HETEROCYCLES

■ Preface
Honoring the 65th Birthday of Professor Barry M. Trost

Alan R. Katritzky

*Gainesville, Florida, USA

■ Preface

Gilbert Stork

*Department of Chemistry, Columbia University, Havemeyer Hall, New York
NY 10027, U.S.A.

■ Biographical Data

Barry M. Trost*

*The Trost Resarch Group, Department of Chemistry, Stanford University, 337 Campus Drive
Stanford, CA 94305-5080, U.S.A.

■ Complete Sequential Listing - B. M. Trost Bibliography

Barry M. Trost*

*The Trost Resarch Group, Department of Chemistry, Stanford University, 337 Campus Drive
Stanford, CA 94305-5080, U.S.A.

■ Direct Comparison of S_N2 Mesylate Displacement versus the Mitsunobu Protocol for 2’,3’-Dideoxyspirocarbanucleoside Construction

Ryan E. Hartung and Leo A. Paquette*

*Evans Chemical Laboratories, The Ohio State University, 120 W. 18th Avenue, Columbus, Ohio 43210, U.S.A.

Abstract

The two title reactions have been evaluated in order to maximize the efficiency with which pyrimidine and purine nucleobases can be introduced into 2’,3’-dideoxyspirocarbanucleosides.

■ Estrogen Receptor Ligands. Part 15: Synthesis of Benzothiopyran-based Selective Estrogen Receptor Alpha Modulators (SERAM)

Seongkon Kim,* Frank DiNinno, Elizabeth T. Birzin, Wanda Chan, Yi Tien Yang, and Milton L. Hammond

*Division of Merck & Co., Inc., Merck Research Laboratories, P.O.Box 2000, Rahway, NJ 07065, U.S.A.

Abstract

Benzothiopyran (2) was prepared and the bioactive (+)-2 was found to exhibit a reduced affinity toward the estrogen receptors (ERα/β) when compared to the corresponding dihydrobenzoxathiin (+)-1.

■ A Palladium Mediated Spiroketal Synthesis

Jeremy C. Conway, Peter Quayle,* Andrew C. Regan, and Christopher J. Urch

*Chemistry Department, University of Manchester, Oxford Road, Manchester, M13 9PL, U.K.

Abstract

A Stork-Negishi olefination-coupling sequence has been applied to the synthesis of spiroketals.

■ Ruthenium-catalyzed ROM-RCM of Cyclopentene-yne. Concise Synthesis of a Pyrrolizidine Derivative

Hideaki Wakamatsu, Yoshihiro Sato, Reiko Fujita,* and Miwako Mori*

*Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12 Nishi 6, Kita-ku, Sapporo, Hokkaido 060-0812, Japan

Abstract

ROM-RCM (Ring-Opening Metathesis and Ring-Closing Metathesis) of cyclopentene-yne having an ester moiety was demonstrated using first- and second-generation Grubbs’ catalysts. When the reaction of cycloalkene-yne was carried out in the presence of 5 mol % of a ruthenium carbene complex under ethylene atmosphere at room temperature, ROM-RCM proceeded smoothly to give a pyrrolidine derivative in good yield, which could be converted to a pyrrolizidine derivative.

■ Immobilized Indolylboron as a Key Intermediate for Solid-Phase Synthesis of Bisindole Alkaloid Analogs

Takahiro Kasahara and Yoshinori Kondo*

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

Abstract

Immobilized indolylboron was easily prepared from resin-bound iodoindole and the subsequent Suzuki coupling reaction was used for the syntheses of bisindole alkaloid analogs.

■ Rhodium-catalyzed Cycloisomerization of Allyl Propargyl Ethers: An Efficient Synthesis of 3,4-Disubstituted Furans

Hiroshi Kawai, Shuichi Oi,* and Yoshio Inoue*

*Graduate School of Engineering, Tohoku University, Aramaki, Aoba-ku, Sendai 980-8578, Japan

Abstract

Cycloisomerization of allyl propargyl ethers was found to be catalyzed by a cationic rhodium complex to give 3,4-disubstituted furans in one step. Addition of carboxylic acids to the reaction improved the yield of the products. Generation of a rhodium hydride species from a rhodium complex with the carboxylic acids followed by hydrorhodation of the substrate with the rhodium hydride species would be involved in the reaction pathway.

■ Synthetic Study of α(2,8) Oligosialoside Using N-Troc Sialyl N-Phenyltrifluoroimidate

Hiroshi Tanaka, Yuji Nishiura, Masaatsu Adachi, and Takashi Takahashi*

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

Abstract

An effective approach for the synthesis of oligo-α(2,8) sialosides using N-Troc sialyl donors is described. Glycosylation of N-Troc sialoside with N-Troc sialyl N-phenyltrifluoroimidate and phosphites smoothly proceeded to provide α(2,8) disialosides in good yield and selectivity.

■ The Mannich-type Reaction between N,O-Acetals and Carbon Nucleophiles under Solvent-free Conditions

Yoshihiro Matsumura,* Takashi Ikeda, and Osamu Onomura

*School of Pharmaceutical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan

Abstract

The Mannich-type reaction for 1-methoxycarbonyl- or 1-benzyloxycarbonyl-2-methoxylpyrrolidine with carbon nucleophiles such as acetylacetone, methyl acetoacetate, dimethyl malonates, benzoylacetone, dibenzoylmethane, or cyclohexane-1, 3-dione proceeded by acid catalysis under solvent-free conditions with more efficiency than that in dichloromethane.

