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Published online: 21st October, 2021

Paper | Regular issue | Prepress
DOI: 10.3987/COM-21-14559
■ Optimization of Nampt (Nicotinamide Phosphoribosyltransferase) Activators: Discovery of N,N-Diethyl-1,2-Benzoxazole-3-Carboxamide Derivatives as Potent Nampt Activators with Mitigated Mutagenic Risks

Mayuko Akiu,* Takashi Tsuji, Yoshitaka Sogawa, Koji Terayama, Mika Yokoyama, Daigo Asano, Tomohiro Honda, Tomomichi Ishizaka, Tomoko Hasegawa, Anthony B. Pinkerton, and Tsuyoshi Nakamura

*Group I, Medicinal Chemistry Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan

Abstract

DS68702229, a potent NAMPT activator developed from HTS followed by a hit-to-lead campaign, is a promising candidate compound that significantly reduced body weight when orally administered to mice with high fat diet-induced obesity. However, in vitro toxicology profiling of DS68702229 revealed bacterial mutagenicity using Salmonella typhimurium TA98 and TA100 strains upon S9 activation. Hypothesizing that DNA intercalation is the likely cause, we employed several approaches to disrupt the putative DNA intercalation, including modulation of the molecular shape. Our efforts culminated in the discovery of compounds 20k and 20l, which increased intracellular NAD+ levels in a cell-based assay without inducing mutagenicity, along with acceptable plasma exposure in mice after oral administration.

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Published online: 21st October, 2021

Paper | Regular issue | Prepress
DOI: 10.3987/COM-21-14562
■ A New Template of MIitsunobu Acylate Cleavable in non-Alkaline Conditions

Yoshimichi Sakakibara, Yusuke Sai, Yasumitsu Uraki, Makoto Ubukata, and Kengo Shigetomi*

*Research Faculty of Agriculture, Hokkaido University, Kita 9 Nishi 9, Kita-ku, Sapporo, Hokkaido 060-0589, Japan

Abstract

The Mitsunobu inversion is one of the reliable methods for stereospecific substitution of chiral alcohols, but its deacylation step has limited the substrate scope. Here, we propose a new template of the Mitsunobu acylate that can be deacylated in non-alkaline treatments. The 3,4-dihydroxy-2-methylenebutanoate was selected as a template structure, and its acetonide- or bisTBS derivatives were synthesized. The latter especially showed excellent inversion efficiency (up to >99% ee) and good elimination performance for a series of secondary alcohols in near-neutral conditions. The results demonstrated the applicability of the new template for the substrates labile in alkaline conditions, such as α-hydroxyesters.

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Published online: 20th October, 2021

Paper | Regular issue | Prepress
DOI: 10.3987/COM-21-14553
■ Synthesis and Reactivity of Novel 5-Imino-1,2-Oxazole

Khalid Saleh Widyan*

*Department of Chemistry, Tafila Technical University, P.O Box 179, Tafila-Jordan, Jordan

Abstract

A convenient synthetic approach towards 5-imino-1,2-oxazoles beginning from N-substituted C-benzotriazolated nitrones and Reformatsky reaction reagent is developed. The conversion of trisubstituted 5-imino-1,2-oxazoles into the corresponding 5-functionalized 1,2-oxazoles by interactions with phenyl isocyanates and 20% HCl is provided. In addition, one-pot synthesis of 1,2-oxazole-5-ones is achieved with yield of 85-90%

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Published online: 19th October, 2021

Short Paper | Regular issue | Prepress
DOI: 10.3987/COM-21-14542
■ MS 4A-Promoted Aqueous Phospho-Aldol-Brook Rearrangement Reaction of Isatins

Fan Liu, Wei Han,* and Takeshi Oriyama*

*Department of Chemistry, Faculty of Science, Ibaraki University, 2-1-1 Bunkyo, Mito, Ibaraki 310-8512, Japan

Abstract

An efficient, simple, environment-friendly, and low-cost protocol for the hydrophosphonation of isatins using inexpensive and non-toxic MS 4A as a recyclable additive in water has been developed. This protocol is also suitable for the aldol reaction of isatin with acetone or acetophenone.

