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Published online: 1st October, 2019

Paper | Special issue | Prepress
DOI: 10.3987/COM-19-S(F)14
Extraction Properties of 4-Tetra(hydroxyphenyl)BTPhen in Liquid-Liquid Extraction Systems with Cyclohexanone/Octanol or in a Solid-Phase Extraction System

Ashfaq Afsar, Jasraj S. Babra, Petr Distler, Laurence M. Harwood,* Iain Hopkins, Jan John,* James Westwood, and Zoe Y. Selfe

*Department of Nuclear Chemistry, Faculty of Nuclear Sciences and Physical Engineering, Czech Technical University in Prague, Břehová 7, 11519 Prague 1, Czech Republic

Abstract

The extraction properties of tetra(4-hydroxyphenyl)BTPhen have been investigated. Liquid-liquid extraction studies in proposed SANEX diluents, cyclohexanone and 1-octanol, indicate that actinide-lanthanide separation is superior in cyclohexanone; whereas actinide-actinide separation is more efficient in 1-octanol. Immobilization of the ligand onto a silica support results in the separation factor becoming dependent upon the concentration of nitrate anions in the aqueous phase. The immobilized ligand was also applied to the extraction of transition metals, resulting in >70% uptake of all transition metals examined, in the presence of alkali and alkaline earth metals.

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Published online: 30th September, 2019

Short Paper | Special issue | Prepress
DOI: 10.3987/COM-19-S(F)38
A New Entry to the Synthesis of (±)-β-Lysine

Keisuke Fukaya, Yuri Kono, Makoto Hibi, Yasuhisa Asano, and Daisuke Urabe*

*Biotechnology Research Center and Department of Biotechnology, Toyama Prefectural University, 5180 Kurokawa, Kosugi, Toyama 939-0398, Japan

Abstract

A 3-step synthesis of (±)-β-lysine from ethyl sorbate featuring the aza-Diels-Alder reaction is described.

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Published online: 25th September, 2019

Paper | Special issue | Prepress
DOI: 10.3987/COM-19-S(F)20
Novel Trifluoromethylated Spiro-1,3,4-thiadiazoles via [3+2]-Cycloadditions of 2,3-Diphenylcyclopropenethione with Selected in situ-Generated Nitrile Imines Derived from Trifluoroacetonitrile

Greta Utecht-Jarzyńska, Marcin Jasiński,* Kamil Świątek, Grzegorz Mlostoń, and Heinz Heimgartner*

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

Abstract

The in situ-generated N-aryl nitrile imines derived from trifluoroacetonitrile react efficiently with 2,3-diphenylcyclopropenethione to give spirocyclic 1,3,4-thiadiazole derivatives as products of a regio- and chemoselective (3+2)-cycloaddition in good to excellent yields. A stepwise mechanism via initial nucleophilic attack of the S-atom onto the electrophilic C-atom of the electron-deficient 1,3-dipole leading to a zwitterionic intermediate is postulated to explain these formal (3+2)-cycloaddition reactions. The presence of the CF3 group is necessary to activate the nitrile imine for the efficient trapping of the cyclopropenethione. These are the first examples of a successful reaction of this C=S dipolarophile affording 1,3,4-thiadiazoles as formal (3+2)-cycloadducts.

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Published online: 25th September, 2019

Communication | Special issue | Prepress
DOI: 10.3987/COM-19-S(F)34
An Approach to a 2-Hydroxy-3-phenyldibenzofuran Skeleton Based on Rh(PPh3)3Cl-Catalyzed [2+2+2] Cycloaddition between a 1-Ethynyl-2-(ethynyloxy)benzene and an (Alkoxyethynyl)benzene

Daisuke Sato, Kenshu Fujiwara,* Yoshihiko Kondo, Uichi Akiba, and Tetsuo Tokiwano

*Graduate School of Engineering Science, Department of Life Science, Akita University, 1-1 Tegatagakuen-machi, Akita 010-8502, Japan

Abstract

A Rh(PPh3)3Cl-catalyzed [2+2+2] cycloaddition of a 2-(trimethylsilylethynyl)-1-(ethynyloxy)benzene derivative (a 1,6-diyne unit) with an (alkoxyethynyl)benzene (an alkoxyacetylene unit) was studied for the construction of the 2-hydroxy-3-phenyldibenzofuran skeleton of kehokorin E. Although the dimerization of the 1,6-diyne unit was a serious problem in the initial trial, installation of a bulky substituent at the terminal of the ethynyloxy group of the 1,6-diyne unit was found to inhibit the dimerization to produce cycloadducts in good yield. It was also found that the use of a 2-hydroxypropan-2-yl group as the bulky group increased the ratio of the desired 2-alkoxy-3-phenyldibenzofuran isomer to a 3-alkoxy-2-phenyldibenzofuran isomer.

