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Published online: 15th August, 2018

Short Paper | Regular issue | Prepress
DOI: 10.3987/COM-18-13943
(+)-12-epi-Fragilide G, a New Chlorinated Briarane from the Sea Whip Gorgonian Coral Junceella fragilis

Li-Guo Zheng, Yu-Chia Chang, Jih-Jung Chen, Zhi-Hong Wen,* Tsong-Long Hwang,* and Ping-Jyun Sung*

*National Museum of Marine Biology and Aquarium, Pingtung 944, Taiwan

Abstract

Chemical investigation on the EtOAc-soluble fraction from the MeOH/DCM extract of a gorgonian coral Junceella fragilis afforded a new chlorinated briarane-type diterpenoid, (+)-12-epi-fragilide G (1) and this compound was found to be the enantiomer of 12-epi-fragilide G (2). The structure of 1 was established on the basis of spectroscopic methods. Briarane 1 was found to inhibit the protein expression of pro-inflammatory iNOS in a murine macrophage-like cell line, RAW 264.7, stimulated with LPS and briarane 2 displayed inhibitory an effect on the generation of superoxide anion by human neutrophils.

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Published online: 15th August, 2018

Short Paper | Regular issue | Prepress
DOI: 10.3987/COM-18-13958
Two New C19-Diterpenoid Alkaloids from Aconitum franchetii var. Villosulum 

Wenliang Xu, Lin Chen, Feng Gao, and Xianli Zhou*

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

Abstract

Two new C19-diterpenoid alkaloids, named villosudine A (1) and villosudine B (2), along with seven known diterpenoid alkloids, were isolated from the root of Aconitum franchetii var. villosulum. Their structures were elucidated by extensive spectroscopic analyses including 1D, 2D NMR, and HR-ESI-MS. Compounds (1-7) were evaluated for their cytotoxicity against the MCF-7 and HepG2 human cancer cell lines.

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Published online: 13th August, 2018

Paper | Special issue | Prepress
DOI: 10.3987/COM-18-S(F)18
Indium Mediated Allylation of N-tert-butanesulfinyl Imines with 1,3-Dibromopropene: Stereoselective Synthesis of Aziridines

Edgar Maciá, Francisco Foubelo,* and Miguel Yus*

*Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Alicante, Apdo. 99 03080 Alicante, Spain

Abstract

The reaction of N-tert-butanesulfinyl imines 1 with 1,3-dibromopropene (2), in the presence of indium metal, in saturated aqueous solution of sodium bromide, produced bromohomoallylamine derivatives 3 with total facial diastereoselectivity for the imine addition, and moderate yields. These compounds were easily transformed into the corresponding vinyl aziridines 5 upon deprotonation with KHMDS in THF, the intramolecular cyclization taking place in a stereospecific manner in moderate to high yields.

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Published online: 13th August, 2018

Paper | Special issue | Prepress
DOI: 10.3987/COM-18-S(F)20
Diastereoselective Synthesis of Poly-Substituted SYN-Imidazolidine-2-thiones via Microwave-assisted Three-Component [2+2+1] Heterocyclizations

Jie-Yu Hu, Yi-Yun Gao, Wen-Wen Zhang, Ke-Ying Zhang, Wen-Lian Li, Wen-Juan Hao,* Bo Jiang, and Guigen Li*

*Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX 79409-1061, U.S.A.

Abstract

An efficient and simple three-component reaction of arylglyoxals, isothiocyanates and arylamines has been developed, delivering poly-substituted syn-imidazolidine-2-thione derivatives with high diastereo- and regioselectivity (up to > 99:1). The microwave-assisted transformation is easy to perform simply by mixing readily available starting materials, thereby featuring mild reaction conditions, bond-forming efficiency and atom-economy.