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Published online: 18th October, 2021

Review | Regular issue | Prepress
DOI: 10.3987/REV-21-970
■ Click Chemistry toward the Synthesis of Anticancer Agents

Ashutosh Pal* and Bimal Krishna Banik*

*Department of Chemistry, Raja Peary Mohan College, West Bengal, India

Abstract

The copper(I)-induced synthesis of 1,2,3-triazoles using azides and alkynes (click chemistry) has become extremely significant. Click chemistry has been used in all aspects of drug discovery research. The product triazole serves as a linker as it readily combines with targets through hydrogen-bonding and dipole interaction. This review summarizes the application of click chemistry and triazoles as anticancer drugs. These types of reactions proceed with high selectivity, specificity, and yields. A variety of complex molecules are synthesized by this method.

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Published online: 12th October, 2021

Short Paper | Regular issue | Prepress
DOI: 10.3987/COM-21-14549
■ Hybrid Linker Mode C2-Symmetrical 1,3,5-Triazine Derivatives and Their Biological Evaluation

Shunsuke Shimomura, Kazumi Yokomizo, Jian-Rong Zhou, Kaori Ota, Nobuko Mibu, Makoto Furutachi, and Kunihiro Sumoto*

*Faculty of Pharmaceutical Sciences, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan

Abstract

We report the preparation of some new multivalent hybrid-type C2-symmetrical molecules having a methylene linker group and 1,3,5-triazine (TAZ) moieties in the molecule and the results of biological evaluation of their anti-herpes simplex virus type 1 (anti-HSV-1) activity and cytotoxic activity against Vero cells. Some of the mid-sized C2-symmetrical multivalent hybrid-type molecules (3a) showed considerably high levels of anti-HSV-1 activity (EC50 = 28.8 ~ 32.0 μM) with low levels of cytotoxicity (CC50 = > 200 μM) against Vero cells. Among the tested hybrid-type TAZ derivatives, we reconfirmed that the hybrid-type C2-symmetrical multivalent molecule (3a-4) is an interesting candidate in the search for new hybrid-type multivalent mid-sized antiviral compounds.

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Published online: 8th October, 2021

Short Paper | Regular issue | Prepress
DOI: 10.3987/COM-21-14547
■ Inverted Positioning of DNMT1 Inhibitor in the Active Site of DNMT1 Caused by Hydrophobicity/Hydrophilicity of the Terminal Structure

Toshifumi Tojo,* Yuhei Kubo, Takeshi Kondo, and Makoto Yuasa

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

Abstract

DNA (cytosine-5)-methyltransferase 1 (DNMT1) is one of the enzymes that regulate DNA modification. It has been demonstrated that overexpression of DNMT1 is associated with the development of cancer, making DNMT1 an attractive molecular target for cancer therapy. Focused on the terminal structures of existing DNMT1 inhibitors, we designed and screened test compounds that possessed another functional group. Binding simulations identified compounds with a trifluoromethylphenyl group to insert in an inverted position against DNMT1 compared to existing DNMT1 inhibitors. These results suggest that the binding form against DNMT1 may depend on the hydrophobicity/hydrophilicity of the inhibitor’s terminal structure.

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Published online: 6th October, 2021

Communication | Regular issue | Prepress
DOI: 10.3987/COM-21-14545
■ Synthetic Study of the C’D’E’ Ring System of Maitotoxin via Furan Based Strategy

Yuta Watanabe, Kohei Torikai, Yoko Yasuno, and Tohru Oishi*

*Department of Chemistry, Faculty and Graduate School of Science, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan

Abstract

Synthetic study of the C’D’E’ ring system of maitotoxin was examined via Suzuki–Miyaura coupling of an exo-iodoolefin and a furanylborane derivative, followed by Sharpless asymmetric dihydroxylation, Achmatowicz reaction, borylation/oxidation, and reductive etherification.

