabicyclo[4.4.0]dec-5-ene), MTBD(7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene), DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), and TMG (tetramethylguanidine), as well as TBAF in acetonitrile. Dioxetane 3c bearing a 3,5-dihydroxyphenyl moiety showed diverse chemiluminescence profiles depending on the base used. BTPP caused chemiluminescent decomposition due to the di-oxido anion of dioxetane, while DBU and TMG induced chemiluminescence from the mono-oxido anion of dioxetane. On the other hand, TBAF caused effective chemiluminescence due to the mono-oxido anion, though it acted as a stronger base than BTPP with regard to the rate of decomposition of 3c.
Published online: 22nd June, 2018
■ 2-Functionalized Derivatives of 2-Bromo-1,3-dimethylimidazole
Martin Lampl, Gerhard Laus, Klaus Wurst, Volker Kahlenberg, Thomas Gelbrich, Sven Nerdinger,* Hubert Huppertz, and Herwig Schottenberger
*Global Portfolio, Sandoz GmbH, Biochemiestrasse 10, 6250 Kundl, Austria
Abstract
Attempts of direct bromination of 1,3-dimethylimidazolium salts with bromine were futile. A tribromide or a carbene–lithium–THF adduct were received instead. The quaternary 2-bromo compound was obtained by methylation of 2‑bromo‑1‑methylimidazole and subsequent ion metathesis, which was converted to the corresponding 2-cyano and 2-azido derivatives. Typical reactions of the latter include a dipolar cycloaddition and the Staudinger reaction. Crystal structures of eight compounds have been determined by single-crystal X-ray diffraction.
Published online: 22nd June, 2018
■ Asymmetric Synthesis of β-Lactams by Intramolecular Conjugate Addition of Serine and Cysteine Derivatives via Memory of Chirality
Ryuichi Hyakutake, Tomoyuki Yoshimura, Yoshihiro Ueda, Kazuhiro Hayashi, Takumi Furuta, and Takeo Kawabata*
*Institute for Chemical Research, Kyoto University, Gokasho, Uji, Kyoto, 611-0011, Japan
Abstract
The 4-exo-trig cyclization of axially chiral enolates generated from L-serine and L-cysteine dervatives proceeded predominately over β-elimination to give chiral β-lactams with contiguous tri- and tetrasubstituted carbon centers in up to 96% ee. The key to smooth production of β-lactams is the use of Cs2CO3 and CF3CH2OH as a base and a proton source, respectively. A strongly electron-withdrawing Michael acceptor in the substrates was also critical for high enantioselectivity of the β-lactam formation.
Published online: 30th May, 2018
■ Design and Synthesis of a DNA-Like Structure Composed of Alkynyl C-Nucleotide with 2-Aminopyrimidin-4-one as a Nucleobase
Fumihiro Kurosaki, Junya Chiba,* and Masahiko Inouye*
*Graduate School of Medicines and Pharmaceutical Sciences for Research, Toyama University, 2630 Sugitani, Toyama, Toyama 930-0194, Japan
Abstract
A heterocyclic compound, 2-aminopyrimidin-4-one, was found to be a new candidate of a non-natural nucleobase that forms a novel base pair by self-dimerization. 2-Aminopyrimidin-4-one was connected to a deoxyribose through an acetylene linkage. The non-natural nucleoside was derivatized to its phosphoramidite that could be subjected to a conventional solid-phase DNA synthesis. The solid-phase auto-synthesis successfully afforded a non-natural DNA-like oligomer bearing 2-aminopyrimidin-4-one as a nucleobase. The synthetic oligomer exhibited reversible formation of a higher-order structure that would be a duplex like natural DNA. The present study means creation of a novel artificial DNA-like system with unordinary odd numbers of genetic alphabets.
Published online: 24th April, 2018
■ Total Synthesis of Rhoiptelol B
Nobuhiro Tanaka, Hiroyoshi Takamura, and Isao Kadota*
*Graduate School of Natural Sciences and Technology, Okayama University, 3-1-1 Tsushima-naka, Okayama 700-8530, Japan
Abstract
A stereoselective total synthesis of rhoiptelol B, a diarylheptanoid isolated from the fruits of Rhoiptelea chiliantha, is described. The tetrahydropyran ring was constructed via an intramolecular allylation methodology.