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Published online: 10th August, 2018

Short Paper | Regular issue | Prepress
DOI: 10.3987/COM-18-13953
Cs2CO3-Promoted Vinylation of Phenols with Trichloroethylene: Facile Synthesis of (E)-1,2-Dichloro-1-phenoxyethenes

Kazunori Takahashi,* Naho Mamiya, Kei Fukushima, Masayoshi Tsubuki, and Toshio Honda

*Institute of Medicinal Chemistry, Hoshi University, Ebara 2-4-41, Shinagawa-ku, Tokyo 142-8501, Japan

Abstract

An efficient method for the synthesis of (E)-1,2-dichloro-1-phenoxyethenes 2 has been developed. The reaction of phenol derivatives 1 with trichloroethylene at ambient temperature by means of Cs2CO3-DMSO system furnished the corresponding aryl vinyl ethers 2 in excellent yields. On the other hand, the same reaction of phenol derivatives 1i, 1k and 1p possessing an electron-withdrawing group at the o- or p-position of the hydroxy group required a harsh reaction conditions to heat at 70 °C for the synthesis of the desired products 2i, 2k and 2p.

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Published online: 10th August, 2018

Paper | Regular issue | Prepress
DOI: 10.3987/COM-18-13959
An Efficient Synthesis of 4-Mono- and 4,4-Di-Substituted 3,4-Dihydro-2H-1-benzothiopyran 1,1-Dioxides by LDA-Mediated Cyclization of o-(Methylsulfonyl)styrenes

Kazuhiro Kobayashi* and Takuma Ueyama

*Applied Chemistry Field, Chemistry and Biotechnology Course, Department of Engineering, Graduate School of Sustainability Science, Tottori University, 4-101 Koyama-minami, Tottori 680-8552, Japan

Abstract

A new and efficient method for the preparation of 3,4-dihydro-2H-1-benzothiopyran 1,1-dioxide derivatives has been developed. α-Substituted o-(methylsulfonyl)styrenes, which can be derived from α-substituted o-bromostyrenes by an easily operated two-step sequence, are cyclized on treatment with lithium diisopropylamide (LDA) to give, after aqueous workup, the corresponding 4-monosubstituted 3,4-dihydro-2H-1-benzothiopyran 1,1-dioxides. Addition of electrophiles prior to aqueous workup provides 4,4-disubstituted derivatives.

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Published online: 9th August, 2018

Communication | Special issue | Prepress
DOI: 10.3987/COM-18-S(F)19
Diastereoselective Synthesis of 5-Iodoalkenyl-2-oxazolines by Electrophilic Cyclization of Allenyl Amides

Tsukasa Hirokane, Ayaka Kawakami, Kenji Matsumoto, and Masahiro Yoshida*

*Faculty of Pharmaceutical Sciences, Tokushima Bunri University, 180 Nishihamabouji, Yamashiro-cho, Tokushima, 770-8514, Japan

Abstract

The electrophilic cyclization of allenyl amides is described. Allenyl amides were easily prepared from the propargyl aziridines via the [1,5]-hydrogen shift followed by the conversion of the imine moiety to the amides. 5-Iodoalkenyl-2-oxazolines having a variety of substituents were diastereoselectively obtained by the reaction of the allenyl amides with iodine.

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Published online: 8th August, 2018

Short Paper | Regular issue | Prepress
DOI: 10.3987/COM-18-13932
One-Pot Preparation of Ethyl 2(Z)-4-(Anilinoxy)pentenoate by α-Aminoxylation of Propanal Followed by Z-Selective HWE Reaction and the Study on Its Cyclization Reaction

Kaori Ando,* Mami Takao, Ikumi Oyama, and Kouki Furuta

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

Abstract

A one-pot sequence of α-aminoxylation of n-propanal catalyzed by L-proline followed by the Z-selective Horner-Wadsworth-Emmons reaction was developed. The highly functionalized chiral γ-anilinoxy-Z-α,β-unsaturated ester 6 was obtained in 57-58% yield with 98:2 Z-selectivity from n-propanal in one-pot procedure. The transformation of the anilinoxy group of 6 into a hydroxyl group can be carried out by treatment with catalytic amount of CuSO4 in methanol to give either the corresponding alcohol 8 or chiral γ-valerolactone 4a in moderate yield. Chiral 6-methyl-2-phenyl-2H-1,2-oxazin-3(6H)-one 7 was obtained in 75% yield from 6 by treatment with CSA.