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Published online: 25th September, 2019

Communication | Special issue | Prepress
DOI: 10.3987/COM-19-S(F)40
Synthesis of Dihydrobenzo[1,4]oxazines by Palladium-Catalyzed Cyclization of N-Substituted 2-Aminophenols with Propargylic Carbonates

Masahiro Yoshida,* Shunya Mori, Kenji Matsumoto, and Tsukasa Hirokane

*Faculty of Pharmaceutical Sciences, Tokushima Bunri University, 180 Nishihamabouji, Yamashiro-cho, Tokushima, 770-8514, Japan

Abstract

The reaction of N-substituted 2-aminophenols with propargylic carbonates in the presence of a palladium-catalyst is described. The functionalized dihydrobenzo[1,4]oxazines were synthesized.

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Published online: 25th September, 2019

Paper | Special issue | Prepress
DOI: 10.3987/COM-19-S(F)51
5-Amino-2-thiazolylpyridine N-Oxides: Synthesis and Properties

Toshiaki Murai,* Yuuta Nakatsu, Yuki Tsuchiya, Kirara Yamaguchi, Toshifumi Maruyama, Yohei Miwa, and Shoichi Kutsumizu

*Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University , 1-1 Yanagido, Gifu, Gifu 501-1193, Japan

Abstract

5-Amino-2-thiazolylpyridine N-oxides were prepared in low to moderate yields by the oxidation of 2-pyridyl-5-aminothiazoles with m-CPBA. The molecular structures of the resulting N-oxides were unequivocally determined by X-ray analyses. The N-oxides exhibited the absorption maxima at around 415 ± 20 nm in a CHCl3 solution, while the emission spectra were observed in the range of 505 to 604 nm. The red-shift of the emission was attributed to the methoxy groups attached to the para-position of an aromatic group on the nitrogen atom at the 5-position. The N-oxides exhibited halochromism with the addition of B(C6F5)3. The change in absorption implied the formation of a 1:1 complex between N-oxide and B(C6F5)3. The emission wavelengths of the N-oxides were observed at 510 ± 25 nm in a solid state. Interestingly, one of the N-oxides having methoxy groups exhibited mechanofluorochromism. The solid-state emission of the N-oxide at 527 nm shifted to a longer wavelength (599 nm) when it was subjected to grinding.

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Published online: 25th September, 2019

Paper | Special issue | Prepress
DOI: 10.3987/COM-19-S(F)49
Expedient Routes to 1,2,4-Triazolinium Salts

Lukas Fliri, Gabriel Partl, Thomas Gelbrich, Sven Nerdinger,* Klaus Wurst, and Herwig Schottenberger

*Early Stage Development, Sandoz GmbH, Biochemiestrasse 10, 6250 Kundl, Austria

Abstract

Concomitant S-alkylation and ketazonation of thiosemicarbazide in acetone eventually led to unanticipated ring closure and formation of (3-alkylthio)-1,2,4–triazolinium salts. This initial finding was complemented by employing another three representative aldehydes and ketones. Supplementarily, some respective intermediates have been isolated by stepwise synthetic procedures. In addition to the usual spectroscopic characterization, the structures of six 1,2,4-triazolinium heterocycles, as well as two unexpected by-products thereof have been characterized by single-crystal X-ray diffraction.

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Published online: 24th September, 2019

Paper | Special issue | Prepress
DOI: 10.3987/COM-19-S(F)36
Stereoselective Construction of a Berberine C-8 Benzyl Group for the Synthesis of Javaberine Derivatives

Rina Kakigi, Mai Nakano, Ayana Ueno, Akari Miyawaki, Kiyoshi Tomioka, and Yasutomo Yamamoto*

*Faculty of Pharmaceutical Sciences, Department of Medicinal Chemistry, Doshisha Women’s College of Liberal Arts, Kodo, Kyotanabe, Kyoto 610-0395, Japan

Abstract

Diastereoselective synthesis of 8-benzyltetrahydroprotoberberines was examined. Although Stevens rearrangement of N-benzylxylopinine resulted in poor yield and diastereoselectivity, benzylation of tetracyclic iminium successfully gave H8-H14 trans benzyltetrahydroprotoberberines with high stereoselectivity.

