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Published online: 16th October, 2019

Paper | Special issue | Prepress
DOI: 10.3987/COM-19-S(F)53
■ N-Glycosylation Reaction of Thio-Glycoside Using Hypervalent Iodine(Ill) Reagent

Koji Morimoto, Kana Yanase, Takumi Ikeda, Chihiro Uchikawa, Yasuyuki Kita,* and Tetsuya Kajmoto*

*Research Organization of Science and Technology, Ritsumeikan University, 1-1-1 Nojihigashi, Kusatsu, Shiga, 525-8577, Japan

Abstract

We discovered that the hypervalent iodine(III) reagent could mediate the N-glycosylation reaction using the thio-glycoside donors with triazoles.  By using this method, glycosyl triazole could be easily synthesized under mild reaction conditions.

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Published online: 16th October, 2019

Paper | Regular issue | Prepress
DOI: 10.3987/COM-19-14147
■ Synthesis of Cycloalkyl/Steroidal Heteroaryl Sulfides Using Rhodium-Catalyzed Heteroaryl Exchange Reaction

Mieko Arisawa,* Katsuya Nakai, Tomoki Yamada, Ren Suzuki, and Masahiko Yamaguchi*

*Graduate School of Pharmaceutical Sciences, Tohoku University, Aramaki, Aoba-ku, sendai 980-8578, Japan

Abstract

Cycloalkyl heteroaryl sulfides are efficiently synthesized by the single-bond cleavage and exchange reaction of S-cycloalkyl thioesters and heteroaryl ethers without using a base. The method is applicable to steroids at the A- and D-rings, and provides diverse heteroarylthiolated steroids with five- and six-membered heteroarenes.

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Published online: 10th October, 2019

Short Paper | Special issue | Prepress
DOI: 10.3987/COM-19-S(F)50
■ Lewis Acid Mediated Synthesis of Indolizidine Derivatives

Sambasivarao Kotha* and Sunil Pulletikurti

*Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai - 400076, India

Abstract

Here, we have reported a short and efficient BF3•Et2O catalyzed synthesis of indolizidine derivatives. Morever, we have expanded this strategy to synthesize oxa-aza-cyclic derivatives. The stereochemistry of the indolizidine derivative 16 was confirmed by X-ray studies.

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Published online: 10th October, 2019

Paper | Special issue | Prepress
DOI: 10.3987/COM-19-S(F)56
■ Protonation-Assisted Conjugate Addition of Axially Chiral Enolates: Asymmetric Synthesis of β-Lactams with Contiguous Tetrasubstituted Stereocenters from α-Amino Acids via Memory of Chirality

Pan Yang, Tomoyuki Yoshimura, Takahiro Sasamori, Norihiro Tokitoh, Kazuhiro Morisaki, and Takeo Kawabata*

*Institute for Chemical Research, Kyoto University, Gokasho, Uji, Kyoto, 611-0011, Japan

Abstract

A method for asymmetric synthesis of highly strained β-lactams with contiguous two tetrasubstituted stereocenters from readily available α-amino acids has been developed via MOC strategy. In situ protonation of the labile β-lactam enolate intermediates formed through 4-exo-trig cyclization of the axially chiral enolates generated from α-amino acid derivatives seems to be the key to successfully produce highly strained β-lactams. A salient feature of this transformation is that a proton source does not quench axially chiral enolate C, but accelerate the overall reaction by protonation of the intermediary β-lactam enolate D.

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Published online: 9th October, 2019

Paper | Special issue | Prepress
DOI: 10.3987/COM-19-S(F)54
■ Ligand Assessment for the Suzuki-Miyaura Cross Coupling Reaction of Aryl and Heteroaryl Bromides with n-Butylboronic Acid. The Advantages of Buchwald’s S-Phos

Thomas Jagusch, Sven Nerdinger, Bernd Lehnemann, Stefan Scherer, Andreas Meudt, Victor Snieckus,* Sandro Neuner, and Herwig Schottenberger

*Department of Chemistry, Queen's University, 90 Bader Lane K7L 3N6, Canada

Abstract

An investigation of biarylphosphine ligands for the Suzuki-Miyaura cross coupling reaction of aryl and heteroaryl bromides with n-butylboronic acid is presented. The results obtained on ligand modification and aryl as well as heteroaryl bromides variation represent a significant improvement in the state of the art of alkylboronic acid cross coupling methodology.

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Published online: 8th October, 2019

Paper | Special issue | Prepress
DOI: 10.3987/COM-19-S(F)42
■ Synthesis of Lactonized Valoneoyl Group-Containing Ellagitannins, Oenothein C and Cornusiin B

Hitoshi Abe,* Haruka Imai, Daichi Ogura, and Yoshikazu Horino

*Graduate School of Science and Engineering, University of Toyama, 3190 Gofuku, Toyama 930-8555, Japan

Abstract

The total synthesis of two ellagitannins, oenothein C and cornusiin B, which involve a lactonized valoneoyl group (LVG) in the molecules, was accomplished starting from glucose and gallic acid. Classical Ullmann coupling reactions were effective for preparation of the key intermediate, the lactonized valoneic acid derivative, which was subjected to a condensation reaction with glucose, and finally converted to the ellagitannins.