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Published online: 6th August, 2018

Short Paper | Special issue | Prepress
DOI: 10.3987/COM-18-S(F)17
Site-Selective Synthesis of Acacetin and Genkwanin through Lipase-catalyzed Deacetylation of Apigenin 5,7-Diacetate and Subsequent Methylation

Rie Fujita, Susanta Mandal, Kengo Hanaya, Mitsuru Shoji, Shuhei Higashibayashi, and Takeshi Sugai*

*Department of Pharmaceutical Sciences, Faculty of Pharmacy, Keio University, 1-5-30 Shiba-Kouen, Minato-ku, Tokyo, Japan

Abstract

Candida antarctica lipase B-catalyzed deacetylation proceeded with high site-selectivity on the C-4’ acetyl group in apigenin triacetate to give apigenin 5,7-diacetate. Methylation of the liberated hydroxy group with the combination of trimethyloxonium tetrafluoroborate (Meerwein reagent) and 1,8-bis(dimethylamino)naphthalene (proton sponge) in CH2Cl2 proceeded in a quantitative manner to give the product methylated at the C-4’ hydroxy group (acacetin 5,7-diacetate). Even with the same precursor, a different methylation product at the C-7 hydroxy group (genkwanin 4’,5-diacetate) was obtained in 86% yield by applying iodomethane and Cs2CO3 in dimethyl sulfoxide (DMSO). The methylated products were deprotected to form acacetin and genkwanin. We inferred that the latter unexpected methylation was ascribable to the intermolecular migration of an acetyl group from C-7 to C-4’. DFT calculations indicated that the C-7 phenoxide ion was 12.6 kJ/mol more stable than the initially formed C-4’ phenoxide ion.

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Published online: 26th July, 2018

Short Paper | Regular issue | Prepress
DOI: 10.3987/COM-18-13946
Synthesis of 3-Hydroxy-2,3-dihydro-1H-isoindole-1-thione Derivatives by the Reaction of 2,N-Dilithiobenzamides with Carboxylic Esters

Kazuhiro Kobayashi,* Daiki Fujiwara, Kazuma Nozaki, and Takashi Nogi

*Applied Chemistry Field, Chemistry and Biotechnology Course, Department of Engineering, Graduate School of Sustainability Science, Tottori University, 4-101 Koyama-minami, Tottori 680-8552, Japan

Abstract

An efficient one-pot method for the preparation of 2,3-disubstituted 3-hydroxy-2,3-dihydro-1H-isoindole-1-thiones from secondary benzothioamides and carboxylic esters has been developed. Thus, the reaction of the starting thioamides with two equivalents of butyllithium generates the corresponding 2,N-dilithiobenzothioamides, which are then allowed to react with carboxylic esters to give the desired products. The similar preparation of 4- and 5-aza-analogues from 2(or 3)-bromopyridine-3(or 4)-carbothioamides, respectively, is also described.

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Published online: 23rd July, 2018

Short Paper | Special issue | Prepress
DOI: 10.3987/COM-18-S(F)12
Lipase-Catalyzed Site-Selective Deacetylation of Sterically Hindered Naphthohydroquinone Diacetate and Its Application to the Synthesis of a Heterocyclic Natural Product

Riichi Hashimoto, Ayaka Sakakura, Kengo Hanaya, Shuhei Higashibayashi, and Takeshi Sugai*

*Department of Pharmaceutical Sciences, Faculty of Pharmacy, Keio University, 1-5-30 Shiba-Kouen, Minato-ku, Tokyo, Japan

Abstract

Lipase-catalyzed site-selective deacetylation of 2,5-dimethylnaphthalene-1,4-diol diacetate was examined. With Candida antarctica lipase B, the suppressing effect of a methyl substituent at the peri-position of the α-naphthyl ester over that at the ortho-position was significant. This site-selectivity was in contrast to that of chemical hydrolysis reported to date. From the resulting monoacetate, mansonone F, a physiologically active heterocyclic orthoquinone, was synthesized in 38% yield in as few as three steps.