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Published online: 24th September, 2019

Paper | Regular issue | Prepress
DOI: 10.3987/COM-19-14123
Synthetic Studies on Marineosins Based on a Direct Coupling Reaction of Pyrrole and δ-Lactone

Kohei Yamamoto, Yuki Morii, Akihisa Suga, Keita Komine, Hayato Fukuda, Jun Ishihara,* and Susumi Hatakeyama*

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

Abstract

A promising precursor of marineosins A and B, unusual macrocyclic pyrrole and spiroiminal alkaloids isolated from marine microorganism has been synthesized employing a direct coupling of pyrrole and δ-lactone.

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Published online: 24th September, 2019

Communication | Regular issue | Prepress
DOI: 10.3987/COM-19-14124
Alternative Chiral Preparations of a Swaminathan Ketone via Asymmetric Aldol Reactions Mediated by Chiral Amines Bearing a Pyrrolidine

Yuichi Akahane, Arisa Miura, and Kohei Inomata*

*Phamaceutical Department, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan

Abstract

We established a novel chiral route to provide a Swaminathan ketone (3) bearing a 7-membered ring via intramolecular aldol reaction of trione (7) mediated by chiral pyrrodinylmethylamine derivatives. Despite the moderate enantioselectivity of 3, we succeeded in increasing optical purities by using a lipase-mediated asymmetric esterification of an alcohol (16) at a later synthetic stage. The absolute configuration was determined by Mosher’s ester method, and relations between absolute configurations and optical rotations of 3 were clarified.

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Published online: 20th September, 2019

Short Paper | Regular issue | Prepress
DOI: 10.3987/COM-19-14118
Syntheses of Indirubins by Aldol Condensation of Isatins with Indoxyl Anion Generated in situ by Lipase-Catalyzed Deacetylation of Indoxyl Acetate

Takeshi Sugai,* Kengo Hanaya, and Shuhei Higashibayashi

*Department of Pharmaceutical Sciences, Faculty of Pharmacy, Keio University, 1-5-30 Shiba-Kouen, Minato-ku, Tokyo, Japan

Abstract

The syntheses of indirubin (76% yield), 6-bromoindirubin (82% yield), and 6-bromoindirubin-3′-oxime (78% yield in two steps) were achieved via the lipase-triggered aldol condensation between isatins and an indoxyl anion in tetrahydrofuran under anhydrous and anaerobic conditions as the key step. The aldol donor was generated in situ by Burkholderia cepacia lipase (Amano PS-IM)-catalyzed deacetylation of commercially available and stable indoxyl acetate in the presence of triethylamine and with 2-propanol as the transesterification reagent. The scale-up of the presently developed reactions is easier than that in the previously reported chemical aldol condensations, because of the simplicity of the isolation procedure and suppression of the oxidative byproduct formation from indoxyl acetate.

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Published online: 20th September, 2019

Paper | Regular issue | Prepress
DOI: 10.3987/COM-19-14130
Artificial Intelligence-Designed Stereoselective One-Pot Synthesis of trans-β-Lactams and Its Application to Cholesterol Absorption Inhibitor SCH 47949 Synthesis

Tetsuhiko Takabatake, Takumi Yoneda, Jyo Otsuka, Natsuko Kagawa, and Masahiro Toyota*

*Department of Chemistry, Graduate School of Science, Osaka Prefecture University, 1-1 Gakuencho, Sakai, Osaka 599-8531, Japan

Abstract

Cholesterol absorption inhibitor drug SCH 47949 is synthesized stereoselectively using an artificial intelligence design proposed by SYNSUP. The key step involves a stereoselective one-pot preparation of the trans-β-lactam system through thermal electrocyclization. The trans-β-lactam intermediate is converted to SCH 47949 by a series of functional group transformations proposed by SYNSUP.