Published online: 9th April, 2018
■ Synthesis of Oroxylin a Starting from Naturally Abundant Baicalin
Rie Fujita, Kengo Hanaya, Shuhei Higashibayashi, and Takeshi Sugai*
*Department of Pharmaceutical Science, Keio University, 1-5-30, Shibakoen, Minato-ku, Tokyo 105-8512, Japan
Abstract
A new approach to oroxylin A, a monomethylated trihydroxyflavone, is described. The starting material was baicalin, a representative naturally abundant flavonoid glucuronide. First, conditions for the cleavage of the glycosidic bond were established, using a mixture of water and conc. sulfuric acid (5:2) at 121 °C for 40 min. The hydrolysis was performed in a high-pressure steam sterilizer so that the temperature and reaction time were precisely controlled. Subsequent acetylation of the crude material furnished baicalein 6,7-diacetate on a preparative scale and in a reproducible manner. Next, the C-7 position was protected site-selectively with a methoxymethyl (MOM) group, taking advantage of an unexpected sequential migration of the two acetyl groups among the C-5, C-6, and C-7 positions under basic conditions. The removal of the two remaining acetyl groups followed by site-selective methylation of the C-6 position furnished 5-hydroxy-6-methoxy-7-methoxymethoxyflavone (oroxylin A C-7 MOM ether). Finally, by the deprotection of the MOM ether, oroxylin A was obtained in 6 total steps and 62% overall yield from baicalin.
Published online: 3rd April, 2018
■ Intramolecular Heck Insertion of a Diene-Allylic Amination Cascade to Synthesize a 2-Alkenyl-3,4-fused Indole Structure
Takahito Kuribara, Jun Ueda, Yuito Tanaka, Masaya Nakajima, Shingo Harada, and Tetsuhiro Nemoto*
*Pharmaceutical Chemistry, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo, Chiba, Japan
Abstract
Iodoanilines bearing a diene side-chain at the 3-position were converted to tricyclic fused indole derivatives under palladium catalysis. This cascade reaction proceeds through an intramolecular Heck insertion of the diene, followed by an allylic amination reaction sequence. Experimental and computational studies indicated that 3--allyl palladium complex-mediated substitution was operative for the latter cyclization.
Published online: 28th March, 2018
■ Highly Convergent Straightforward Stereoselective Synthesis of (+)-C(9a)-Epiepiquinamide
Meriem Benlahrech, Alejandro Lahosa, Cherif Behloul,* Francisco Foubelo,* and Miguel Yus*
*Departamento de Química Orgánica, Universidad de Alicante, APDO 99-03080 Alicante, Spain
Abstract
The total synthesis of (+)-C(9a)-epiepiquinamide has been achieved starting from ethyl 5-bromopentanoate, (RS)-tert-butanesulfinamide, nitromethane, ethyl acrylate and acetic anhydride. The diastereoselective coupling of ethyl 4-nitrobutanoate and a chiral N-tert-butanesulfinyl imine, along with a double cyclization involving a primary amine through an intramolecular N-alkylation and lactam formation, are key steps of this synthesis
Published online: 25th April, 2018
■ Amide Bond Formation of Sialic Acid in Oligosaccharide without Protecting Group
Shino Manabe,* Junpei Abe, and Yukishige Ito
*Synthetic Cellular Chemistry Laboratory, Cluster for Pioneering Research, RIKEN, Wako-shi, Saitama 351-0198, Japan
Abstract
With the aim of preparing glycan-linked antibody-drug conjugates, we investigated the feasibility of amide bond formation at the carboxylic acid of sialic acid in a protection-free oligosaccharide. The use of a phosphonium salt-based reagent, PyBOP, gave the desired compound. Bio-orthogonal functional groups were conjugated at the carboxylic acid site of sialic acid in glycans.
Published online: 17th April, 2018
■ Towards New Sila- or Germa-Derivatives of Motesanib
Thomas Boddaert, Olivier Querolle, Lieven Meerpoel, Patrick Angibaud, Jacques Maddaluno, and Muriel Durandetti*
*COBRA UMR CNRS 6014, Normandie Univ, UNIROUEN, INSA Rouen, CNRS, 76000 Rouen, France
Abstract
Developing new access to original silylated heterocycles is an emerging challenge in medicinal chemistry. In this paper, we describe a synthesis of silylated and germylated Motesanib analogues relying on a peptide coupling between a nicotinic acid derivative and silylated or germylated heterocycles, prepared according to our previous reports.