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Published online: 20th July, 2018

Paper | Special issue | Prepress
DOI: 10.3987/COM-18-S(F)16
Structure–Activity Relationship Study of Gatastatin Based on the Topliss Tree Approach

Ichiro Hayakawa,* Shuya Shioda, Takumi Chinen, Takeo Usui, and Hideo Kigoshi*

*Division of Applied Chemistry, Graduate School of Natural Science and Technology, Okayama University, 3-1-1 Tsushima-naka, Okayama 700-8530, Japan

Abstract

Various analogues of gatastatin, a γ-tubulin-specific inhibitor, were designed and synthesized by systematically optimizing the aromatic ring at the O7-benzyl group in accordance with an operational Topliss tree, and their biological activities were evaluated. Some derivatives showed stronger cytotoxicity against HeLa cells than gatastatin. Especially, the cytotoxicity of the meta-chloro derivative was about 18-fold stronger than that of gatastatin. However, these derivatives did not exhibit binding ability to the yeast γ-tubulin small complex or inhibitory activity against α,β-tubulin polymerization. These results suggested that γ-tubulin strongly recognized the unsubstituted phenyl ring of the O7-benzyl group in gatastatin.

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Published online: 12th July, 2018

Paper | Special issue | Prepress
DOI: 10.3987/COM-18-S(F)11
New Indole Alkaloids from Ervatamia cumingiana

Mariko Kitajima, Shumpei Nakano, Noriyuki Kogure, Sanan Subhadhirasakul, and Hiromitsu Takayama*

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

Abstract

Two new Iboga-vobasine-type bisindole alkaloids N-demethylervahanine A (1) and N-demethylervahanine B (2) and one new chippiine-type alkaloid 3-O-methyl-10,11-demethoxychippiine (3) were isolated from the roots of Ervatamia cumingiana collected in Thailand. Their chemical structures were determined by spectroscopic analyses. Compounds 1 and 2 are bisindole alkaloids having a linkage between C-3 in the vobasine unit and C-11' or C-10' in the Iboga unit, respectively.

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Published online: 11th July, 2018

Short Paper | Special issue | Prepress
DOI: 10.3987/COM-18-S(F)13
C-Glycosidation of Unprotected Aldopentoses with Ketones Using Proline-Triethylamine as Catalyst

Jithender Enukonda, Sherida Johnson, 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

Reactions of unprotected aldopentoses with ketones catalyzed by proline and triethylamine that afford C-glycoside derivatives are described.

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Published online: 6th July, 2018

Communication | Special issue | Prepress
DOI: 10.3987/COM-18-S(F)2
Synthesis of Orthogonally Protected Actinoidic Acid Trimethyl Ether

Yusuke Amino* and Robert M. Williams*

*Department of Chemistry, Colorado State University, 301 West Pitkin Street, 80523, U.S.A.

Abstract

We describe the asymmetric synthesis of actinoidic acid trimethyl ether with orthogonal protecting groups on the respective amino and carboxyl groups. The Stille biaryl coupling reaction of suitably functionalized aryl bromide and (trimethylstannyl)benzaldehyde gave the key intermediate biaryl aldehyde. Synthesis was accomplished by applying the asymmetric Strecker reaction to this aldehyde, followed by selectively removing the chiral auxiliary. By comparing its 1H-NMR spectra with those obtained from vancomycin, the stereochemistry of the synthesized diastereoisomer of actinoidic acid trimethyl ether was confirmed as an atropisomer of the (αS,αR)-isomer.