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Published online: 17th September, 2019

Short Paper | Special issue | Prepress
DOI: 10.3987/COM-19-S(F)35
Synthesis of a Biphenylalanine Analogue of Apratoxin a Displaying Substantially Enhanced Cytotoxicity

Yuichi Onda, Kazuki Fukushi, Kosuke Ohsawa, Masahito Yoshida, Yuichi Masuda, and Takayuki Doi*

*Graduate School of Pharmaceutical Science, Tohoku University, Aramaki, Aoba-ku, Sendai 980-8578, Japan

Abstract

The concise synthesis of the 3,7-dihydroxy-2,5,8,8-tetramethylnonanoic acid moiety of apratoxin A and the total synthesis of compound 3, a 4-biphenylalanine (Bph) analogue of apratoxin A, have been demonstrated. The Bph analogue 3 exhibited a 16-fold increase in cytotoxicity against HCT-116 cells with respect to apratoxin A. This evidence indicated that existing the 4-phenyl group of Bph in 3 significantly enhanced its cytotoxicity, a conclusion corroborated by the 100-fold difference in cytotoxicity against HCT-116 cells observed between apratoxin M7 and apratoxin M16, which is characterized by the presence of a 4-phenyl group where apratoxin M7 displays a 4-methoxy group. Results from a conformational study using a distance geometry method suggested that 3 and apratoxin A adopt similar conformations in CD3CN.

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Published online: 13th September, 2019

Short Paper | Special issue | Prepress
DOI: 10.3987/COM-19-S(F)4
Stereoselective Synthesis of β-Amino Acids by Aldol-Type Addition

David Benito-Garagorri, Wolfgang Felzmann, Sven Nerdinger, and Kathrin Höferl-Prantz*

*Global Portfolio, Sandoz GmbH, Biochemiestrasse 10, 6250 Kundl, Austria

Abstract

A synthesis of α-oxygenated β-amino acid derivatives using an aldol-type addition is described. Depending on the enol equivalent different oxidation states of the oxygen substituent are accessible, while choosing a chiral imine allows to generate the aldol product in a stereoselective manner. This methodology has been applied to the synthesis of the biologically active compound Telaprevir, used in the traetment of Hepatitis C.

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Published online: 13th September, 2019

Paper | Special issue | Prepress
DOI: 10.3987/COM-19-S(F)45
Chemistry of Renieramycins Part 18. Synthesis of Renieramycin M and So-called Fennebricin A from (+/-)-Jorunnamycin A

Masashi Yokoya,* Kento Monden, Mitsuhiro Sato, Natchanun Sirimangkalakitti, and Naoki Saito*

*Department of Medicinal Chemistry, Pharmaceutical Chemistry, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan

Abstract

We report the syntheses of renieramycin M along with so-called fennebricin A from jorunnamycin A, which was prepared from pentacyclic lactam intermediate 4 in our previous total synthesis of renieramycin G, as well as the re-assignment of the NMR data of fennebricin A, which offered very important information for structure elucidation.

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Published online: 12th September, 2019

Paper | Special issue | Prepress
DOI: 10.3987/COM-19-S(F)32
Synthetic Challenges in the Construction of 8- to 10-Membered Pyrazole-Fused Rings via Ring-Closing Metathesis

Yoshihide Usami,* Yasuyuki Tsujiuchi, Yudai Machiya, Akihiro Chiba, Tomomi Ikawa, Hiroki Yoneyama, and Shinya Harusawa

*Department of Pharmaceutical Organic Chemistry, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan.

Abstract

Novel pyrazole-fused heterobicyclic systems, i.e., trihydrooxocino[3,2-c]pyrazoles, tetrahydrooxonino[3,2-c]pyrazoles, and pentahydrooxecino[3,2-c]pyrazoles, were synthesized starting from 3- or 5-allyl-4-hydroxy-1H-pyrazoles via ring-closing metathesis (RCM) as the key step for the construction of the medium-sized rings (8- to 10-membered rings). The RCM reactions at room temperature required longer times and gave lower yields than those in our previous studies on the preparation of normal RCM products with 6- or 7-membered rings. The microwave-assisted RCM generally afforded double-bond migrated products or ring-contracted products along with normal RCM products.

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Published online: 11th September, 2019

Short Paper | Special issue | Prepress
DOI: 10.3987/COM-19-S(F)33
Construction of Quaternary Carbon Center by the Reaction of Aza-o-Quinone Methide Mediated Carbocation Intermediate

Yukiko Karuo, Shintaro Dousei, Minori Sakamoto, Atsushi Tarui, Kazuyuki Sato, Kentaro Kawai, and Masaaki Omote*

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

Abstract

Reactions of carbocationic intermediate corresponding to aza-o-quinone methide with indoles to construct quaternary carbon center were described. Treatment of N-tosylated 2-(2-aminophenyl)propan-2-ol with iron(III) chloride provided tertiary benzylic carbocation intermediate possible to isomerize to the corresponding aza-o-quinone methide. The electron-deficient intermediate enabled to undergo nucleophilic attack by indoles, representing the first example of intermolecular formation of quaternary carbon center using aza-o-quinone methide mediated carbocation intermediate.