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Published online: 8th October, 2019

Communication | Regular issue | Prepress
DOI: 10.3987/COM-19-14117
■ Synthetic Studies On Keramaphidin B: Formation Of A Macrocyclic Ring By Intramolecular Diels-Alder Reaction

Hiroki Shimoda, Takahiro Shibata, Daisuke Sekine, and Masahisa Nakada*

*Department of Chemistry and Biochemistry, School of Advanced Science and Engineering, Waseda University, 3-4-1 Okubo, Shinjuku-ku, Tokyo 169-8555, Japan

Abstract

The possibility of constructing the macrocyclic ring of keramaphidin B via an intramolecular Diels-Alder (IMDA) reaction has been investigated. The IMDA reaction of a substrate possessing dihydropyridone and diene moieties, which were tethered by an alkyl chain including a linear triple bond, was found to proceed in the presence of SnCl4 at 80 °C.

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Published online: 8th October, 2019

Paper | Regular issue | Prepress
DOI: 10.3987/COM-19-14139
■ Benzylic Oxidation and Functionalizations of Xanthenes by Ligand Trasfer Reactions of Hypervalent Iodine Reagents

Toshifumi Dohi, Keina Komiyama, Shohei Ueda, Nobutaka Yamaoka, Motoki Ito, and Yasuyuki Kita*

*Research Organization of Science and Technology, Ritsumeikan University, 1-1-1 Nojihigashi, Kusatsu, Shiga, 525-8577, Japan

Abstract

The benzylic oxidation, amidation, and unprecedented heteroarylation proceed at room temperature using iodosobenzene, (sulfonylimido)iodobenzenes, and diaryliodonium(III) salts are described for the direct Csp3-H functionalizations of xanthene molecules. This study has demonstrated that hypervalent iodine reagents serve as unified synthetic tools for versatile xanthene Csp3-H transformations based on the radical and SET oxidation processes.

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Published online: 7th October, 2019

Paper | Special issue | Prepress
DOI: 10.3987/COM-19-S(F)44
■ Synthesis and Optical Properties of L-Shaped Dinaphthofluoresceins with two Peripheral Hydroxy Groups

Hikari Yamashita, Chihiro Minari, Eriko Azuma, Kouji Kuramochi, Ayumi Imayoshi, and Kazunori Tsubaki*

*Graduate School of Life and Environmental Sciences, Kyoto Prefectural University, Shimogamo, Sakyo-ku, Kyoto 606-8522, Japan

Abstract

The four compounds 6 and 8–10 having the same L-shaped dinaphthofluorescein skeleton were constructed. The only structural differences among these four compounds were the positions of the two peripheral hydroxy groups. Their dianion forms are a resonance system, thus 6 and 8–10 were expected to exhibit similar optical properties such as the maximum absorption wavelength, molar absorptivity, maximum emission wavelength and fluorescence quantum yield. However, 6 and 8‒10 showed quite different optical properties. For example, the maximum absorption wavelengths of 6, 8, 9 and 10 in aqueous pH 11 solution were 650 nm, 733 nm, 558 nm and 746 nm, respectively. Thus, the positions of the two peripheral hydroxy groups on the same skeleton significantly affected the optical properties.

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Published online: 7th October, 2019

Paper | Special issue | Prepress
DOI: 10.3987/COM-19-S(F)48
■ Trialkylsulfonium and Tetraalkylammonium Salts as Hydrogen-Bonding Catalysts in an Aza-Diels-Alder Reaction: Experimental and Computational Studies

Masahiro Yamanaka,* Ayaka Mochizuki, Takumi Nakamura, Keiji Maruoka, and Seiji Shirakawa*

*Department of Chemistry, Faculty of Science, Rikkyo University, 3-34-1 Nishiikebukuro, Toshima-ku, Tokyo 171-8501, Japan

Abstract

Hydrogen-bonding catalysis by cyclic trialkylsulfonium and tetraalkylammonium salts in an aza-Diels-Alder reaction was investigated. Among the examined onium salt catalysts, cyclic trialkylsulfonium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate possessing a non-coordinating counter anion was the most effective. Details of the activation modes of cyclic trialkylsulfonium and tetraalkylammonium salts were discussed on the basis of DFT calculation.

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Published online: 4th October, 2019

Paper | Regular issue | Prepress
DOI: 10.3987/COM-19-14151
■ The One-Pot Synthesis of Pyridine Derivatives from The Corresponding 1,5-Dicarbonyl Compounds

Hiromichi Mihara, Takeru Miyakoshi, Yui Kikuchi, and Hiroyuki Konno*

*Graduate School of Science and Engineering, Yamagata University, 3-16 Jonan 4-Chome, Yonezawa 992-8510, Japan

Abstract

The optimization of the one-pot, acid-promoted synthesis of pyridine and alkylpyridine derivatives from simple alkyl-1,5-dicarbonyl derivatives and via the corresponding oxime intermediate is described. Of all the combinations of acids and solvents tested, the use of HCl in refluxing dioxane was found to result in the highest chemical yields. Twelve pyridines were prepared using this method.

