HETEROCYCLES

■ Contents

■ Preface to Heterocycles Issue Honoring the 77th Birthday of Professor Dr. Yasuyuki Kita

Norio Shibata*

*Department of Frontier Materials, Graduate School of Engineering, Nagoya Institute of Technology, Gokiso-cho, Showa-ku, Nagoya 466-8555, Japan

■ Preface to Heterocycles Issue Honoring the 77th Birthday of Professor Dr. Yasuyuki Kita

Shuji Akai*

*Synthetic Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan

■ Preface to Heterocycles Issue Honoring the 77th Birthday of Professor Dr. Yasuyuki Kita

Toshifumi Dohi*

*College of Pharmaceutical Sciences, Ritsumeikan University, 1-1-1 Nojihigashi, Kusatsu, Shiga, 525-8577, Japan

■ Curriculum Vitae

Yasuyuki Kita*

*

■ Publications List by Yasuyuki Kita

Yasuyuki Kita*

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

■ Recent Advances in the Microwave Assisted Synthesis of Benzofuran and Indole Derivatives

Thaipparambil Aneeja, Sankaran Radhika, C M A Afsina, and Gopinathan Anilkumar*

*School of Chemical Sciences, Mahatma Gandhi University, Priyadarsini Hills, Kottayam, Kerala , India

Abstract

Abstract – Microwave (MW) assisted syntheses are environment friendly, efficient, rapid and convenient methodology for the synthesis of organic compounds. Benzene ring fused to a five membered ring containing N or O atom exhibits wide range of biological activities. Benzofuran is present in polymers, pharmaceuticals, and bioactive natural products. Benzofuran is significant as insecticides, herbicides, anti-inflammatory and anti-viral agents. Indoles are well known scaffold showing noteworthy activities like anti-tumor, anti-viral, anti-microbial and anti-oxidant. Indole derivatives are valuable moiety in different therapeutically active drug molecules. On account of the biological significance of benzofuran and indole scaffold, this review describes the recent advances in microwave assisted synthesis of benzofurans and indoles, and covers literature from 2012-2020.

■ Environmentally Benign Synthesis of Cyclic Carbonates from Epoxides and Carbon Dioxide Using Binary and Bifunctional Catalysts

Ken Okuno, Ryuichi Nishiyori, Mana Hiraki, and Seiji Shirakawa*

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

Abstract

The extensive utility of five-membered cyclic carbonates has been well established in the chemical industry. Among the various methods available for the synthesis of five-membered cyclic carbonates, coupling reactions that involve epoxides and carbon dioxide are ideal. This review introduces environmentally benign catalytic systems for the synthesis of cyclic carbonates under mild reaction conditions. Application of chiral catalysts to the asymmetric synthesis of optically active cyclic carbonates is also discussed.

■ Recent Advances in Synthetic Strategies for the C4a,C9a-Fused Tetracyclic Hydrocarbazole Core Structure of Minfiensine and Related Akuammiline Alkaloids

Keisuke Hosoya, Keita Iida, Minami Odagi,* and Kazuo Nagasawa*

*Department of Biotechnology and Life Science, Faculty of Technology, Tokyo University of Agriculture and Technology, Koganei, Tokyo 184-8588, Japan

Abstract

The Strychnos alkaloid minfiensine and its analogs among the akuammiline alkaloids have a variety of biological activities, including anti-tumor and analgesic activities, and have therefore attracted considerable synthetic interest. Here we provide an overview of recent advances in methodologies for the construction of the characteristic tetracyclic hydrocarbazole core structure containing a fused pyrrolidine ring at C4a and C9a.

■ Lesinurad – There are More Ways than One of Synthesizing the Drug

Piotr P. Graczyk* and Sven Nerdinger*

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

Abstract

Over the last several years significant efforts have been devoted, particularly in China, to develop new syntheses of Lesinurad. Virtually all key bonds in this molecule can now be created in many different ways, often in a very high yield. Although almost all of the chemistry examples presented in this review come from patent applications and as such have not been subjected to rigorous peer review, they may serve as an inspiration to solve analogous synthetic problems. However, the readers are encouraged to pay particular attention to the very recent trends in the literature which use multicomponent reactions and flow chemistry to minimize the environmental impact and achieve high yields of API at the same time.