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Published online: 30th August, 2019

Short Paper | Special issue | Prepress
DOI: 10.3987/COM-19-S(F)27
Synthesis of Three Stereoisomers of Erythrochelin, a Hydroxamate-Type Tetrapeptide Siderophore from Saccharopolyspora erythraea

Michiyasu Nakao, Ayumu Adachi, Syuji Kitaike, and Shigeki Sano*

*Graduate School of Pharmaceutical Sciences, Tokushima University, 1-78 Sho-machi, Tokushima 770-8505, Japan

Abstract

Details of the synthesis of three stereoisomers of erythrochelin, a hydroxamate-type tetrapeptide siderophore produced by Saccharopolyspora erythraea, were described. Both enantiomers of protected δ-N-hydroxyornithine were used as key intermediates in the synthesis of stereoisomers of erythrochelin containing a (3S,6S)-3,6-disubstituted-2,5-diketopiperazine ring. From comparisons of 1H and 13C NMR spectra, neither of stereoisomers provided a match for the erythrochelin spectral data, and the absolute configuration of erythrochelin was unambiguously reconfirmed to be (R,R,S,S).

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Published online: 30th August, 2019

Short Paper | Regular issue | Prepress
DOI: 10.3987/COM-19-14120
An Improved Synthesis of a Salicylated Divinylcarbinol Derivative as a Part of Salicylic Macrolides

Aki Kohyama, Yoshihito Oguma, Takumi Yamagishi, Kenji Sugimoto, and Yuji Matsuya*

*Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan

Abstract

An improved enantioselective synthesis of (R)-salicylated divinyl carbinol derivative (4), the key intermediate for the total synthesis of natural salicyclic macrolides, has been achieved. Key steps of the synthesis involve the introduction of the chirality by reliable Sharpless asymmetric epoxidation, carbon-carbon bond formation via Heck reaction and the regeneration of a terminal alkene structure via deoxygenation. The efficient route shortened the reaction sequence and enabled the preparation of (R)-4 in 4 steps in 28% overall yield from divinyl carbinol.

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Published online: 29th August, 2019

Short Paper | Special issue | Prepress
DOI: 10.3987/COM-19-S(F)37
Selective Aromatic Nucleophilic Substitution of 4-Dimethylamino-2-methoxy-3-(trifluoroacetyl)quinoline with Alcohols – DFT Calculation Study

Norio Ota, Yusuke Harada, Yasuhiro Kamitori, and Etsuji Okada*

*Department of Chemical Science and Engineering, Graduate School of Engineering, Kobe University, 1-1 Rokkodai-cho, Nada-ku, Kobe 657-8501, Japan

Abstract

The nucleophilic aromatic substitution proceeds exclusively at the 4-position of 4-dimethylamino-2-methoxy-3-(trifluoroacetyl)quinoline 1 by simple alcoholysis to give the corresponding N-O exchanged products solely, and no O-O exchange reactions at the 2-position are performed. Our DFT calculation study provides a rational explanation regarding this complete selectivity based on relative energies of the intermediates VII, VIII which are corresponding to the O-protonated Meisenheimer complexes at carbonyl oxygen in 3-trifluoroacetyl group. The reaction pathway for the present unique selective substitution with alcohols is elucidated by referring to the analogous selective substitutions on 1 with amines and thiols as nucleophiles.

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Published online: 29th August, 2019

Communication | Special issue | Prepress
DOI: 10.3987/COM-19-14121
Design and Synthesis of 4-(2-Pyrrolyl)-4-phenylheptane Derivatives as Estrogen Receptor Antagonists

Miyako Naganuma, Hidetomo Yokoo, Takashi Misawa, Kenji Matsuno, Genichiro Tsuji,* and Yosuke Demizu*

*Division of organic chemistry, National Institute of Hygienic Sciences, 3-25-26, Tonomachi, Kawasaki-ku, Kawasaki-shi, Kanagawa 210-9501, Japan

Abstract

The estrogen receptor (ER) has been recognized as a potential target for the treatment of breast cancer, which is the most common malignancy found in woman. In this study, a series of 4-(2-pyrrolyl)-4-phenylheptane derivatives as ER antagonists were designed and synthesized. The ER antagonistic activity of these compounds was evaluated to study their structure-activity relationships.