Published online: 29th March, 2018
■ Isolation of Aaptic Acid from the Marine Sponge Aaptos lobata and Inhibitory Effect of Aaptamines on RANKL-Induced Formation of Multinuclear Osteoclasts
Arina Fukumoto, Yuki Hitora, Aika Kai, Hikaru Kato, Esther D. Angkouw, Remy E. P. Mangindaan, Nicole J. de Voogd, and Sachiko Tsukamoto*
*Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-hon-machi, Kumamoto 862-0973, Japan
Abstract
A new aaptamine congener, aaptic acid (1), was isolated from the marine sponge Aaptos lobata collected in Indonesia, together with aaptamine (2), demethyl(oxy)aaptamine (3), and isoaaptamine (4). The chemical structure of 1 was assigned on the basis of NMR data. The isolated compounds were tested for inhibitory activities against osteoclastogenesis in RAW264 cells. At 5 μM concentration, 2-4 inhibited RANKL-induced multinuclear osteoclast formation by 25%, 54%, and 17%, respectively. In contrast, 1 did not inhibit osteoclastogenesis even at 50 μM.
Published online: 12th June, 2018
■ Synthesis of N-[4-(2'-[18f]Fluoroalkoxybenzoyl)]- and N-(3-[123i]Iodo-4-methoxybenzoyl)pyrrolidin-2-ones As Potential Brain Imaging Agents
Murthy Akula, David Blevins, George Kabalka,* and Dustin Osborne
*Department of Chemistry, University of Tennessee, Knoxville, Tennessee, 37996-1600, U.S.A.
Abstract
The microfluidic synthesis of promising brain imaging PET agents N-[4-(2’-[18F]fluoroalkyloxybenzoyl)]pyrrolidin-2-ones 13a-c was accomplished by nucleophilic radiofluorination of the corresponding tosylate precursors 9a-c with Kryptofix-potassium carbonate-[18F]fluoride. Decay corrected radiochemical yields of 35±5% (13a), 38±8% (13b) and 40±5% (13c) were obtained with radiochemical purities of ≥ 93%. The total reaction time, including HPLC purification was 40 min. N-(3-[123I]Iodo-4- methoxybenzoyl)pyrrolidin-2-one, 18, was prepared by radioiododestannylation of tin precursor 17 using Na123I and 0.3% peracetic acid in 84% radiochemical yield in 20 min.
Published online: 21st May, 2018
■ Total Synthesis of Coriariin B
Hitoshi Abe,* Yoshiyasu Kato, Haruka Imai, and Yoshikazu Horino
*Graduate School of Science and Engineering, University of Toyama, 3190 Gofuku, Toyama 930-8555, Japan
Abstract
The total synthesis of coriariin B (1), which is a type of ellagitannin, and originally obtained from the leaves of Coriaria japonica, was achieved by esterification between the glucose derivative and partially protected dehydrodigallic acid (5). The HHDP (hexahydroxydiphenoyl) unit was constructed by the oxidative phenol coupling reaction in a stereoselective manner.
Published online: 31st May, 2018
■ Facile Synthesis of Stable Uracil-Iodonium(III) Salts with Various Counterions
Naoko Takenaga,* Shohei Ueda, Takumi Hayashi, Toshifumi Dohi, and Shinji Kitagaki
*Laboratory of Medicinal Chemistry, Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya 468-8503, Japan
Abstract
Aryliodonium(III) salts, one of the useful and important classes of hypervalent iodine compounds, have a wide range of applicability, i.e., photoacid generator, active bactericides, and coupling agents for reacting a wide range of nucleophiles even under metal-free conditions. In this report, we present an approach to the design of stable uracil-iodonium(III) salts with various counterions. Uracil is an important substructure that exists in many biologically active compounds and the introduction of such a moiety in iodonium(III) salts would be of high utility in organic chemistry.
This paper is dedicated to Professor Kiyoshi Tomioka on the occasion of his 70th birthday.