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Published online: 4th October, 2021

Paper | Regular issue | Prepress
DOI: 10.3987/COM-21-14544
■ Semi-Synthetic Chasmanthinine Analogues with Antifeedant Effects against Spodoptera exigua

Ziyu Song, Ke Xu, Jing Li, Yayun Xie, Xiang Li, Shuai Huang, Feng Gao, Lin Chen, and Xianli Zhou*

*School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, Sichuan, P. R. China

Abstract

The synthesis and structure modification of active natural lead compounds is an important approach for the discovery of novel green pesticides. Nineteen derivatives of chasmanthinine, a natural C19-diterpenoid alkaloids, were prepared, and their structures were unambiguously determined by 1H NMR, 13C NMR, and HR-ESI-MS. Moreover, the antifeedant activities of title compounds were evaluated against larvae of Spodoptera exigua (Hübner). The results illustrated that compounds p with a thienyl group at the C-14 position (EC50 = 0.10 mg/cm2) showed the strongest antifeedant activities among all tested compounds. This present study is the first report on the antifeedant effects of synthetic chasmanthinine analogs aganist S. exigua (Hübner) larvae.

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Published online: 28th September, 2021

Short Paper | Regular issue | Prepress
DOI: 10.3987/COM-21-14540
■ Efficient Synthesis of Cyclotriphosphazene Tripodal Tridentate Ligand via the Copper(I)-Template Method

Kazumasa Kajiyama,* Junpei Iwanami, and Hidetaka Yuge

*Division of Molecular Sciences, Graduate School of Science, Kitasato University, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0373, Japan

Abstract

An efficient synthesis of a cyclotriphosphazene tripodal tridentate ligand, cis,cis,cis-N/O trispirocyclic cyclotriphosphazene, via the copper(I)-template method was described. The reaction of hexachlorocyclotriphosphazene, N3P3Cl6, with 3 equiv of the dianion generated from 2-(1H-pyrazol-3-yl)phenol and NaH in THF in the presence of CuI afforded a copper(I) complex of the cyclotriphosphazene ligand in 51% yield. The solution of the complex in CH2Cl2 was treated with 25% NH3 aqueous solution to give the ligand in 82% yield. The 42% overall yield of the ligand via the complex starting from N3P3Cl6 was adequately improved compared to the yield of 8% in the reported synthesis of the ligand in the absence of CuI.

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Published online: 17th September, 2021

Review | Regular issue | Prepress
DOI: 10.3987/REV-21-965
■ Recent Progress on Synthesis of Spirochromanone and Spirochromane Derivatives

S. Chakroborty,* P. Panda, S. C. Ramírez-Lopìez, M. A. Garcia Eleno, E. C. Yañez, L. Strekowski, and M. V. B. Unnamatla*

*School of Sciences, Auro University, earthspace, Hazira Road, opp. ONGC, Surat, Gujarat 394510, India

Abstract

Nature offers plenty of opportunities to the researchers of different communities to explore heterocyclic compounds. Among the various magic heterocyclic scaffolds, chromane and chromanone are the most privileged heterocycles due to their omnipresence in most value-added chemical entities. On the other hand, spirocyclic heterocyclic moieties offer unique three-dimensional frameworks which can fit into the cavity of the proteins, including enzymes, thereby enhancing the biological properties. Considering the remarkable significance of spirocyclic systems of chromanes and chromanones, various novel strategies such as Kabbe condensation, organocatalyzed reactions, oxa/sulfa-Michael-Aldol cascade reaction, oxa-Michael/addition and 1,3-dipolar cycloaddition, among others, have emerged to access this precious heterocyclic architecture in good to excellent yields. This review summarizes the synthesis of a variety of spirochromane and spirochromanone derivatives covering the literature from 1991-2020.

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Published online: 15th September, 2021

Review | Regular issue | Prepress
DOI: 10.3987/REV-21-969
■ Total Synthesis of Natural Products and Medicinal Molecules via Chelation-Controlled Diastereoselective Hydride Reduction of Amino Ketones

Tian Jin,* Lu Zhao, Chichong Lu,* Zhe-Bin Zheng, and Won-Hun Ham*

*Antibiotics Research and Re-evaluation Key Laboratory of Sichuan Province, Sichuan Industrial Institute of Antibiotics, School of Pharmacy, Chengdu University, Chengdu 610106, People’s Republic of China

Abstract

The chiral β-amino alcohols are widely presented in the natural products, privileged ligands, and medicinal molecules. In the past decades, the construction of anti-β-amino alcohols have attracted in the interest of synthetic chemists. A number of studies indicated that the chelation-controlled hydride reduction approach is straightforward for the preparation of anti-β-amino alcohol motifs in high yield with excellent diastereoselectivity and they can be used as chiral building block in the total synthesis of natural products and medicinal molecules. The aim of this review is to highlight application of chelation-controlled hydride reduction in total synthesis of natural products and medicinal molecules on the basis of a collection of recent literature studies.

