HETEROCYCLES

■ Contents

■ Production of Unnatural Bioactive Glycosides Using Plant Secondary Product Glycosyltransferases

Sayaka Masada and Hajime Mizukami*

*Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan

Abstract

Plant glycosyltransferases mediate transfer of a glycosyl residue from activated nucleotide sugars to lipophilic small molecules, thus affecting the solubility, stability and pharmacological activities of the compounds. Biotechnological application of the plant glycosyltransferases in glycoside synthesis has attracted attention recently. This review describes the in vivo and in vitro glycosylation of natural organic compounds using the glycosyltransferases, focusing on our current investigation for enzymatic synthesis of curcumin glycosides.

■ Ring Transformations of 2H-Pyran-2-ones and Fused Pyran-2-ones with Nucleophilic Reagents

Franc Pozgan and Marijan Kocevar*

*Department of Organic Chemistry, Faculty of Chemistry and Chemical Technology, University of Ljubljana, Askerceva 5, P.O. Box 537, SI-1000 Ljubljana, Slovenia

Abstract

In this review we report on several recently described nitrogen- and carbon-nucleophile-induced ring transformations of selected pyran-2-one derivatives. These reactions provide convenient routes for the synthesis of different heterocycles and carbocycles as well as β-heteroaryl-α,β-didehydroamino acid derivatives.

■ The Lycopodium Alkaloids

Yusuke Hirasawa, Jun'ichi Kobayashi, and Hiroshi Morita*

*Faculty of Pharmaceutical Sciences, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan

Abstract

Lycopodium alkaloids are unique heterocyclic alkaloids having C11N, C15N2, C16N, C16N2, C22N2, and C27N3 types from genus Lycopodium and have attracted great interest from biogenetic and biological points of view as well as providing challenging targets for total synthesis. This review covered the structure elucidation and biological activity of new Lycopodium alkaloids and total synthesis of some Lycopodium alkaloids reported in the literature from 2004 to July in 2008.

■ A Novel Δ-Thiolactone Scaffold by a Versatile Intramolecular Multicomponent Reaction

Stuti Srivastava, Barbara Beck, Eberhardt Herdtweck, Kareem Khoury, and Alexander Dömling*

*Department of Pharmaceutal Science and Chemistry, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, U.S.A.

Abstract

The three component reaction of α-aminoacids, mercaptoacetaldehyde and an isocyanide smoothly and stereoselectively yields the novel scaffold 1,2-disubstituted N-alkyl(aryl)-6-oxo thiomorpholine-3-carboxamide. In this communication we present our preliminary results on six compounds derived from this unprecedented reaction.

■ Novel Photoinduced Electron Transfer-initiated Cyclization of 1,2,4-Triazole-substituted α-Dehydronaphthylalaninamides in the Presence of Triethylamine

Kei Maekawa, Atsushi Tomod, Tetsutaro Igarashi, and Tadamitsu Sakurai*

*Material and Life Chemistry, Faculty of Engineering, Kanagawa University, 3-27-1 Rokkakubashi, Kanagawa-ku, Yokohama 221-8686, Japan

Abstract

The irradiation of the title compounds [(Z)-1] in nitrogen-saturated methanol containing triethylamine (TEA) at room temperature was found to quantitatively afford 2(1H)-benzo[f]quinolinone (2) and 3,4-dihydro-3-(3-methyl-5-substituted 1,2,4-triazol-4-yl)-2(1H)-benzo[f]quinolinone (3) derivatives, which were described as being formed via electron transfer from TEA to the excited-state (E)-1. Analysis of solvent and substituent effects on the composition ratio of 2 to 3 confirmed that this ratio is increased from 0.2 to 9.0 with an increase in the proton-donating ability and polarity of solvent as well as in the electron-withdrawing ability of substituent bonded to the triazole ring.

■ First Synthesis of Biopterin α-D-Glucoside

Tadashi Hanaya,* Hiroki Baba, and Hiroshi Yamamoto

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

Abstract

A novel glycosyl donor, 4,6-di-O-acetyl-2,3-di-O-(4-methoxybenzyl)-α-D-glucopyranosy bromide (15) was efficiently prepared from D-glucose in 8 steps. The first synthesis of 2’-O-(α-D-glucopyranosyl)biopterin (2) was achieved by treatment of the key precursor, N²-(N,N-dimethylaminomethylene)-1’-O-(4-methoxybenzyl)-3-[2-(4-nitrophenyl)ethyl]biopterin (6) with 15 in the presence of silver triflate and tetramethylurea, followed by removal of the protecting groups.