■ Azido, Cyano, and Nitrato Cyclic Hypervalent Iodine(III) Reagents in Heterocycle Synthesis

Naoko Takenaga,* Hideyasu China, Ravi Kumar, and Toshifumi Dohi*

*Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya 468-8503, Japan

Abstract

In recent years, synthetic applications of cyclic hypervalent iodine reagents have undergone significant developments. Among them, benziodoxol(on)es containing azido, cyano, and nitrato ligands have been found to be useful synthetic tools for the preparation of functionalized heterocyclic compounds. This review aims to summarize recent synthetic applications of benziodoxol(on)es as effective heteroatom-introducing reagents.

■ 5-Arylidenetetronate as a Versatile Electrophore for Pi-Extended Electron Acceptors

Yuki Hayashi, Yusuke Ishigaki, Jérémy Merad, Takanori Suzuki,* and Maurice Médebielle*

*Department of Chemistry, Faculty of Science, Hokkaido University, Kita 10 Nishi 8, Kita-ku, Sapporo, Hokkaido 060-0810, Japan

Abstract

Bis[4-methoxy-5-methylenefuran-2(5H)-one]-type electron acceptors with anthracene-9,10-diyl and thiophene-2,5-diyl spacer were prepared by one-pot condensation of methyl tetronate with the corresponding dialdehydes. They undergo reversible electrochemical reduction, thus showing the potential utility of 5-arylidenetetronate as an electrophore for developing novel electron acceptors.

■ Synthetic Studies on Densanins: Stereoselective Construction of a Pyrrolidine Ring Containing a Quaternary Carbon

Kyosuke Ueda and Satoshi Yokoshima*

*Graduate School of Pharmaceutical Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, Aichi 464-8601, Japan

Abstract

We disclose our synthetic studies on densanins, which feature the stereoselective cycloaddition of a cycloheptenone and an azomethine ylide to construct a pyrrolidine ring containing a quaternary carbon

■ Synthesis of Lactone-Fused Cyclopropanes by Ring Contractive α-Ketol Rearrangement of Ketal-Fused Cyclobutanones

Kiyosei Takasu,* Koichi Shigenaga, Kazuma Shimoda, Hiroshi Takikawa, and Yousuke Yamaoka

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

Abstract

Ring contraction of cyclic silyl ketal-fused cyclobutanones into lactone-fused cyclopropanes under desilylative conditions is described. The reaction affords 1-hydroxy- and 1-amino-1-cyclopropanecarboxylic acid derivatives from cyclobutanone substrates and their imine congeners, respectively.

■ Studies on Rotational Stability of 2-Aryl-3-(2-Fluorophenyl)Quinazolin-4-One Derivatives

Asumi Iida, Kazuya Saito, Nanami Asada, Yuuki Fujimoto, and Osamu Kitagawa*

*Department of Applied Chemistry, Faculty of Engineering, Shibaura Institute of Technology, 3-7-5 Toyosu, Kohto-ku, Tokyo 135-8548, Japan

Abstract

The rotational barriers around an N-(2-F)C6H4 bond in 2-aryl-3-(2-fluorophenyl)quinazolin-4-ones considerably lowered (ca. 4 kcal mol-1 lower) in comparison with those of 2-alkyl-3-(2-fluorophenyl)quinazolin-4-ones. The transition state structure estimated by the DFT calculation indicates that the considerable decrease in the rotational barriers in 2-aryl derivatives is caused by the alleviation of the steric repulsion between an ortho-substituent of 2-fluorophenyl group and 2-aryl group.

■ Transition-Metal-Free Aziridination of Alkenes with Sulfamate Esters Using tert-Butyl Hypoiodite

Kensuke Kiyokawa,* Shogo Nakamura, and Satoshi Minakata*

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

Abstract

The transition-metal-free aziridination of alkenes with sulfamate esters in the presence of tert-butyl hypoiodite (t-BuOI) is reported. The reaction can be used in intra- and intermolecular reactions, offering a practical and environmentally benign method for the synthesis of valuable aziridine compounds.