Published online: 29th May, 2018
■ Efficient Synthesis of t-Butyl 3-Alkyl-N-hydroxyoxindole-3-carboxylates from Di-t-butyl 2-nitrophenylmalonates
Yu-suke Yamai, Kyoji Ishida, Itaru Natsutani, Shinichi Uesato, Yasuo Nagaoka, and Takaaki Sumiyoshi*
*Faculty of Chemistry, Materials and Bioengineering, Kansai University, 3-3-35 Yamate-cho, Suita, Osaka 564-8680, Japan
Abstract
A selective and efficient synthesis of t-butyl 3-alkyl-N-hydroxy- oxindole-3-carboxylates from di-t-butyl 2-nitrophenylmalonates is described. A tandem reduction-cyclization approach involving reduction of di-t-butyl 2-methyl-(2-nitrophenyl)malonate to di-t-butyl 2-(2-(hydroxyamino)phenyl)-2-methylmalonate followed by accelerated cyclization reaction using a combination of Rh/C and hydrazine monohydrate smoothly and selectively afforded the N-hydroxy-oxindole scaffold. This methodology was successfully applied to gram-scale-synthesis of the t-butyl N-hydroxy-3-methyl-oxindole-3-carboxylate 1 without silica gel column chromatographic separation step.
Published online: 18th May, 2018
■ Direct Enantioselective Indolylation of Peptidyl Imine for the Synthesis of Indolyl Glycine-Containing Peptides
Tsubasa Inokuma, Kodai Nishida, Akira Shigenaga, Ken-ichi Yamada, and Akira Otaka*
*Graduate School of Pharmaceutical Sciences, University of Tokushima, Sho-machi, Tokushima 770-8505, Japan
Abstract
A novel synthetic method involving the direct application of a catalytic asymmetric reaction to peptides was developed. The conditions optimized for the model asymmetric reaction of a simple α-imino amide with an indole derivative were successfully applied to an asymmetric Friedel–Crafts reaction of α-imino peptide possessing a hydrophobic anchor to afford the indolyl glycine-containing peptide. This novel strategy will be of great value for the synthesis of the biologically important peptides bearing varieties of unnatural amino acids.
Published online: 20th June, 2018
■ A Synthetic and Spectroscopic Investigation of the Asymmetric α-Lithiation-trapping of Six-Membered N-Boc Heterocycles Using Alexakis Diamines
James D. Firth, Giacomo Gelardi, Peter J. Rayner, Darren Stead, and Peter O'Brien*
*Department of Chemistry, University of York, Heslington, York YO10 5DD, U.K.
Abstract
The asymmetric lithiation-trapping of six-membered N-Boc heterocycles using s-BuLi and two different Alexakis diamines is reported. These readily available ligands outperform the current ‘best-in-class’ sparteine-type diamines in the lithiation and benzophenone trapping of N-Boc piperazines and the lithiation-cyclisation-trapping of N-Boc-4-chloropiperidine. In situ IR spectroscopy has been used to optimise lithiation times and to discover previously unknown subtleties regarding the lithiation step.
Published online: 18th May, 2018
■ 5-((3-Bromoallyl)Sulfonyl)-1H-Tetrazoles for Bromodiene Synthesis
Takuro Suzuki, Seiya Fukagawa, Tatsuhiko Yoshino, Masahiro Anada, and Shigeki Matsunaga*
*Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita 12 Nishi 6, Kita-ku, Sapporo, Hokkaido 060-0812, Japan
Abstract
Reagents for one-step construction of conjugated bromodienes from aldehydes are described. Various 1-alkyl- and 1-aryl-tetrazoyl bromoallylic sulfones were synthesized and evaluated in bromodiene synthesis. 1-Alkyl-tetrazoyl sulfones selectively afforded (1E,3Z)-bromodienes, while 1-aryl-tetrazoyl sulfones resulted in low selectivity.
Published online: 8th June, 2018
■ Polymorphism of Macrocyclic Oligothiophehe 8-Mers
Hideyuki Shimizu, Tahmina Haque, Masataka Takashika, Hiroyuki Otani, and Masahiko Iyoda*
*Department of Chemistry, Graduate School of Science and Engineering, Tokyo Metropolitan University, Hachioji, Tokyo 192-0397, Japan
Abstract
Macrocyclic oligothiophene 8-mer E,E-8T6A composed of eight thienylene, six ethynylene, and two vinylene units exhibits unique polymorphism. In the solid state, E,E-8T6A formed nanostructured polymorphs such as single crystals, fibers, long and short rods, and square tubes depending on the solvent used for crystallization. In contrast, E-8T7A with one vinylene unit and 8T8A without vinylene unit afforded single crystals, microcrystalline, and short rods in the solid state. Morphological difference between E,E-8T6A and E-8T7A/8T8A is due to the flexibility of the macroring of E,E-8T6A with two vinylene units, and the shape-persistent but rather flexible E,E-8T6A forms various polymorphs in the solid state.