■ Preparation of Unsymmetric Phthalocyanines with Benzylchalcogeno and Butoxy Groups

Takeshi Kimura,* Takeru Obonai, and Toshiharu Namauo

*Center for Instrumental Analysis, Iwate University, 4-3-5 Ueda, Morioka, Iwate 020-8551, Japan

Abstract

A mixture of 4,5-dibenzylchalcogeno-3,6-diethylphthalonitrile and 4,5-dibutoxyphthalonitrile was treated with lithium in n-pentanol at 110 °C to give unsymmetric phthalocyanines. Optical and electrochemical properties of them were examined by UV-vis spectroscopy and cyclic voltammetry.

■ Synthetic Studies of Mangostin Derivatives with an Inhibitory Activity on PDGF-Induced Human Aortic Smooth Cells Proliferation

Yuko Nishihama, Takahisa Ogamino, Wen Lei Shi, Byung-Yoon Cha, Takayuki Yonezawa, Toshiaki Teruya, Kazuo Nagai, Kiyotake Suenaga, Je-Tae Woo, and Shigeru Nishiyama*

*Department of Chemistry, Faculty of Science and Technology, Keio University, Hiyoshi, Kohoku-ku Yokohama 223-8522, Japan

Abstract

The mangostin derivatives 3-10, were synthesized by halogenation, electrochemical oxidation, and mCPBA oxidation of α- and γ-mangostins (1, 2). Among them, the hydroxyl 9 and the benzopyran 10 derivatives produced by mCPBA, showed remarkable antiproliferative activities against human aortic smooth muscle cells (HASMC) induced by platelet-derived growth factor (PDGF).

■ Friedel-Crafts Reaction of Indole Derivatives Using the Iminium Salt Generated by the Oxidation of Amino Ketene Silyl Acetal

Takuya Iwao and Makoto Shimizu*

*Department of Chemistry for Materials, Faculty of Engineering, Mie University, 1577 Tsu, Mie 514-8507, Japan

Abstract

Friedel-Crafts reaction of various indole derivatives proceeded with the iminium salt generated by the oxidation of amino ketene silyl acetal to give the addition products in good yields. Further reaction of the introduced glycine moiety of the adducts with the second nucleophiles provided double nucleophilic addition products.

■ Synthesis of Sundiversifolide and Diversifolide via a Diastereoselective [3+2] Nitrile Oxide Cycloaddition Reaction

Hiroyuki Sasaki, Hiromasa Yokoe, Mitsuru Shindo, Masahiro Yoshida, and Kozo Shishido*

*Faculty of Pharmaceutical Sciences, University of Tokushima, 1-78 Sho-machi, Tokushima 770-8505, Japan

Abstract

The enantioselective synthesis of the unnatural enantiomers (-)-sundiversifolide and (+)-diversifolide has been accomplished employing a diastereoselective intramolecular [3+2] nitrile oxide cycloaddition reaction as the key step.

■ Polymethylated γ-Carbolines with Potent Anti-bovine Viral Diarrhea Virus (BVDV) Activity

Hiroshi Aoyama,* Kumiko Sako, Shinichi Sato, Masahiko Nakamura, Hiroyuki Miyachi, Yukinori Goto, Mika Okamoto, Masanori Baba,* and Yuichi Hashimoto

*Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan

Abstract

Several anti-BVDV agents with a polymethylated γ-carboline skeleton were synthesized, and their anti-BVDV activity was evaluated. The most potent antiviral agent, SK3M4M5M (20), was synthesized by Pd-catalyzed Buchwald-Hartwig amination reaction followed by annulation reaction as key steps. The structure-activity relationship was analyzed.

■ Construction of Cyclopentyl Carbinols from ω-Tosyloxy-1-alkenyl Boronate Esters and Grignard Reagents

Yuichi Kobayashi,* Moriteru Asano, and Yohei Kiyotsuka

*Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama 226-8501, Japan

Abstract

Addition of RMgCl (R = n-Bu, Ph) to pinacol esters of 6-tosyloxy-1-alkenyl boronic acids at -78 °C gave the borates, which upon warming to room temperature underwent migration of R on boron to C(1) carbon and concomitant ring construction C-C bond formation between C(2) and C(6), eventually producing cyclopentyl alkyl (or aryl) carbinols after oxidative workup of the borane intermediates with 35% H₂O₂. Eight examples are presented and the reaction was applied to construction of a cyclohexyl carbinol.