■ Catalytic Enantioselective Oxa-Hetero-Diels-Alder Reactions of Enones with Aryl Trifluoromethyl Ketones: Synthesis of Tetrahydropyranones

Maira Pasha 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

Diastereo- and enantioselective oxa-hetero-Diels-Alder reactions of enones with aryl trifluoromethyl ketones that afford tetrahydropyranone derivatives catalyzed by an amine-based catalyst system are reported. The major diastereomers of the tetrahydropyranone products obtained in these reactions had the relative stereochemistry different from that of the previously synthesized tetrahydropyranone derivatives.

■ Rhodium-Catalyzed Crossed [2+2+2] Cycloaddition with Ynamides: Key-Strategy for the Concise Total Synthesis of 3-Oxygenated Carbazole Alkaloids

Carole Alayrac* and Bernhard Witulski*

*Laboratoire de Chimie Molèculaire et Thioorganique (LCMT) , National Graduate School of Engineering and Research Center, France

Abstract

Total syntheses of a set of naturally occurring 3-oxygenated carbazole alkaloids - 6-chlorohyellazole, carazostatin, carbazomycins A and B - are described. The key-strategy underlines a highly chemo- and regioselective rhodium-catalyzed [2+2+2] cyclotrimerization between appropriately tailored yne-ynamides and 1-methoxypropyne that is stirred by the interplay of stereoelectronic and steric effects allowing the introduction of four ring substituents of the natural carbazoles within a single step and making the overall syntheses short and efficient.

■ Hybrid Catalysis of 8-Quinolinecarboxaldehyde and Brønsted Acid for Efficient Racemization of α-Amino Amides and Its Application in Chemoenzymatic Dynamic Kinetic Resolution

Kohsuke Ohmatsu, Mari Kiyokawa, Yuto Shirai, Yuya Nagato, and Takashi Ooi*

*Institute of Transformative Bio-Molecules (WPI-ITbM), and Department of Molecular and Macromolecular Chemistry, Graduate School of Engineering, Nagoya University, Nagoya, 464-8601, Japan

Abstract

The combination of 8-quinolinecarboxaldehyde and benzoic acid proved to be an effective catalyst system for the racemization of N-unprotected α-aryl- or α-alkyl-substituted α-amino amides. Application of this system to chemoenzymatic dynamic kinetic resolution provided an efficient access to enantiomerically pure N-acetyl-α-amino amides in good to high yields.

■ Preparation of Optically Pure Dinuclear Cobalt(III) Complex with Λ-Configuration as a Dianionic Chiral Catalyst

Mohamed S. H. Salem, Ankit Kumar, Makoto Sako, Tsukasa Abe, Shinobu Takizawa,* and Hiroaki Sasai*

*The Institute of Scientific and Industrial Research, Osaka University, 8-1, Mihogaoka, Ibaraki, Osaka 567-0047, Japan

Abstract

The disodium salt of enantiomerically pure dimeric Λ-cobalt(III) complex 1 was prepared in one-pot from sodium triscarbonatocobaltate(III) and Schiff base ligand (Ra,S,S)-2 formed by the condensation of (R)-3,3ʹ-diformyl-2,2ʹ-dihydroxy-1,1ʹ-binaphthyl 3 with (S)-tert-leucine 4. Preliminary screening of 1 as a chiral catalyst was conducted for the bromocyclization of a tryptamine derivative.

■ Synthesis of Probe Molecules, 6-(Dimethylamino)-2-phenylisoindolin-1-ones, for Mechanistic Studies of Firefly Luciferase Inhibition

Medha J. Gunaratna, Bo Hao, Man Zhang, Madoka Nakagomi, Ai Ito, Takeo Iwamoto, and Duy H. Hua*

*Department of Chemistry, Kansas State University, Manhattan, KS 66506, U.S.A.