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Published online: 15th September, 2021

Paper | Regular issue | Prepress
DOI: 10.3987/COM-21-14531
■ Five New Compounds from Arenga pinnata (Wurmb.) Merr. Fruits

Ji-Fei Liu, Xin Cai, Feng-Jin Li, Chang Wang, Jin-Hai Huo,* and Wei-Ming Wang*

*Institute of Chinese Materia Medica, HeilongJiang Academy of Chinese Medicine Sciences, Harbin 150036, China

Abstract

Phytochemical investigation of Arenga pinnata (Wurmb.) Merr. fruits led to the isolation of 5 new compounds, designated A. pinnata A-E (1–5), and 13 known compounds (6–18). All compounds were isolated from A. pinnata for the first time. Their chemical structures were identified based on extensive spectroscopic methods, including HR-ESI-MS, 1D and 2D-NMR. To the best of our knowledge, this is the first systematic scientific study on the chemical composition of the Arenga genus.

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Published online: 14th September, 2021

Short Paper | Regular issue | Prepress
DOI: 10.3987/COM-21-14538
■ Oscillatoxin E and Its C7 Epimer Show Distinct Growth Inhibition Profiles against Several Cancer Cell Lines

Yusuke Hanaki,* Yusuke Araki, Toshio Nishikawa, and Ryo C. Yanagita

*Faculty of Agriculture, Kagawa University, Kagawa 761-0795, Japan

Abstract

Oscillatoxins (OTXs) are naturally occurring polyketides produced by some marine cyanobacteria. We have recently reported the total synthesis and in vitro biological activities of OTX-D, E, and F. Their spiro-ether structure was synthesized with an intramolecular Mukaiyama aldol reaction as a key step. Although the desired isomer was stereoselectively obtained, some amount of its C7 epimer was also produced as a byproduct. Using the C7 epimer, we investigated the effect of stereochemistry at the spiro-center of OTX-E (1) on its antiproliferative activity against several cancer cell lines. Growth inhibitory activity of 1 and its C7 epimer 2 was not strong, but they showed different efficacy profiles from each other. This result suggests that our synthetic method for OTXs would contribute to not only total synthesis of natural products but also to construction of chemical libraries containing unique biologically active compounds.

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Published online: 8th September, 2021

Paper | Special issue | Prepress
DOI: 10.3987/COM-21-S(R)6
■ Application of Reversible Detection Method for N-terminus Amino Groups: Solid Phase Synthesis of Stylissatin B

Ao Tan, Keigo Takamatsu, Fusheng Xu, Seren Osanai, and Hiroyuki Konno*

*Department of Biological Engineering, Graduate School of Science and Engineering, Yamagata University, Yonezawa, Yamagata 992-8510, Japan.

Abstract

The first synthesis of the proline-rich cyclic heptapeptide stylissatin B is described. Reversible detection method of N-terminus amino groups using tetrachloro-N-hydroxyphthalimide was applied as the Fmoc-solid phase peptide synthesis. The end points of all reactions of solid support could be pursued by the detection methods.

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Published online: 7th September, 2021

Paper | Regular issue | Prepress
DOI: 10.3987/COM-21-14526
■ Synthesis and Biological Evaluation of New Pyrimidine Derivatives as FAK Inhibitors for Development of Antitumor Agents

Di Zhang, Qin Wang, Jing Yang, Qing Zhang, Yi Le, Li Liu, and Longjia Yan*

*School of Pharmaceutical Sciences, Guizhou University, Guiyang 550025, China

Abstract

In this paper, a set of new pyrimidine derivatives was designed and synthesized. Subsequently, all the final targets were evaluated for antitumor activities in vitro on four human cancer cell lines including U-87 MG, MDA-MB-231, PC-3, and MCF-7, which were high expressed with focal adhesion kinase (FAK). The results were shown that these compounds performed well antitumor activities. Especially 2-((2-((4-((2-((2-acrylamidoethyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-N-methylbenzamide (7b) exhibited the highest antitumor activities with 2.16 μM, 2.03 μM, 6.19 μM, and 21.31 μM, respectively. In addition, all the compounds were tested activities against FAK and compound 7b was also the best candidate with IC50 value of 5.9 nM.