■ Uncariagambiriine and Gambircatechol: Novel Constituents of Uncaria gambir Leaves

Naomi Yoshikado, Shoko Taniguchi, Naoki Kasajima, Fumiaki Ohashi, Kou-Ichi Doi, Takashi Shibata, Takashi Yoshida, and Tsutomu Hatano*

*Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushima-naka, Okayama 700-8530, Japan

Abstract

Two new polyphenolic compounds, uncariagambiriine (1) and gambircatechol (2), were isolated from Uncaria gambir leaves, along with dehydrodicatechin A (3), catechin-(8→6’)-catechin (4), catechin-(6→6’)-catechin (5), and (+)-catechin (6). The structures of the new compounds, one of which is composed of an indole alkaloid and (+)-catechin, were established based on spectroscopic data.

■ 2,2-Disubstituted Propionic Anhydrides: Effective Coupling Reagents for the Kinetic Resolution of Secondary Benzylic Alcohols Using BTM

Isamu Shiina,* Kenya Nakata, Masuhiro Sugimoto, Yu-suke Onda, Takashi Iizumi, and Keisuke Ono

*Department of Applied Chemistry, Faculty of Science, Science University of Tokyo, Kagurazaka 1-3, Shinjuku-ku, Tokyo 162-8601, Japan

Abstract

A variety of optically active benzylic alcohols possessing aliphatic substituents at the C-1 position are produced by the kinetic resolution of racemic secondary alcohols using free carboxylic acids with 2,2-disubstituted propionic anhydrides and (+)-benzotetramisole (BTM). Evaluation of the efficiency of this asymmetric esterification using several anhydrides derived from aliphatic carboxylic acids were carried out by comparing the efficiencies of the kinetic resolution of (±)-1-phenyl-1-propanol. It was found that not only pivalic anhydride is a very widely usable reagent to produce the corresponding esters with high ee’s in the presence of BTM, but other 2,2-disubstituted propionic anhydrides, such as 2-methyl-2-phenylpropionic anhydride (MPPRA) and 2,2-diphenylpropionic anhydride (DPPRA), are also applicable as effective coupling reagents for producing the optically active esters and alcohols with high selectivities. This protocol directly provides chiral carboxylic esters from free carboxylic acids and racemic secondary alcohols by utilizing the transacylation process to generate mixed anhydrides from the acid components and sterically hindered carboxylic anhydrides.

■ Reaction of 9-Germaphenanthrene with Dimethyl Acetylenedicarboxylate: Unexpected Formation of a 1,2-Oxagermolane Derivative

Yoshiyuki Mizuhata, Koji Inamura, and Norihiro Tokitoh*

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

Abstract

The reaction of 9-germaphenanthrene with dimethyl acetylenedicarboxylate (DMAD) in benzene afforded a 1:2 adduct containing 1,2-oxagermolane and cyclopentadiene units, the structure and generation mechanism of which are discussed based on X-ray structural analysis and theoretical calculations.

■ Asymmetric Lewis Acid Catalysis of Aluminum (Salalen) Complexes: Friedel-Crafts Reaction of Indole

Keitaro Suyama, Kazuhiro Matsumoto, and Tsutomu Katsuki*

*Department of Chemistry, Graduate School, Faculty of Science, Kyushu University, 6-10-1 Hakozaki, Higashi-ku, Fukuoka 812-8581, Japan

Abstract

We examined the Lewis acid catalysis of chiral Al(salalen)X complexes and found that complex 1b (X = Br) serves as an efficient catalyst for the Friedel-Crafts reaction of indole with N-[(E)-alkenoyl]oxazolidin-2-ones. High enantioselectivity (up to 98% ee) was obtained under the optimized conditions.

■ Reaction of N_β-Benzylserotonin with α,β-Unsaturated and Aryl Aldehydes in the Presence of a Base

Koji Yamada, Yuichi Namerikawa, Takumi Abe, and Minoru Ishikura*

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

Abstract

The reaction of N_β-benzylserotonin with α,β-unsaturated and aryl aldehydes in the presence of a base produced 1H-azepino[5,4,3-cd]indoles.

■ Synthesis of 2-Methylene-tetrahydropyran-3-ol Derivative, a Key Segment for Convergent Synthesis of Polycyclic Ethers Based on Suzuki-Miyaura Coupling

Tomohiro Kimura, Yasuyo Miyagawa, Shingo Ozawa, Mayumi Hagiwara, and Tadashi Nakata*

*Department of Chemistry, Faculty of Science, Tokyo University of Science, Kagurazaka 1-3, Shinjuku-ku, Tokyo 162-8601, Japan

Abstract

2-Methylene-tetrahydropyran-3-ol derivative, a key segment for convergent synthesis of polycyclic ethers based on Suzuki-Miyaura coupling, was efficiently synthesized by two methods; (1) via SmI₂-induced reductive cyclization of β-alkoxyvinyl sulfone with aldehyde followed by elimination of the sulfonyl group, and (2) via SmI₂-induced cyclization of β-alkoxyvinyl sulfoxide with aldehyde followed by dehydration of the 2-hydroxymethyl group.