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Published online: 2nd July, 2018

Paper | Special issue | Prepress
DOI: 10.3987/COM-18-S(F)9
Efficient Synthesis of O-Linked Glycoconjugates of Amino Acids from Carbohydrate-Derived Donor-Acceptor-Cyclopropanes

Gade Kishore, Vibha Gautam, Shrutisagar Dattatraya Haveli, and Srinivasan Chandrasekaran*

*Department of Organic Chemistry, Indian Institute of Science, Bangalore-560 012, India

Abstract

N-Iodosuccinimide (NIS) mediated ring opening of carbohydrate-derived donor-acceptor-cyclopropanes with free “CO2H” group of N-protected L-amino acids at ambient conditions afforded iodo derivatives of glycosyl ester of L-amino acids. The iodides were subsequently converted easily into corresponding azides using NaN3 in DMF followed by reduction with Zn/AcOH to produce ester linked glycosyl amino acids. A similar strategy was adopted to synthesize C-linked glycoamino acid derivatives from different N-protected L-amino alcohols. By using an orthogonal strategy C- and O-linked glycopeptides were also synthesized.

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Published online: 28th June, 2018

Paper | Special issue | Prepress
DOI: 10.3987/COM-18-S(F)5
Csf-Promoted Desilylation and Ring-Contraction Reaction of Electron-Deficient 3-Silyl-2H-Chromenes to 2-Benzylbenzofurans

Kenta Tanaka, Mayumi Sukekawa, Mami Kishimoto, Yujiro Hoshino, and Kiyoshi Honda*

*Graduate School of Environment and Infomation Science, Yokohama National University, Tokiwadai 156, Hodogaya-ku, Yokohama 240-8501, Japan

Abstract

The ring-contraction reaction of electron-deficient 3-silyl-2H-chromenes to 2-benzylbenzofurans under mild conditions was developed. CsF efficiently promoted the reaction at room temperature or 80 ºC to afford a variety of 2-benzylbenzofurans in good yields. 3-Silyl-2H-chromenes having strong electron-withdrawing groups smoothly afforded the desired products. The reaction is proposed to proceed through an allenyl intermediate or dyotropic rearrangement.

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Published online: 25th June, 2018

Paper | Special issue | Prepress
DOI: 10.3987/COM-18-S(F)8
Stereodivergent and Stereoselective Synthesis of cis- and trans-4-Substituted Prolinols

Junki Ando, Aoi Tazawa, Kohei Ishizawa, Minoru Tanaka,* and Hiroyoshi Takamura*

*Department of Chemistry, Graduate School of Natural Science and Technology, Okayama University, 3-1-1 Tsushima-naka, Okayama 700-8530, Japan

Abstract

Stereoselective synthesis of 4-substituted prolinol derivatives has been developed. Thus, Suzuki–Miyaura cross-coupling of vinyl triflate provided the common synthetic intermediates toward the stereodivergent synthesis of cis- and trans-4-substituted prolinols. These two kinds of target compounds were obtained by diastereoselective hydrogenation of the coupling products with Pd/C and Crabtree catalyst, respectively. In addition, the obtained 4-substituted prolinol was transformed to the corresponding proline derivative via oxidation in one step.

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Published online: 22nd June, 2018

Paper | Special issue | Prepress
DOI: 10.3987/COM-18-S(T)95
Asymmetric Synthesis of β-Lactams by Intramolecular Conjugate Addition of Serine and Cysteine Derivatives via Memory of Chirality

Ryuichi Hyakutake, Tomoyuki Yoshimura, Yoshihiro Ueda, Kazuhiro Hayashi, Takumi Furuta, and Takeo Kawabata*

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

Abstract

The 4-exo-trig cyclization of axially chiral enolates generated from L-serine and L-cysteine dervatives proceeded predominately over β-elimination to give chiral β-lactams with contiguous tri- and tetrasubstituted carbon centers in up to 96% ee. The key to smooth production of β-lactams is the use of Cs2CO3 and CF3CH2OH as a base and a proton source, respectively. A strongly electron-withdrawing Michael acceptor in the substrates was also critical for high enantioselectivity of the β-lactam formation.