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Published online: 3rd October, 2019

Paper | Special issue | Prepress
DOI: 10.3987/COM-19-S(F)55
■ α-L-Vancosamine Aryl C-Glycosides, Less Stable Anomers: A Problem in Synthesis of Pluramycin-Class Antibiotics

Yoshio Ando, Hiromune Asahina, Kei Kitamura, Takashi Matsumoto, and Keisuke Suzuki*

*Depatrtment of Chemistry, Tokyo Institute of Technology, 2-12-1,Oh-Okayama, Meguro-ku, Tokyo 152-8552, Japan

Abstract

The pluramycin-class antibiotics have attracted considerable synthetic interest by their bioactivities and unique chemical structures. By the thermodynamic disadvantage, the selective formation of the aryl α-C-glycoside of an L-vancosamine motif, commonly embedded in this class of natural products, has been one of the problems in their total synthesis. This paper summarizes the stereochemical behavior of the pluramycin-class natural products and reports the results of our model study to address this issue by examining three L-vancosaminyl donors under Lewis acidic conditions.

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Published online: 2nd October, 2019

Paper | Special issue | Prepress
DOI: 10.3987/COM-19-S(F)30
■ Mechanistic Studies of Nickel(II)-Catalyzed Direct Alcoholysis of 8-Aminoquinoline Amides

Hiroyuki Morimoto,* Walaa Akkad, Toru Deguchi, and Takashi Ohshima*

*Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan

Abstract

This paper describes the mechanistic aspects of nickel(II)-catalyzed direct alcoholysis of 8-aminoquinoline amides. Kinetic experiments suggested that the nickel(II) catalyst existed in an oligomeric form in the resting state, and the 8-aminoquinoline generated after cleavage coordinated to the nickel(II) catalyst to decelerate the reaction. In addition, density functional theory calculations revealed that the reactions proceeded via the intermediate with N,N,O-tridentate coordination of 8-aminoquinoline amides to the nickel(II) metal center, and that the alcoholysis reaction did not involve deprotonation of the N–H bond of 8-aminoquinoline amides, in contrast to the proposed mechanism for C–H bond functionalization reactions of 8-aminoquinoline amides.

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Published online: 2nd October, 2019

Paper | Special issue | Prepress
DOI: 10.3987/COM-19-S(F)47
■ Development of Near-infrared Fluorescent Probes with Large Stokes Shifts for Non-invasive Imaging of Tumor Hypoxia

Kensuke Okuda, Bahaa G. M. Youssif, Ryosuke Sakai, Takahiro Ueno, Takayuki Sakai, Tetsuya Kadonosono, Yasuyuki Okabe, Ola I. Abdel Razek Salem, Alaa M. Hayallah, Mostafa A. Hussein, Shinae Kizaka-Kondoh, and Hideko Nagasawa*

*Laboratory of Pharmaceutical　& Medicinal Chemistry, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan

Abstract

A series of near-infrared (NIR) fluorochromes with large Stokes shifts was designed, synthesized, and evaluated for application in non-invasive imaging of tumor hypoxia. Each NIR fluorescent hypoxia probe comprised a tricarbocyanine dye and a 2-nitroimidazole-containing moiety as a hypoxia marker that binds to cellular nucleophiles via bioreductive activation under hypoxic conditions. Nucleophilic displacement of the amino-nucleophilic linker moiety of heptamethine cyanine dyes having a 2-chloro-1-cyclohexenyl ring and a 2-nitroimidazole moiety yielded various fluorochromes with different hydrophilicity. These exhibited long emission wavelengths (747–758 nm) with large Stokes shifts (111–125 nm) and high quantum yield (0.04–0.34). GPU-210, 297, and 316 showed significantly higher levels of fluorescence under hypoxic than under normoxic conditions on treating SUIT-2/HRE-Luc pancreatic cancer cells. Among these, only GPU-316 showed significant fluorescence intensity in tumor tissue in in vivo fluorescence imaging of mouse xenograft models.

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Published online: 1st October, 2019

Communication | Special issue | Prepress
DOI: 10.3987/COM-19-S(F)46
■ Synthesis of 2-Amino-1,3-benzoselenazole via Metal-Free Cyclization from Isothiocyanate and Bis(o-Aminophenyl)diselenide

Hayato Ichikawa,* Naoka Miyashi, Yui Ishigaki, and Minako Mitsuhashi

*Department of Applied Molecular Chemistry, College of Industrial Technology, Nihon University, 1-2-1, Izumi-cho, Narashino, Chiba 275-8575, Japan

Abstract

Amino-1,3-benzoselenazoles were generated from the reactions of bis(o-aminophenyl)diselenide and various isothiocyanates under metal-free cyclization conditions. The cyclization of isothiocyanate bearing bulky substituents proceeded in excellent yields because the amounts of byproducts generated were reduced. Acid hydrolysis of acetamide produced 2-amino-1,3-benzoselenazole (4).

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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 Jasinski,* 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, Klaus Wurst, Thomas Gelbrich, Sven Nerdinger,* and Herwig Schottenberger

*Global Portfolio, 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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