■ Synthesis and Electrochromic Properties of Bis(2-tetrathiafulvalenylethynylphenyl)ethynes

Masashi Hasegawa, Yusuke Kobayashi, Kenji Hara, Hideo Enozawa, and Masahiko Iyoda*

*Graduate School of Science, Tokyo Metropolitan University, 1-1, Minami-ohsawa, Hachioji, Tokyo 192-0364, Japan

Abstract

Bis(2-tetrathiafulvalenylethynylphenyl)ethynes 1a and 1b have been synthesized by the Sonogashira coupling reaction of 4-iodotetrathiafulvalenes with bis(2-ethynylphenyl)ethyne. The dimeric TTFs 1a and 1b form an open-chain anti conformation in the neutral and tetracation states, whereas 1a and 1b form a helical syn conformation in the mono- and dication states owing to their face–to–face interaction between the two TTF units. Such conformational changes lead to unique electrochromic and on–off switching properties of 1a and 1b in UV–vis–NIR spectra.

■ Direct and Stereoselective Synthesis of 2-Azido-2-deoxy-β-D-mannosides Using the Phosphate Method

Seiichi Nakamura, Toshifumi Tsuda, Noritoshi Suzuki, and Shunichi Hashimoto*

*Laboratory of Synthetic and Industrial Chemistry, Graduate School of Life Science, Division of Life Science, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12, Nishi 6, Kita-ku, Sapporo, Hokkaido 060-0812, Japan

Abstract

TMSOTf-promoted glycosidation of 2-azido-3-O-benzyl-4,6-O-benzylidene-2-deoxy-α-D-mannosyl diphenyl phosphate with a variety of acceptor alcohols in CH2Cl2 at –30 °C in the presence of pulverized 4-Å molecular sieves (MS) afforded 2-azido-2-deoxy-β-mannosides in high yields and with good to high β-selectivities.

■ The Facile Synthesis of 6-Azapurines by Transformation of Toxoflavins (7-Azapteridines)

Tomohisa Nagamatsu,* Jun Ma, and Fumio Yoneda

*Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushima-naka, Okayama 700-8530, Japan

Abstract

This paper describes a reliable and facile synthesis of 6-azapurines (1,5-dimethyl-1H-imidazo[4,5-e][1,2,4]triazin-6(5H)-ones) by treatment of toxoflavins (7-azapteridines) with 10% aqueous sodium hydroxide at 5–25 °C along with a benzilic acid type rearrangement, followed by decarboxylation and oxidation by air. Furthermore, heating the 6-azapurines in 10% ethanolic sodium hydroxides afforded the corresponding 1,2,4-triazine-5,6(1H,4H)-diones to be caused by ring fission of the imidazole of 6-azapurines.

■ Flexible Access to Monoterpenoid Indole Alkaloids Using a Cyclopentanoid Chiral Building Block

Masato Hayashi, Keiichi Motosawa, Atsushi Satoh, Masatoshi Shibuya, Kunio Ogasawara, and Yoshiharu Iwabuchi*

*Pharmaceutical Institute, Tohoku University, Aobayama, Sendai 980-8578, Japan

Abstract

Expedient, diasterocontrolled transformations of 1 to the key synthetic intermediate of corynanthe, iboga, and aspidosperma-class of monoterpenoid indole alkaloids which led up to a formal synthesis of (+)-20R-dihydrocleavamine, (–)-eburnamonine, and a total synthesis of (+)-aspidospermidine (2) have been demonstrated.

■ Synthesis of New Chiral 5,6,7,8-Tetrahydrotetrazolo[1,5-a]pyrazines from α-Amino Acid Derivatives Following “Click“ Chemistry

Debendra K. Mohapatra,* Pradip K. Maity, Ravindra V. Ghorpade, and Mukund K. Gurjar

*Division of Organic Chemistry, National Chemical Laboratory, Pashan Road, Pune 411 008, India

Abstract

An efficient and practical synthesis of new chiral fused tetrazoles have been synthesized following [3+2] cycloaddition reaction starting from α-amino acid derivatives.