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Published online: 22nd June, 2018

Paper | Special issue | Prepress
DOI: 10.3987/COM-18-S(T)94
2-Functionalized Derivatives of 2-Bromo-1,3-dimethylimidazole

Martin Lampl, Gerhard Laus, Klaus Wurst, Volker Kahlenberg, Thomas Gelbrich, Sven Nerdinger,* Hubert Huppertz, and Herwig Schottenberger

*Sandoz GmbH, Biochemiestrasse 10, 6250 Kundl, Austria

Abstract

Attempts of direct bromination of 1,3-dimethylimidazolium salts with bromine were futile. A tribromide or a carbene–lithium–THF adduct were received instead. The quaternary 2-bromo compound was obtained by methylation of 2‑bromo‑1‑methylimidazole and subsequent ion metathesis, which was converted to the corresponding 2-cyano and 2-azido derivatives. Typical reactions of the latter include a dipolar cycloaddition and the Staudinger reaction. Crystal structures of eight compounds have been determined by single-crystal X-ray diffraction.

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Published online: 20th June, 2018

Short Paper | Special issue | Prepress
DOI: 10.3987/COM-18-S(T)87
A Synthetic and Spectroscopic Investigation of the Asymmetric α-Lithiation-trapping of Six-Membered N-Boc Heterocycles Using Alexakis Diamines

James D. Firth, Giacomo Gelardi, Peter J. Rayner, Darren Stead, and Peter O'Brien*

*Department of Chemistry, University of York, Heslington, York YO10 5DD, U.K.

Abstract

The asymmetric lithiation-trapping of six-membered N-Boc heterocycles using s-BuLi and two different Alexakis diamines is reported. These readily available ligands outperform the current ‘best-in-class’ sparteine-type diamines in the lithiation and benzophenone trapping of N-Boc piperazines and the lithiation-cyclisation-trapping of N-Boc-4-chloropiperidine. In situ IR spectroscopy has been used to optimise lithiation times and to discover previously unknown subtleties regarding the lithiation step.

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Published online: 20th June, 2018

Review | Special issue | Prepress
DOI: 10.3987/REV-18-SR(T)3
β-Amino Alcohol Organocatalysts for Asymmetric Additions

Hiroto Nakano,* Isiaka Alade Owolabi, Madhu Chennapuram, Yuko Okuyama, Eunsang Kwon, Chigusa Seki, Michio Tokiwa, and Mitsuhiro Takeshita

*Division of Sustainable and Environmental Engineering, Graduate School of Engineering, Muroran Institute of Technology, 27-1 Mizumoto, Muroran, Hokkaido 050-8585, Japan

Abstract

A design of a chiral organocatalyst is very important for obtaining of a chiral product with a high optical purity in a catalytic asymmetric reaction. Recently, we developed a series of chiral β-amino alcohol organocatalysts A that showed high level of catalytic activity in some asymmetric reactions. These β-amino alcohols are stable in air, and have two advantageous features, easy preparation and exhibiting high stereoselectivity in an enantioselective reaction. This review summarizes our recent works involving the Diels-Alder (DA) reactions of 1,2-dihydropyridines, anthrones or 3-hydroxy-2-pyridones as dienes with dienophiles, the asymmetric 1,3-dipolar cycloaddition of nitrones with α,β-unsaturated aldehydes and the crossed aldol reaction of isatins with acetaldehyde, by the use of the simple primary β-amino alcohols as efficient chiral organocatalysts for the asymmetric reactions.

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Published online: 14th June, 2018

Review | Regular issue | Prepress
DOI: 10.3987/REV-18-885
Developments toward the Production of Diverse Natural-Product-Like Compounds: Diversity-Oriented Synthesis and Diversity-Enhanced Extracts

Haruhisa Kikuchi* and Yoshiteru Oshima*

*Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aza-Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan

Abstract

Natural products and their derivatives have proven very useful in the search for biologically active compounds and in the development of new drugs because of their structural diversity. However, new approaches that may increase the chemical diversity of such natural products must be developed in order to retain the future usefulness of these compounds. Diversity-oriented synthesis (DOS) has recently emerged as an efficient methodology for constructing complex and diverse compounds from simple and similar precursors. Through the combination of natural product chemistry and DOS, we therefore propose a new approach, diversity-enhanced extracts, for increasing the diversity of natural-product-like compounds. This review describes recent developments toward the production of diverse natural-product-like compounds by DOS based on natural products and direct chemical derivatization of natural extracts, including diversity-enhanced extracts.

