Special Issue

Kaoru Fuji's Special Issues, Vol. 101, No. 2, 2020

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Contents | Special issue | Vol 101, No. 2, 2020
Published online: 18th September, 2018
DOI: 10.3987/Contents-19-10102
Contents
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Review | Special issue | Vol 101, No. 2, 2020, pp. 373 - 382
Published online: 7th August, 2019
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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Review | Special issue | Vol 101, No. 2, 2020, pp. 383 - 406
Published online: 28th August, 2019
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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Communication | Special issue | Vol 101, No. 2, 2020, pp. 407 - 416
Published online: 24th July, 2019
DOI: 10.3987/COM-19-S(F)22
One-Pot Synthesis of 9-Spirofluorenes via Tandem Copper-Catalyzed Arylative Cyclization and Spirocyclization of Biaryl-Substituted Alkynyl Alcohols

Noriko Okamoto, Takuya Sueda, and Reiko Yanada*

*Faculty of Pharmaceutical Sciences, Hiroshima International University, 5-1-1, Hirokoshingai, Kure, Hiroshima, 737-0112, Japan

Abstract

A tandem copper-catalyzed arylative cyclization and spirocyclization strategy to access spiro cyclic compounds is described. This method enables the one-pot construction of 9-spirofluorenes from readily available alkynyl alcohols with biaryl-substituents via the copper-catalyzed arylative ring-closing reaction and the Friedel–Crafts reaction.

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Communication | Special issue | Vol 101, No. 2, 2020, pp. 417 - 422
Published online: 25th September, 2019
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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Communication | Special issue | Vol 101, No. 2, 2020, pp. 423 - 428
Published online: 13th August, 2019
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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Communication | Special issue | Vol 101, No. 2, 2020, pp. 429 - 434
Published online: 29th August, 2019
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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Communication | Special issue | Vol 101, No. 2, 2020, pp. 435 - 443
Published online: 25th September, 2019
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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Communication | Special issue | Vol 101, No. 2, 2020, pp. 444 - 451
Published online: 1st October, 2019
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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Paper | Special issue | Vol 101, No. 2, 2020, pp. 453 - 460
Published online: 14th August, 2019
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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Paper | Special issue | Vol 101, No. 2, 2020, pp. 461 - 470
Published online: 16th August, 2019
DOI: 10.3987/COM-19-S(F)29
Formation of Seven-Membered-Ring Fused Bithiophene Derivatives by Nosyl Annulation

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

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

Abstract

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

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Paper | Special issue | Vol 101, No. 2, 2020, pp. 471 - 485
Published online: 2nd October, 2019
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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Paper | Special issue | Vol 101, No. 2, 2020, pp. 486 - 495
Published online: 13th August, 2019
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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Paper | Special issue | Vol 101, No. 2, 2020, pp. 496 - 511
Published online: 12th September, 2019
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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Paper | Special issue | Vol 101, No. 2, 2020, pp. 512 - 523
Published online: 24th September, 2019
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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Paper | Special issue | Vol 101, No. 2, 2020, pp. 524 - 535
Published online: 8th October, 2019
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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Paper | Special issue | Vol 101, No. 2, 2020, pp. 536 - 547
Published online: 7th October, 2019
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 810 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 810 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 810 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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Paper | Special issue | Vol 101, No. 2, 2020, pp. 548 - 558
Published online: 13th September, 2019
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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Paper | Special issue | Vol 101, No. 2, 2020, pp. 559 - 579
Published online: 2nd October, 2019
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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Paper | Special issue | Vol 101, No. 2, 2020, pp. 580 - 592
Published online: 7th October, 2019
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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Paper | Special issue | Vol 101, No. 2, 2020, pp. 593 - 610
Published online: 25th September, 2019
DOI: 10.3987/COM-19-S(F)49
Expedient Routes to 1,2,4-Triazolinium Salts

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

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

Abstract

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

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Paper | Special issue | Vol 101, No. 2, 2020, pp. 611 - 620
Published online: 25th September, 2019
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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Paper | Special issue | Vol 101, No. 2, 2020, pp. 621 - 630
Published online: 16th October, 2019
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 Kajimoto*

*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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Paper | Special issue | Vol 101, No. 2, 2020, pp. 631 - 644
Published online: 9th October, 2019
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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Paper | Special issue | Vol 101, No. 2, 2020, pp. 645 - 663
Published online: 3rd October, 2019
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*

*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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Paper | Special issue | Vol 101, No. 2, 2020, pp. 664 - 678
Published online: 10th October, 2019
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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Short Paper | Special issue | Vol 101, No. 2, 2020, pp. 679 - 691
Published online: 17th September, 2019
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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Short Paper | Special issue | Vol 101, No. 2, 2020, pp. 692 - 700
Published online: 29th August, 2019
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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Short Paper | Special issue | Vol 101, No. 2, 2020, pp. 701 - 706
Published online: 30th September, 2019
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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Short Paper | Special issue | Vol 101, No. 2, 2020, pp. 707 - 716
Published online: 16th August, 2019
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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