■ A Tetracarbonyl Paal Knorr Approach to Semicorrins

Anna Innitzer and Johann Mulzer*

*Institute of Organic Chemistry, University of Vienna, Währingerstraße 38, A-1090 Vienna, Austria

Abstract

A semicorrin model system was prepared via a novel twofold Paal-Knorr type cyclization of a tetracarbonyl precursor which was obtained from an aldol reaction between virtually identical partners, readily available from one and the same precursor.

■ Synthesis and Properties of Benzene-fused Diporphyrins with Various Metals

Hidemitsu Uno,* Masakazu Hahimoto, and Akiko Fujimoto

*Integrated Center for Science, Ehime University, Bunkyo-cho 2-5, Matsuyama 790-8577, Japan

Abstract

Various metalloporphyrins bearing a dihydroethanoisoindole unit were prepared by the inverse-type [3+1] porphyrin synthesis of a bicyclo[2.2.2]octadiene[BCOD]-connected dipyrrole with tetrahydrotripyrrin- dicarbaldehyde followed by metallation. Another [3+1] porphyrin synthesis of the pyrrole-connected porphyrins followed by the second metallation afforded BCOD-connected diporphyrins with different metals. Thermal conversion of the BCOD skeleton into benzene moiety gave π-system-fused diporphyrin with the different metals in a highly pure form.

■ Transformations of Diethyl 2-[(Dimethylamino)methylene]-3-oxopentanedioate. A simple Synthesis of Substituted 2-Amino-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidine-8-carboxylates

Silvo Zupancic, Jurij Svete, and Branko Stanovnik*

*Department of Organic Chemistry, Faculty of Chemistry and Chemical Technology, University of Ljubljana, Askerceva 5, P.O. Box 537, SI-1000 Ljubljana, Slovenia

Abstract

Diethyl 2-[(dimethylamino)methylene]-3-oxopentanedioate (2), prepared from acetone-1,3-dicarboxylates (1) and N,N-dimethylformamide dimethyl acetal (DMFDMA) was, without isolation, transformed by treatment with guanidine hydrochloride into ethyl 2-amino-4-(2-ethoxycarbonylmethyl)pyrimidine-5-carboxylate (3). Compound 3 was transformed with DMFDMA first into intermediate 4 and with an excess of DMFDMA into ethyl 4-[1-(dimethylamino)-3-ethoxy-3-oxoprop-1-en-2-yl]-2-[(dimethylamino)methyleneamino]pyrimidine-5-carboxylate (5). By treatment of compound 5 with ammonia, primary amines, hydrazine or hydroxylamine intermediates 6a-j were formed, which cyclized into 6-substituted 2-amino-5-oxo-5,6-dihydropyrido[4,3-d]pyridine-8- carboxylates (7a-j).

■ Studies toward the Total Synthesis of Carba Analogue of Motif of M. TB Cell Wall AG Complex

Mukund K. Gurjar,* Challa Nageswar Reddy, Uttam R. Kalkote, and Mukund S. Chorghade

*Division of Organic Chemistry, National Chemical Laboratory, Pashan Road, Pune 411 008, India

Abstract

Herein we describe the synthesis of the carba analogue of motif C of arabinogalactan complex present in M. tuberculosis cell wall. Pd(0) catalyzed allylic alkylation and Fraser-Reid’s glycosidation are the two key reactions that were employed for the synthesis of central glycosyl accepter unit and the glycosylation respectively.

■ Chirality Control of Tropos Diphenylmethane-derived Phosphoramidites by Chiral Dienes: Its Application to Asymmetric Michael Addition

Kazuki Wakabayashi, Kohsuke Aikawa, and Koichi Mikami*

*Department of Applied Chemistry, Graduate School of Science and Technology, Tokyo Institute of Technology, 2-12-1 Ookayama, Meguro-ku, Tokyo 152-8552, Japan

Abstract

The Rh complex of tropos diphenylmethane-derived phosphoramidite could be chirally controlled to adopt single chiral conformation upon addition of a chiral diene. In the asymmetric Michael addition of α-cyanocarboxylates catalyzed by the Rh complexes, the chiral diene and bisphenylmethane-derived phosphoramidite functioned to attain higher enantioselectivity and catalytic activity via asymmetric activation.

■ A Short Total Synthesis of (+)-Cryptocarya Diacetate

Mukund K. Gurjar,* N. Raghupathi, adn Mukund S. Chorghade

*Division of Organic Chemistry, National Chemical Laboratory, Pashan Road, Pune 411 008, India

Abstract

A short synthesis of (+)-cryptocarya diacetate was achieved by employing three component linchpin coupling, diastereoselective reduction of β-hydroxyketone, and Z-selective HWE reaction as key transformations.