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Published online: 14th June, 2018

Short Paper | Special issue | Prepress
DOI: 10.3987/COM-18-S(F)4
Efficient Synthesis of Methyl (S)-4-(1-Methylpyrrolidin-2-yl)-3-oxobutanoate as the Key Intermediate for Tropane Alkaloid Biosynthesis with Optically Active Form

Nanda Kumar Katakam, Cole W. Seifert, John D’Auria,* and Guigen Li*

*Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX 79409-1061, U.S.A.

Abstract

Methyl (S)-4-(1-methylpyrrolidin-2-yl)-3-oxobutanoate has been synthesized for enzymatic studies on cyclization enzymes during cocaine biosynthesis in Erythroxylum coca plants. During the present new synthesis, L-proline was first protected with Cbz group and reduced to chiral amino alcohol, which were then followed by Swern oxidation, Wittig reaction and decarboxylative condensation. At the last step, N-methylamino acid precursor was treated with 1,1’-carbonyldiimidazole followed by reacting with methyl potassium malonate to give the 3-oxobutanoate in 54% overall yield. This new strategy has proven to avoid obvious racemization of the L-proline chiral center during the synthesis. In addition, six of the eight synthesis steps were performed via GAP chemistry/technology without the use of column chromatography for purification.

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Published online: 12th June, 2018

Paper | Special issue | Prepress
DOI: 10.3987/COM-18-S(T)91
Preparation of meso-Silylporphyrins via Nickel-Catalyzed Coupling of meso-Brominated Ni(II) Porphyrins with Silylzinc Reagents

Satoshi Hayashi,* Taiga Endo, and Toshikatsu Takanami*

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

Abstract

In this paper, we developed a technique for the nickel-catalyzed coupling of meso-brominated Ni(II) porphyrins with silylzinc reagents in order to prepare meso-silyl-substituted Ni(II) porphyrins. Porphyrin silylation occurs under mild conditions and exhibits both excellent substrate generality and functional group compatibility.

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Published online: 12th June, 2018

Short Paper | Special issue | Prepress
DOI: 10.3987/COM-18-S(T)75
Synthesis of N-[4-(2'-[18f]Fluoroalkoxybenzoyl)]- and N-(3-[123i]Iodo-4-methoxybenzoyl)pyrrolidin-2-ones As Potential Brain Imaging Agents

Murthy Akula, David Blevins, George Kabalka,* and Dustin Osborne

*Department of Chemistry, University of Tennessee, Knoxville, Tennessee, 37996-1600, U.S.A.

Abstract

The microfluidic synthesis of promising brain imaging PET agents N-[4-(2’-[18F]fluoroalkyloxybenzoyl)]pyrrolidin-2-ones 13a-c was accomplished by nucleophilic radiofluorination of the corresponding tosylate precursors 9a-c with kryptofix-potassium carbonate-[18F]fluoride. Decay corrected radiochemical yields of 35±5% (13a), 38±8% (13b) and 40±5% (13c) were obtained with radiochemical purities of ≥ 93%. The total reaction time, including HPLC purification was 40 min. N-(3-[123I]Iodo-4- methoxybenzoyl)pyrrolidin-2-one, 18, was prepared by radioiododestannylation of tin precursor 17 using Na123I and 0.3% peracetic acid in 84% radiochemical yield in 20 min.