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Published online: 7th September, 2021

Paper | Regular issue | Prepress
DOI: 10.3987/COM-21-14541
■ Detection of New 3,4-Dimethylpyrrole Derivatives upon the Incubation of Exogenous Amines with Extract of Onion (Allium cepa) and Crude Alliinase from Garlic (A. sativum)

Taichi Yoneda, Seikou Nakamura,* Shogo Okui, Sayaka Okazaki, Souichi Nakashima, and Hisashi Matsuda

*Kyoto Pharmaceutical University, Misasagi, Yamashina-ku, Kyoto 607-8414, Japan

Abstract

Seven new N-substituted 3,4-dimethylpyrroles were obtained in situ through the reaction of an amine ((L)-phenylalanine, (L)-tryptophan, (L)-leucine, (L)-methionine, 1-phenethylamine, aniline or dodecylamine) and a mixture of unstable sulfur-containing compounds derived from the reaction of amino acids in Allium cepa and plant enzyme alliinase. In addition, a plausible reaction mechanism for the synthesis of N-substituted 3,4-dimethylpyrroles was displayed.

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Published online: 3rd September, 2021

Paper | Regular issue | Prepress
DOI: 10.3987/COM-21-14530
■ Synthetic Approaches for Construction of Novel 3-Heteroarylchromeno[2,3-b]pyridines and Annulated Chromenopyridopyrazolopyrimidines

Magdy A. Ibrahim* and Youssef A. Alnamer

*Department of Chemistry, Faculty of Education, Ain Shams University, Roxy 11757, Cairo, Egypt

Abstract

Hydrazinolysis of ethyl 2,5-dioxo-1,5-dihydro-2H-chromeno[2,3-b]- pyridine-3-carboxylate (2) afforded chromeno[2,3-b]pyridine-3-carbohydrazide 3 which utilized as a precursor for building a diversity of heterocyclic compounds at position 3. Condensation of carbohydrazide 3 with 3-formylchromone produced the condensation product 4, while addition of carbohydrazide 3 to phenyl isothiocyanate gave hydrazinecarbothioamide derivative 5 which upon cyclization afforded 3-thiadiazolylchromeno[2,3-b]pyridine-2,5(1H)-dione 6. Condensation of carbohydrazide 3 with some monoelectrophilic reagents namely ethyl chloroformate, carbon disulfide, acetyl chloride and benzoyl chloride and chromone-3-carboxylic acid gave a variety of novel 3-oxadiazolylchromeno-[2,3-b]pyridines 7-10 and 12. Treatment of carbohydrazide 3 with a variety of 1,3-bielectrophiles such as acetylacetone, ethyl acetoacetate and diethyl malonate yielded 3-(pyrazolyl)carbonylchromeno[2,3-b]pyridines 13-15. Finally, reaction of carbohydrazide 3 with ethyl cyanoacetate and (ethoxymethylene)malononitrile afforded heteroannulated chromeno[2``,3``:6`,5`]pyrido[2`,3`-d]pyrazolo[1,5-a]-pyrimidines 17 and 18. Structures of the synthesized products were confirmed based on their analytical and spectral data.

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Published online: 2nd September, 2021

Short Paper | Regular issue | Prepress
DOI: 10.3987/COM-21-14521
■ Quinoline Alkaloids from the Leaves of Cigar Tobacco and Their Anti-Tobacco Mosaic Virus Activity

Guang-Hui Kong, Guang-Hai Zhang, Zhong-Long Lin, Gao-Kun Zhao, Yin-Ke Li, Heng Yao, Guang-Yu Yang, Qiu-Fen Hu,* and Yu-Ping Wu*

*Yunnan Academy of Tobacco Agricultural Sciences, Kunming, Yunnan 650031, P. R. China

Abstract

Three new (1-3), together with three known (4-6) quinoline alkaloids were isolated from the leaves of cigar tobacco (a variety of Nicotiana tabacum). Their structures were elucidated by spectroscopic methods, including extensive 1H, 13C, and 2D-NMR techniques. Compounds 1-6 were tested for their anti-tobacco mosaic virus (anti-TMV) activity. The results showed that compound 3 exhibited high anti-TMV activity with inhibition rate of 42.2% at the concentration of 20 μM. This rate in higher than that of positive control (with inhibition rate of 32.5% at the concentration of 20 μM). Compounds 1, 2, 4~6 also showed potential anti-TMV activity with inhibition rates of 28.2, 31.0, 22.8, 26.6, and 29.5% at the concentration of 20 μM, respectively. These rates are slightly lower than that of positive control.

