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Published online: 20th September, 2019

Paper | Regular issue | Prepress
DOI: 10.3987/COM-19-14113
■ Functionalization of Benzylic sp3 C-H of 2-Methylazaarenes in Deep Eutectic Solvent

Guo-Qing Chen, Zong-Bo Xie,* Feng Ai, Zhong-Sheng Chen, Jin Lan, Zhi-Yu Hu, and Zhang-Gao Le*

*Department of Applied Chemistry, East China University of Technology, Guanglan Road 330013, China

Abstract

The catalyst-free addition of 2-methylazaarene benzylic sp3 C-H to electron-deficient olefins in deep eutectic solvents is reported. Moderate to good yields were obtained in 2 h at 80 °C in deep eutectic solvents. The method was operationally easy and involved mild reaction conditions. This expands the application of deep eutectic solvent in sp3 C-H functionalization reaction.

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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: 2nd September, 2019

Short Paper | Regular issue | Prepress
DOI: 10.3987/COM-19-14138
■ A Comparison between KBH4 and NaBH4 in Their Reduction of Pyridinium Salts

Hao Quan, Bin Zhu, Xiaolin Li, Li Zhan, and Yu Luo*

*Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200241, China

Abstract

This paper compares potassium borohydride and sodium borohydride in the reduction of pyridinium salts to tetrahydropyridines. The results indicate that potassium borohydride is more suitable for this reaction with low costs, mild reaction conditions and improved yields.

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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 8–14 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 C−Br 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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Published online: 13th August, 2019

Communication | Special issue | Prepress
DOI: 10.3987/COM-19-S(F)39
■ Synthesis of Dibenzoxazonines by Domino (2+2) Cycloaddition—4π Electrocyclic Ring Opening Reaction of Cyclic Imines with Ynamides

Kiyosei Takasu,* Masaki Tsutsumi, Tomohiro Ito, Hiroshi Takikawa, and Yousuke Yamaoka

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

Abstract

Dibenzo[b,h][1,4]oxazonines and the thiazonine congener were synthesized from cyclic imines with ynamides by acid-mediated domino (2+2) cycloaddition—4π electrocyclic ring opening reaction. The reaction enables two carbon-enlargement of the cyclic imine substrates. The X-Ray crystallography made clear that the oxazonine skeleton has a unique bent-conformation.

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Published online: 8th August, 2019

Paper | Special issue | Prepress
DOI: 10.3987/COM-19-S(F)24
■ Synthesis and Hybridizing Property of Oligonucleotides Including 2′-C,4′-C-ethyleneoxy-bridged 2′-Deoxyadenosine with an Exocyclic Methylene Unit

Takashi Osawa, Yoshinori Onishi, Sawako Wakita, Yuta Ito, and Yoshiyuki Hari*

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

Abstract

2′,4′-Bridged nucleic acids (2′,4′-BNAs) are of interest because oligonucleotides that include them have excellent duplex-forming capability and high nuclease resistance compared to natural oligonucleotides. We have recently developed 2′-C,4′-C-ethyleneoxy-bridged thymidine with an exocyclic methylene unit (methylene-EoDNA-T) as a novel 2′,4′-BNA analog. Oligonucleotides that include methylene-EoDNA-T have marked hybridizing capability, nuclease resistance, and in vitro gene-silencing potency. In the present study, we designed and synthesized a 2′-deoxyadenosine analog of methylene-EoDNA (methylene-EoDNA-A), and incorporated it into oligonucleotides. The results of melting temperature (Tm) analysis of duplexes formed from methylene-EoDNA-A-modified oligonucleotides indicated that the hybridizing capability with regard to complementary DNA was almost the same or slightly higher than that of natural DNA. Moreover, methylene-EoDNA-A:methylene-EoDNA-T base pairs increased the thermal stability of DNA duplexes compared to that of DNA duplexes containing methylene-EoDNA-A- or methylene-EoDNA-T-modification in one strand.

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Published online: 7th August, 2019

Paper | Special issue | Prepress
DOI: 10.3987/COM-19-S(F)19
■ A Mild Bischler–Napieralski-Type Cyclization of Trichloromethyl Carbamates for the Synthesis of β-Carbolinones

Seiya Hirao, Mayumi Kitamori, Tomoki Itoh, Yuusuke Chiba, and Takumi Abe*

*Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido 061-0293, Japan

Abstract

A straightforward synthesis of β-carbolinones by the Bischler–Napieralski-type cyclization of the corresponding trichloromethyl carbamates, which does not require acids, bases, oxidants, or transition-metals to promote the cyclization, has been achieved.