Abstract

Firefly luciferase is used in high-throughput screening based on the detection of chemiluminescence. It catalyzes an esterification reaction of luciferin with adenosine 5’-triphosphate (ATP) followed by decarbonylation with oxygen and concomitance of light. Previously, we reported that firefly luciferase also possesses acyl-CoA synthetase activity and catalyzes an aromatic carboxylic acid group of F-53, using ATP, Mg2+ and coenzyme A (CoA), to produce F-53 covalently attached to active-site lysine-529 residue of firefly luciferase through the formation of an amide group. The amidation of lysine-529 resulted in a deactivation of luciferase. In order to probe firefly luciferase inhibition’s mechanism, we synthesized two probe molecules 1 and 2, mimicking F-53. Molecule 1 contains an azido-appended side chain in the aromatic ring of F-53, while 2 possesses an azido and a carboxylic acid group appended side chains. Both synthetic schemes are readily amenable to large-scale syntheses. Molecule 1 was made from 2-allylaniline, which was derived from a thermal-induced aromatic-Claisen rearrangement of N-allylaniline. The azido-appended side chain of 2 was installed from a Horner-Wadsworth-Emmons reaction and the carboxylic acid side chain from a Sonogashira reaction.

■ Thermally-Induced Doping of the Regioregular Polythiophene Bearing Alkylene Spacered Benzene sulfonate Group at the Side Chain

Chihiro Kubota, Daisuke Morita, Keisuke Fujita, Sonoka Yamamoto, Toyoko Suzuki, Kentaro Okano, Masahiro Funahashi, Masaki Horie, and Atsunori Mori*

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

Abstract

Regioregular polythiophene bearing a benzenesulfonate group, which involved an alkylene spacer between thiophene and benzene ring, was synthesized. The obtained polythiophene was shown to improve its conductivity by heating the polymer thin film through the transformation of the ester group into the corresponding sulfonic acid.

■ Synthesis of 5-H Thiazoles via Thioamide Dianions with Thioformamides: Pyridylmethyl Group on the Nitrogen Atom of Thiazole Promotes the Formation of 5-H Thiazoles

Khurnia Krisna Puji Pamungkas , Shizuka Hattori, Toshifumi Maruyama, Masahiro Ebihara, and Toshiaki Murai*

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

Abstract

The reaction of in situ-generated thioamide dianions having a pyridylmethyl group on the nitrogen atom with thioformamides resulted in the formation of 5-H thiazoles as major products along with 5-N,N-dimethylaminothiazoles. The presence of a pyridylmethyl group plays an important role in the formation of 5-H thiazoles. A wide range of substituents at the 2-position of a thiazole ring tolerated the reaction conditions, and the intramolecular cyclization reaction proceeded smoothly. However, a phenyl substituent at the 4-position of a thiazole ring significantly reduced the yields of 5-H thiazoles.

■ Concise Preparation and Biological Evaluations of 9-cis-Retinoic Acid Analogues Having an Aromatic Ring

Takashi Okitsu,* Kinya Iwatsuka, Kimie Nakagawa, Toshio Okano, and Akimori Wada*

*Faculty of Pharmaceutical Science, Kobe Pharmaceutical University, 4-19-1, Motoyamakita, Higashinada, Kobe 658-8558, Japan

Abstract

A series of 9-cis-retinoic acid analogues having an aromatic ring were prepared in only two steps, and were evaluated for transcriptional activities with retinoic acid response element (RARE) and retinoid X response element (RXRE). Among them, compound 6c, bearing a 2-naphthyl substituent, exhibited the highest transcriptional activity with RXR selectivity.

■ 3-Trifluoromethanesulfonyloxy-4,7-dihydropyrazolo[1,5-a]pyridine via Ring-Closing Metathesis: Synthesis and Transformation to Withasomnine Homologs

Yoshihide Usami,* Yuya Tatsui, Kodai Sumimoto, Ayami Miyamoto, Nanase Koito, Hiroki Yoneyama, and Shinya Harusawa

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

Abstract

3-Trifluoromethanesulfonyloxy-4,7-dihydropyrazolo[1,5-a]pyridine (9) was successfully synthesized from the starting material, pyrazole, via a sequence of reactions containing ring-closing metathesis as a key step. Suzuki-Miyaura coupling of 9 with various arylboronic acids, followed by oxidation or hydrogenation, readily afforded pyrazolo[1,5-a]pyridines (11) or 3-aryl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridines (12), respectively. Compounds 12 were found to be withasomnine homologs