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Published online: 2nd September, 2021

Short Paper | Regular issue | Prepress
DOI: 10.3987/COM-21-14529
■ Synthesis of Benzimidazoles, Benzoxazoles and Benzothiazole by the Reaction of 2-Amino-4,5-dihydro-3-furancarbonitrile and o-Substituted Anilines in the Catalysis of Trimetylamine Hydrochloride

Fumi Okabe-Nakahara,* Hayate Nagabuchi, Eiichi Masumoto, and Hiroshi Maruoka

*Faculty of Pharmaceutical Sciences, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan

Abstract

Efficient synthesis of benzimidazoles, benzoxazoles and benzothiazole from the reaction of 2-amino-4,5-dihydro-3-furancarbonitrile with o-substituted anilines in the catalysis of trimethylamine hydrochloride was achieved. The structures of the obtained products were established by spectroscopic data.

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Published online: 27th August, 2021

Paper | Regular issue | Prepress
DOI: 10.3987/COM-21-14534
■ Synthesis, Characterization, Antibacterial and Cytotoxic Evaluation of New 6-(Chlorothiophenyl)-2-(2-oxopropoxy)pyridine-3-carbonitrile Derivatives and Their Corresponding Furo[2,3-b]pyridine Derivatives

Ala’a B. Said, Mahmoud Al-Refai,* Armin Geyer, Iman A. Mansi, and Basem Fares Ali*

*Department of Chemistry, Al al-Bayt University, Mafraq 25113, Jordan

Abstract

The synthesis of a new series of 6-(chlorothiophenyl)-2-(2-oxopropoxy)pyridine-3-carbonitrile compounds 2 and 5 and their furo[2,3-b]pyridines bearing heteroaryl substituents 3 and 6 in high yield is reported. The 6-(chlorothiophenyl)-2-(2-oxopropoxy)pyridine-3-carbonitrile derivatives (2a-f) and (5a-d) were prepared from the corresponding 3-cyano-(2H)-pyridones (1a-f) and (4a-d) followed by the Thorpe-Ziegler ring cyclization in the presence of sodium methoxide to give the target furo[2,3-b]pyridine derivatives (3a-f) and (6a-d). Proposed structures of the new compounds are based on NMR and mass spectral data. Antibacterial evaluation of (2a-d), (2f), (5a-d), (3a-d), (3f), and (6a-d) derivatives against eight different microorganisms shows no activity towards any of the tested bacteria while compounds (6a) and (6c) showed weak antibacterial activity with inhibition zone of 10 mm. Cytotoxic assessment against MCF7 breast cancer cells reveals that 10 of the derivatives were found to decrease cell viability in a dose dependent manner at concentration of 100 μM, but six of them decreased it to less than 50% and had IC50’s ranging from 23.3 to 41.2 μM.

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Published online: 23rd August, 2021

Short Paper | Regular issue | Prepress
DOI: 10.3987/COM-21-14527
■ New Synthesis of Lumateperone Tosylate

Cong Sun, Yongjun Mao,* Bo Li, Zhiyong Xu, Shun Jiang, Linlin Kang, and Han Wang

*College of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, Shanghai 201620, China

Abstract

A new and practical synthesis of lumateperone tosylate is developed. The intermediate, ethyl (4aS,9bR)-6-bromo-1,3,4,4a,5,9b-hexahydro-2H-pyrido-[4,3-b]indole-2-carboxylate (12), is prepared on kilograms scale in 31% overall yield and >99% ee. (6bR,10aS)-3-Methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline hydrochloride (16-HCl) is obtained through reductamination reaction, palladium catalyzed cyclization and ester hydrolysis in 60% yield over 3 steps and >98% purity. Lumateperone tosylate is produced on 20 g scale in 65% yield over 2 steps and >99% purity (HPLC). Purification methods of the intermediates and the final product involved in the route are developed.