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Published online: 7th August, 2019

Short Paper | Special issue | Prepress
DOI: 10.3987/COM-19-S(F)26
■ Intramolecular Oxa-Michael Reactions of Aldols Generated from Enones and Isatins to Afford Spirooxindole Tetrahydropyrans

Maira Pasha, Muhammad Sohail, and Fujie Tanaka*

*Chemistry and Chemical Bioengineering Unit, Okinawa Institute of Science and Technology Graduate University, 1919-1 Tancha, Onna, Okinawa 904-0495, Japan

Abstract

Spirooxindole derivatives are found in bioactive natural products and are used in drug discovery and related research. Here, acid-catalyzed diastereoselective intramolecular oxa-Michael cyclization reactions of β-hydroxyenones generated from enones and isatin derivatives that afford spirooxindole tetrahydropyrans are reported. The major diastereomers of the products of these reactions were previously difficult to access by the amine-catalyzed hetero-Diels-Alder reactions of enones with isatins. With the use of enantiomerically enriched forms of the starting materials in the reactions, enantiomerically enriched spirooxindole tetrahydropyrans that retained the enantiopurities of the starting materials were obtained.

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Published online: 7th August, 2019

Review | Special issue | Prepress
DOI: 10.3987/REV-19-SR(F)2
■ Mini-Review: The Chemistry of Vorapaxar – Is There Any Room for Improvement Left?

Piotr P. Graczyk* and Sven Nerdinger

*Selvita Services Sp. z o. o., Bobrzynskiego 14, 30-348 Krakow, Poland

Abstract

Based on the case of Vorapaxar, this review describes the key role of an early chemistry effort to enable rapid discovery of an optimal synthetic route to a commercially important product. The intramolecular Diels-Alder (IMDA) reaction developed by scientists from Schering to make natural product Himbacine in mid-‘90s allowed formation of the Vorapaxar’s backbone almost 10 years later. Since then this strategy has been followed by all companies. Additional improvements by Schering to the synthesis of Vorapaxar greatly limited the opportunities for generic manufacturers to secure new intellectual property. Most of the chemistry presented in this review comes from the patent applications and as such has not been subjected to rigorous peer review, but in our opinion this paper may serve as helpful information for readers in the area of drug discovery.

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Published online: 6th August, 2019

Review | Special issue | Prepress
DOI: 10.3987/REV-19-SR(F)1
■ Recent Advances in the Chemistry of Azaazulenes and Related Compounds

Noritaka Abe*

*Department of Pure and Applied Chemistry, Faculty of Science and Technology, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan

Abstract

In this review, the synthetic methods and about the biological and physical properties of mono- and poly-azaazulenes including some of their dihydro-, tetrahydro-, oxo-derivatives and aromatics- and heterocycles-fused derivatives and related compounds, such as pyrrolobenzazepines, azepinoindole derivatives, and so on, published from end of 2017 to April 2019, are surveyed.

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Published online: 5th August, 2019

Paper | Special issue | Prepress
DOI: 10.3987/COM-19-S(F)16
■ Pyridine-directed Rh-catalyzed C6-selective C–H Acetoxylation of 2-Pyridones

Sunit Hazra, Koji Hirano,* and Masahiro Miura*

*Department of Applied Chemistry, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan

Abstract

A Rh(III)-catalyzed C-H acetoxylation of 2-pyridones with phenyliodine(III) diacetate (PIDA) in a DCE/AcOH mixed solvent system has been developed using N-2-pyridyl function as directing group. The reaction occurs under mild conditions, typically in air at 40 oC, to selectively produce the corresponding C6-acetoxylated 2-pyridones in moderate to good yields.

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Published online: 1st August, 2019

Paper | Special issue | Prepress
DOI: 10.3987/COM-19-S(F)23
■ Conformational Properties and M1 Antimuscarinic Activity of 4-Substituted Pirenzepine/Telenzepine Analogues

Yuki Kanase, Kosho Makino, Takashi Yoshinaga, Hidetsugu Tabata, Tetsuta Oshitari, Hideaki Natsugari, and Hideyo Takahashi*

*Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda-shi, Chiba 278-8510, Japan

Abstract

The atropisomeric and conformational properties of the 4-Cl/Me-substituted pirenzepine/telenzepine analogues were examined. Although the 4-substitution is not effective in reducing the rotational barrier of the N5–(C1'=O) bond, the butterfly motion of the tricyclic ring system was frozen. The atropisomers showed little racemization after heating at 80 °C for 5 days. While these analogues showed less affinity to the M1 receptor compared with pirenzepine, a ca. 4.4-fold difference in potency between the atropisomers was observed for 1b.

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