■ Synthesis of Pyrrolo[2,3-c]quinoline Alkaloid Marinoquinolines

Takashi Nishiyama, Mari Murakami, Kimiko Taninaka, Erina Hamada, Mai Endo, Daiki Kinou, Noriyuki Hatae, and Tominari Choshi*

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

Abstract

In this study, the synthesis of pyrrolo[2,3-c]quinoline as a common skeleton, is described. The process is based on the thermal electrocyclization of 3-phenylpyrrole containing isocyanate as 2-azahexatriene. Using this approach, the total synthesis of three natural marinoquinolines A, B, and E can be successfully achieved.

■ Selective Reduction and Dihydroxylation of α,β-Unsaturated Esters in the Presence of Enals: One-Pot Synthesis of a 2,5-Disubstituted Tetrahydrofuran

Kenta Morita, Kenichi Murai, Mitsuhiro Arisawa, and Hiromichi Fujioka*

*Graduate School of Pharmaceutical Science, Osaka University, 1-6 Yamadaoka, Suita, Osaka 560-0871, Japan

Abstract

Two-way discriminative conversion, reduction and dihydroxylation of α,β-unsaturated esters were achieved in the presence of enals using two phosphonium salts as in situ protecting groups. Furthermore, a pot-economical one-pot synthesis of a tetrahydrofuran derivative was achieved.

■ The Effect of the Base Triplets Adjacent to a T•CG or 5-MethylC•CG Triplet in the Triplex DNA

Yuta Ito, Chisa Hama, Takashi Osawa, and Yoshiyuki Hari*

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

Abstract

The effect of the base triplets adjacent to an X•CG triplet [X = T, 5-methylcytosine (C), or their LNA and ENA counterparts] in a triplex DNA was examined through the UV-melting experiments. Whereas the triplex containing a T•CG triplet, sandwiched by T•AT triplets, was stable, the replacement of T•AT with C•GC at the 5ʹ-adjacent site significantly destabilized the stability. When one or both of the adjacent T•AT triplets were replaced with C•GC, the triplexes containing a C•CG triplet were generally more stable than those containing a T•CG triplet. Further increases in the thermal stability of the triplexes were observed by LNA and ENA modifications. These results suggested that a C•CG triplet rather than a T•CG triplet would be suitable for triplex formation when C•GC triplets existed at its adjacent site.

■ Identification of a Novel Indoleamine 2,3-Dioxygenase Inhibitor Bearing an Eight-Membered Ring Fused Indole Scaffold and Its Structure-Activity Relationship

Ayuta Yamaguchi, Shinsuke Inuki,* Katsumi Ohta, Shinya Oishi, Akira Asai, and Hiroaki Ohno*

*Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan

Abstract

Indoleamine 2,3-dioxygenase 1 (IDO1) is a promising target for cancer immunotherapy because it is overexpressed in a variety of tumor cells. IDO1 also plays an important role in the process of immune escape by tumors. In this study, we identified a novel IDO1 inhibitor KPYC12532 (5a) bearing an eight-membered ring-fused indole scaffold by screening our compound library. To develop novel IDO1 inhibitors, we conducted a structure-activity relationship study of 5a and found some compounds displaying comparable activity. These results provide useful insight for the design of novel IDO1 inhibitors.

■ Copper-Mediated Trifluoromethylation of Borylporphyrins Using an in situ-Generated CF3 Radical from NaSO2CF3 and tert-Butyl Hydroperoxide

Satoshi Hayashi,* Daisuke Yamazaki, and Toshikatsu Takanami*

*Department of Life and Pharmaceutical Sciences, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan

Abstract

We developed a method for the copper-mediated reaction of borylated Ni(II) porphyrins using NaSO2CF3 (Langlois’ reagent) and tert-butyl hydroperoxide (TBHP) to prepare trifluoromethylated Ni(II) porphyrins.Porphyrin trifluoromethylation can be carried out under mild conditions and exhibits both excellent substrate generality and functional group compatibility.