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Published online: 19th August, 2021

Paper | Regular issue | Prepress
DOI: 10.3987/COM-21-14519
■ Ruthenium(II) Complexes with Chelating N-Heterocyclic Carbenes and a Ruthenate(II) Complex as Catalysts for the Anti-Markovnikov Hydroaminations of Styrene

Murat Yiğit,* Yetkin Gök, Özlem Özeroğlu Çelikal, and Beyhan Yiğit

*Department of Chemistry and Chemical Processing Technologies, Vocational School of Technical Sciences, Adiyaman University, 02040-Adıyaman, Turkey

Abstract

New ruthenium chelate and ruthenate complexes were synthesized through the reaction of benzimidazolium salts and [RuCl2(p-cymene)]2 in toluene and characterized by elemental analysis, 1H NMR and 13C NMR spectroscopy. These ruthenium complexes were tested as catalysts in the intermolecular hydroamination reactions between styrene with aromatic amines in ionic liquid. All of these complexes tested here showed good catalytic activity in these reactions. The hydroamination reactions regioselectively produced anti-Markovnikov addition products in moderate to good yields by using 1 mol% of the ruthenium complex.

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Published online: 18th August, 2021

Paper | Regular issue | Prepress
DOI: 10.3987/COM-21-14514
■ A Simple Route for Synthesis of New Triazole Derivatives via Reaction between Arylglyoxals, Acetylacetone and Sodium Azide

Fereshteh Nejad-Shahrokhabadi and Mohammad Anary-Abbassinejad*

*Department of Chemistry, Faculty of Science, Vali-e-Asr University of Rafsanjan, Rafsanjan 7718897111, Iran

Abstract

A fast and green way to preparation of a new series of triazole derivatives is reported using the three-component reaction between arylglyoxals, acetylacetone and sodium azide in water as solvent.

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Published online: 17th August, 2021

Short Paper | Special issue | Prepress
DOI: 10.3987/COM-21-S(R)4
■ Isolation of Ikahonone, 4-methyl-2,4-dihydroxy-3-pentanone from Bacillus cereus IFM12235

Yasumasa Hara, Mareno Chiba, Keiichiro Watanabe, and Masami Ishibashi*

*Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan

Abstract

A new ketone, ikahonone (1), and five known compounds (2-6) were isolated from Bacillus cereus IFM12235 collected in Japan. The structure of compound 1 was elucidated using spectral studies, including NMR. The absolute configurations of 1 and 2 were determined by comparing electronic circular dichroism (ECD) spectra with known compounds and calculating the ECD spectra of 1 and 2. Three compounds (2-4) were previously prepared by synthesis, and first isolated as natural products in the present study.

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Published online: 11th August, 2021

Paper | Special issue | Prepress
DOI: 10.3987/COM-21-S(R)5
■ Azuleno[6,5-b]indoles: Palladium-Catalyzed Oxidative Ring-Closing Reaction of 6-(Arylamino)azulenes

Taku Shoji,* Yukino Ariga, Shunji Ito, and Masafumi Yasunami

*Department of Science, Graduate School of Science and Technology, Shinshu University, Matsumoto 390-8621, Nagano, Japan

Abstract

6-Bromoazulene derivative with two n-butoxycarbonyl groups was prepared by the modification procedure of Nozoe’s azulene synthesis. The aromatic nucleophilic substitution reaction of the 6-bromoazulene derivatives having two-ester functions with aniline derivatives proceeded to give the corresponding 6-(arylamino)azulene derivatives. Palladium-catalyzed oxidative ring-closing reaction of the 6-(arylamino)azulene derivatives provided the azuleno[6,5-b]indoles in moderate to good yields.

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Published online: 5th August, 2021

Short Paper | Regular issue | Prepress
DOI: 10.3987/COM-21-14518
■ An Efficient Synthesis of 2-Amino-4-(guaiazulen-1-yl)-4H-chromenes via Cycloaddition of 1-Hydroxy-2-(3-guaiazulenylium)benzenes with Malononitrile/Ethyl Cyanoacetate

Shuang Yang, Xin-Shuang Xiong, and Dao-Lin Wang*

*College of Chemistry and Material Science, Bohai University, Jinzhou, China

Abstract

An efficient two-step method developed for the synthesis of 2-amino-4-(guaiazulen-1-yl)-4H-chromenes is described. The construction of these compounds was achieved by the reaction of guaiazulene and 2-hydroxy-benzaldehydes in the presence of perchloric acid, followed by cycloaddition of the resulting 1-hydroxy-2-(3-guaiazulenylmethylium)benzenes which allowed access to the title heterocycles.