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Published online: 8th June, 2018

Short Paper | Special issue | Prepress
DOI: 10.3987/COM-18-S(T)92
Polymorphism of Macrocyclic Oligothiophehe 8-Mers

Hideyuki Shimizu, Tahmina Haque, Masataka Takashika, Hiroyuki Otani, and Masahiko Iyoda*

*Department of Chemistry, Graduate School of Science and Engineering, Tokyo Metropolitan University, Hachioji, Tokyo 192-0397, Japan

Abstract

Macrocyclic oligothiophene 8-mer E,E-8T6A composed of eight thienylene, six ethynylene, and two vinylene units exhibits unique polymorphism. In the solid state, E,E-8T6A formed nanostructured polymorphs such as single crystals, fibers, long and short rods, and square tubes depending on the solvent used for crystallization. In contrast, E-8T7A with one vinylene unit and 8T8A without vinylene unit afforded single crystals, microcrystalline, and short rods in the solid state. Morphological difference between E,E-8T6A and E-8T7A/8T8A is due to the flexibility of the macroring of E,E-8T6A with two vinylene units, and the shape-persistent but rather flexible E,E-8T6A forms various polymorphs in the solid state.

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Published online: 5th June, 2018

Paper | Special issue | Prepress
DOI: 10.3987/COM-18-S(T)93
Notable Difference between Tetrabutylammonium Fluoride and Organic Superbases as Triggers for the Chemiluminescent Decomposition of Bicyclic Dioxetanes Bearing a 4-(N-Phenylbenzimidazol-2-yl)-3-hydroxyphenyl Moiety

Nobuko Watanabe, Koh Kumagai, Rei Ohtuka, Ayu Wakatsuki, Hisako K. Ijuin, Yoshio Kabe, and Masakatsu Matsumoto*

*Department of Chemistry, Faculty of Science, Kanagawa University, 2946 Tsuchiya, Hiratsuka 259-1293, Japan

Abstract

Chemiluminescent decomposition of bicyclic dioxetanes 3a−3c bearing a 4-(N-phenylbenzimidazol-2-yl)-3-hydroxyphenyl moiety was effectively induced by organic superbases, BTPP [(tert-butylimino)tris-(pyrrolidino)phosphorene], TBD (1,5,7-triazabicyclo[4.4.0]dec-5-ene), MTBD(7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene), DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), and TMG (tetramethylguanidine), as well as TBAF in acetonitrile. Dioxetane 3c bearing a 3,5-dihydroxyphenyl moiety showed diverse chemiluminescence profiles depending on the base used. BTPP caused chemiluminescent decomposition due to the di-oxido anion of dioxetane, while DBU and TMG induced chemiluminescence from the mono-oxido anion of dioxetane. On the other hand, TBAF caused effective chemiluminescence due to the mono-oxido anion, though it acted as a stronger base than BTPP with regard to the rate of decomposition of 3c.

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Published online: 4th June, 2018

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DOI: 10.3987/COM-18-S(T)85
Synthetic Studies toward Isoschizogamine: Construction of Pentacyclic Core Structure

Kenji Sugimoto, Hiroaki Fujiwara, Akihiro Takada, Dong-Gil Kim, Hirofumi Ueda, and Hidetoshi Tokuyama*

*Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai, 980-8578, Japan

Abstract

Development of a concise construction of the pentacyclic core skeleton of isoschizogamine was described. Tetracyclic A,B,D,F-rings structure was assembled by intramolecular aza-Diels–Alder reaction via an ortho-iminoquinone methide intermediate. The C-ring was formed by oxidation of the benzylic position with a combination of Cr(CO)6 and t-BuO2H, followed by the introduction of an aminoethyl side chain, C–H oxidation of the lactam ring with CrO3 and n-Bu4NI, and final cyclization to construct the cyclic aminal moiety.

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Published online: 4th June, 2018

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DOI: 10.3987/COM-18-S(F)6
Synthesis and Cytotoxicity of Novel Bis-Ellipticines and Bis-Isoellipticines

Judy A. Obaza-Nutaitis and Gordon W. Gribble*

*6128 Burke Laboratory, Department of Chemistry, Dartmouth College, Hanover, New Hampshire 03755, U.S.A.

Abstract

A series of bis-ellipticines 79 and bis-isoellipticines 1012 tethered through the indole nitrogen was synthesized and screened for antitumor cytotoxicity in the L-1210 murine leukemia assay. Activity was only displayed by 1,10-bis(6-ellipticinyl)-n-decane (8).

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