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Published online: 28th August, 2019

Review | Special issue | Prepress
DOI: 10.3987/REV-19-SR(F)3
Synthesis of Sphingosine-Related Azetidine Alkaloids, Penaresidins: Construction of Highly Substituted Azetidine Rings

Tomoya Fujiwara and Takayuki Yakura*

*Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan

Abstract

Penaresidin A and B are sphingosine-related natural products that contain a 2,3,4-trisubstituted azetidine ring and a long alkyl side chain. Stereoselective construction of the trisubstituted azetidine ring is a crucial step in the synthesis of penaresidins, and all the currently reported syntheses have been accomplished by SN2-type cyclization of a precursor having a 1-amino-2,3-diol structure with three continuous stereocenters. This cyclization is strongly influenced by the configurations of the vicinal amino alcohol moieties of the precursors. This review focuses on the SN2-type cyclizations that are used to construct the trisubstituted azetidine ring in penaresidin synthesis.

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Published online: 28th August, 2019

Short Paper | Special issue | Prepress
DOI: 10.3987/COM-19-S(F)28
Hydrogen-Deuterium Exchange of Histidine and Histamine with Deuterated Trifluoromethanesulfonic Acid

Zetryana Puteri Tachrim, Natsumi Kurokawa, Yurika Tokoro, and Makoto Hashimoto*

*Division of Applied Bioscience, Graduate School of Agriculture, Hokkaido University, Kita-9, Nishi-9, Kita-ku, Sapporo, Hokkaido 060-8589, Japan

Abstract

Histidine and its decarboxylated metabolite, histamine, containing imidazole ring, play an important role for biological activity. Deuterated trifluoromethanesulfonic acid (TfOD) is one of the acid hydrogen-deuterium exchange reagents for aromatic compounds. Hydrogen-deuterium exchange of histidine and histamine with TfOD were examined in this report.

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Published online: 21st August, 2019

Paper | Regular issue | Prepress
DOI: 10.3987/COM-19-14096
Synthesis of 4-Aroyl-5-arylpyrazoles and 4-Aroyl-3-arylpyrazoles via the Reaction of Enaminodiketones with Substituted Hydrazines

Rika Kotouge, Takashi Nishiyama, Akira Yamauchi, Kanako Ono, Noriyuki Hatae, Tsutomu Oikawa, Satoshi Hibino, and Tominari Choshi*

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

Abstract

Pyrazole is a five-membered heterocyclic compound and is one of the important heterocycles in the fields of medicine and pharmacology. Here, we demonstrate the reactivity of symmetrical enaminodiketones 814 with substituted hydrazines. When using alkylhydrazines, if the substituent size of the alkyl group is small, it is possible to selectively synthesize 1-substituted 4-aroyl-5-arylpyrazoles and their regioisomers, 1-substituted 4-aroyl-3-arylpyrazoles, by choosing the solvent (EtOH or toluene). When they react with bulky substituted hydrazines (e.g., cyclohexyl, phenyl, or pyridyl), only 1-substituted 4-aroyl-5-arylpyrazoles are selectively obtained.

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Published online: 20th August, 2019

Short Paper | Regular issue | Prepress
DOI: 10.3987/COM-19-14122
Platinum on Carbon–Catalyzed and Chemoselective Aqueous Oxygen Oxidation of Aromatic Acetals to Benzoic Acids

Naoki Yasukawa, Takumi Matsuda, Eisho Shimizu, Hironao Sajiki,* and Yoshinari Sawama*

*Laboratory of Organic Chemistry, Department of Pharmaceutical Sciences, Gifu Pharmaceutical University, 1-25-4 Daigakunishi, Gifu 501-1196, Japan

Abstract

Novel chemoselective transformations can diversify the synthetic pathways of the target molecules. The chemoselective oxidation of aromatic acetals to benzoic acid derivatives under platinum on carbon (Pt/C)–catalyzed oxygen oxidation conditions has been newly developed with a tolerance of aliphatic acetals and ketals. The present oxidation was clean and useful from the viewpoint of the easy removal of Pt/C and the use of molecular oxygen as a green oxidant in water as an abundant, non-toxic and environmentally friendly solvent.