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Published online: 22nd June, 2021

Communication | Special issue | Prepress
DOI: 10.3987/COM-21-S(R)3
■ Synthesis and Optical Properties of Azuleno[1,2-b]benzothiophene and Selenophene

Mio Matsumura,* Taiki Kamiya, Masato Kawakubo, Yukako Hayashi, Tadashi Hyodo, Yuki Murata, Kentaro Yamaguchi, and Shuji Yasuike*

*School of Pharmaceutical Sciences, Aichi Gakuin University, 1-100 Kusumoto-cho, Chikusa-ku, Nagoya 464-8650, Japan

Abstract

Benzothiophene- and benzoselenophene-fused azulene derivatives were synthesized by Cu-catalyzed tandem cyclization via the Ullmann-type S/Se– arylation and Csp2–H chalcogenation of 2-(2′-bromophenyl)azulene. The maximum absorption of tetracyclic products was red-shifted from that of 2-phenylazulene, which does not contain a bridged chalcogen atom. Single-crystal X-ray analysis of azuleno[1,2-b]benzoselenophene revealed that the benzo[b]selenophene and azulene rings are almost coplanar.

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Published online: 22nd June, 2021

Review | Regular issue | Prepress
DOI: 10.3987/REV-21-964
■ Synthesis of Multisubstituted Benzofurans/Indoles Using Multichlorinated Phenols/Anilines via Palladium-Catalyzed Site-Selective Sonogashira Coupling

Miyuki Yamaguchi and Kei Manabe*

*School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga, Shizuoka 422-8526, Japan

Abstract

Multisubstituted benzofurans/indoles are a critical class of compounds in the fields of pharmaceuticals and natural products. A useful method of preparing 2-substituted benzofurans/indoles is the Pd-catalyzed Sonogashira coupling of 2-halophenols/2-haloanilines and terminal alkynes, followed by cyclization. For the syntheses of multisubstituted benzofurans/indoles, the use of multichlorinated phenols/anilines as coupling partners is powerful because the synthetic steps required are reduced and all dichlorophenol and dichloroaniline positional isomers are commercially available and inexpensive. However, their use in benzofuran/indole synthesis is limited because of their low reactivity compared with those of the corresponding iodo or bromo compounds. Furthermore, site-selective Sonogashira coupling at the 2-position of the multihalogenated phenols/anilines is sterically and electronically challenging. To overcome these problems, dihydroxyterphenylphosphine (DHTP) has been developed as a ligand that enables the highly ortho-selective Sonogashira coupling of 2-chlorophenols/2-chloroanilines with terminal alkynes. Using the Pd–DHTP catalyst, chlorinated benzofurans/indoles are successfully obtained, which are easily converted to other derivatives by substitution of the chloro group. In this review, we summarize this and related studies to demonstrate the utility of this method.

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Published online: 1st June, 2021

Paper | Special issue | Prepress
DOI: 10.3987/COM-21-S(R)2
■ New Sugar Based γ-Amino Silyl Ether Organocatalysts for Asymmetric Michael Addition of β-Keto Esters with Nitroolefins

Divakar Ganesan, Perumalsamy Parasuraman, Zubeda Begum, Rajkumar Thiyagarajan, Chigusa Seki, Yuko Okuyama, Eunsang Kwon, Koji Uwai, Michio Tokiwa, Suguru Tokiwa, Mitsuhiro Takeshita, and Hiroto Nakano*

*Graduate School of Engineering, Muroran Institute of Technology, 27-1 Mizumoto-cho, Muroran 050-8585

Abstract

New sugar based γ-amino silyl ether organocatalysts were synthesized and their catalytic ability was examined in asymmetric Michael addition of β-keto esters with nitroolefins affording chiral Michael adducts with quaternary carbon stereocenter in good to excellent chemical yields, diastereoselectivities and moderate enantioselectivities (up to 97%, up to dr. 85:15, up to 56% ee).

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