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Published online: 16th August, 2019

Paper | Special issue | Prepress
DOI: 10.3987/COM-19-S(F)21
Synthesis of Oxygen-Heterocycles Having Linker Components for Trapping Cysteine Derivatives

Eito Yoshioka, Ikko Minato, Hideki Takashima, and Hideto Miyabe*

*Laboratory for Medicinal Chemistry, School of Pharmacy, Hyogo University of Health Sciences, 1-3-6 Minatojima, Chuo-ku, Kobe City, 650-8530, Japan

Abstract

Tricyclic oxygen-heterocycles 10, 13a, 13b and 18 having a linker component were synthesized for the site-specific modification of proteins and peptides. The linker components were initially introduced by Sonogashira-Hagihara cross coupling of 5-bromo-2-hydroxybenzaldehyde 5 and a variety of alkynes. Next, the desired oxygen-heterocycles 10, 13a, 13b and 18 were synthesized by the condensation reaction of coupling products with cyclohexane-1,3-dione in the presence of N,N-diisopropylethylamine. Finally, the trapping ability of these oxygen-heterocycles was demonstrated by the representative reaction of oxygen-heterocycle 10 with glutathione 19 as a nucleophile having a thiol group.

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Published online: 16th August, 2019

Paper | Special issue | Prepress
DOI: 10.3987/COM-19-S(F)29
Formation of Seven-Membered-Ring Fused Bithiophene Derivatives by Nosyl Annulation

Atsunori Mori,* Masayasu Hayashi, Mitsuru Matsuoka, Shiomi Ashida, Yukiko Ito, Kohei Hosokawa, Toyoko Suzuki, Kentaro Okano, Chi-Hsien Wang, and Masaki Horie

*Department of Chemical Science and Engineering, Kobe University, Rokkodai-cho, Nada-ku, Kobe 657-8501, Japan

Abstract

Nosyl annulation of a bithiophene derivative with nosylamide (NsNH2) gives a 5-7-5 fused N, S-heterocyclic compound. The detailed molecular structure of the obtained nosylamide was analyzed by single-crystal X-ray crystallography. The obtained product was transformed into several amines and amides. The CBr bond at the fused heterocycle was also subjected to cross-coupling reactions, where the nosyl group was found to be tolerant.

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Published online: 16th August, 2019

Short Paper | Special issue | Prepress
DOI: 10.3987/COM-19-S(F)43
Concise Synthesis of TPCA-1 and Related Thiophene-carboxamides by Cross Coupling

Norihiko Kawasaki, Hayato Fukuda, and Jun Ishihara*

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

Abstract

A synthesis of 5-substituted 2-[(aminocarbonyl)amino]-3-thiophene- carboxamides is described. The coupling reaction of 2-ureidothiophene- 3-carboxamide and various aryl compounds allows the concise approach of promising candidates for IKK-2 inhibitor, such as TPCA-1

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Published online: 14th August, 2019

Paper | Special issue | Prepress
DOI: 10.3987/COM-19-S(F)25
Photo-Irradiation-Promoted Aminoetherification of Glycals with N-Acyliminoiodinane and Alcohols

Sota Masakado, Yusuke Kobayashi, and Yoshiji Takemoto*

*Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-shimoadachi-machi, Sakyo-ku, Kyoto 606-8501, Japan

Abstract

An efficient trifluoroacetamido-etherification of glycals was achieved using N-acyliminoiodinane and various alcohols under photo-irradiation. This reaction was successfully applied to the efficient synthesis of biologically active compounds.

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Published online: 13th August, 2019

Paper | Special issue | Prepress
DOI: 10.3987/COM-19-S(F)31
Oxidative C-C Bond Cleavage of N-Protected Cyclic Amines by HNO3-TFA System

Kosuke Yamamoto, Hiroyuki Toguchi, Toshihiro Harada, Masami Kuriyama, and Osamu Onomura*

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

Abstract

Oxidative C-C bond cleavage of N-protected cyclic amines was achieved by using 70% HNO3 in trifluoroacetic acid (TFA) to afford ω-amino acid derivatives in high yields. The C-C bond cleavage reaction smoothly proceeded under aerobic condition with a simple procedure. The use of 70% HNO3 as an oxidant source enabled to conduct the reaction at a higher substrate concentration than that of the previous condition using NaNO2 in TFA. In addition, some ω-amino acids were obtained with improved reaction efficiency under the present reaction conditions.

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