■ Enantioselective Alkylation of Reissert Compounds in Phase Transfer Catalysed Reactions

Danuta Brózda, Krzysztof Hoffman, and Maria D. Rozwadowska*

*Department of Chemistry, Adam Mickiewicz University, ul. Grunwaldzka 6, 60-780 Poznán, Poland

Abstract

Isoquinoline Reissert compounds were alkylated under phase-transfer reaction conditions using chiral quaternary ammonium salts derived from Cinchona alkaloids as catalysts. The best stereoselectivity (ee up to 65%) was achieved in the alkylation of 1-cyano-2-phenoxycarbonyl-1.2-dihydroisoquinoline (1d), catalysed by N-benzylcynchoninium bromide (3a), carried in toluene/50% NaOH biphasic system.

■ Total Synthesis of (+)-1893B Aimed at Establishing Its Stereochemistry

Hiroyuki Yasui, Kunihiro Hirai, Shun Yamamoto, Ken-ichi Takao, and Kin-ichi Tadano*

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

Abstract

The total synthesis of (+)-1893B (2) has been completed. The one-pot ring-opening/cross/ring-closing metathesis of (1S,2S,3S,4R)-2-(t-butyldiphenylsilyloxy)methyl-3-methyl-7-oxabicyclo[2.2.1]hept-5-ene (4) provided (1R,6S,7S,8S)-7-hydroxymethyl-8-methyl-9-oxabicyclo[4.2.1]nona-2,4-diene (6) after deblocking. The epoxy-ring opening of an advanced intermediate (1R,6S,7S,8S)-7-[(1S,2S)-1-methoxymethoxy-2,3-epoxypropyl]-8-methyl-9-oxabicyclo[4.2.1]nona-2,4-diene (11a) with trimethylsilylacetylide, followed by palladium(II)-catalyzed oxidation for construction of the γ-lactone moiety in 2.

■ Synthesis of Optically Active Methyl 1,2,3,3a,8,8a-Hexahydropyrrolo[2,3-b]indole-2-carboxylates Having a Halogen or an Oxygen Functional Group at the 3a-Position

Fumio Yamada, Yoshikazu Fukui, Takako Iwaki, Sachiko Ogasawara, Masaki Okigawa, Satomi Tanaka, and Masanori Somei*

*Division of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma, Kanazawa, Ishikawa 920-1192, Japan

Abstract

A simple and new method for the preparation of optically active methyl 3a-chloro-, 3a-bromo-, 3a-hydroxy-, and 3a-alkoxy-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole-2-carboxylates has been developed.

■ Synthesis of Substituted Pyrimidine Hydrazine Acids (PHA) and Their Use in Peptide Recognition

Stefan Miltschitzky, Veronika Michlova, Stefan Stadlbauer, and Burkhard Koenig*

*Institut für Organische Chemie, Universität Regensburg, Universitätsstraße 31, D-93051, Regensburg, Germany

Abstract

Substituted pyrimidine-hydrazine-acids (PHA) were prepared from orotic acid in five synthetic steps and high yields. Their geometry of hydrogen bond acceptor and donor sites make them suitable for the molecular recognition of peptide β-sheets. In non-protic solvents the PHA unit emits at around 420 nm after irradiation at 281 nm. The emission intensity decreases upon peptide binding and signals the binding event. Peptides consisting of PHAs and natural amino acids or a turn structure motif were prepared. The investigation of the intramolecular binding pattern by NMR spectroscopy revealed the expected interaction of the PHA and peptide β-sheet.

■ A Diversity Oriented Synthesis of 2,10-Dioxo-10H-1,2,3,4,4a,5-hexahydropyridazino[3,2-b]quinazolines

Elisabeth Schuler, Nacho Juanico, Jordi Teixidó, Enrique L. Michelotti, and José I. Borrell*

*Grup d’Enginyeria Molecular, Institut Químic de Sarrià, Universitat Ramon Llull, Via Augusta 390, E-08017 Barcelona, Spain

Abstract

A parallel method for the synthesis of the title compounds is described. Thus, methyl anthranilates (5) are transformed into 2-aminobenzohydrazides (3) which were treated with 4-oxo acids (4) to afford in high yields and acceptable purity of piridazino[3,2-b]quinazolines (1). Compounds (1) present four diversity centers (R₁, R₂, R₃, and R₄). The range of chemically acceptable substituents at each center has been evaluated. The isolation of a possible intermediate in the formation of 1, which presents an aminol structure (10), has allowed proposing a complete mechanistic rationalization for the formation of structures (1).

■ Synthesis of Galloyl-substituted Procyanidin B4 Series, and Their DPPH Radical Scavenging Activity and DNA Polymerase Inhibitory Activity

Hironori Sakuda, Akiko Saito,* Yoshiyuki Mizushina, Hiromi Yoshida, Akira Tanaka, and Noriyuki Nakajima*

*Biotechnology Research Center, Toyama Prefectural University, 5180 Kurokawa, Kosugi, Toyama 939-0398, Japan

Abstract

Synthesis of galloyl-substituted procyanidin B4 series, 3-O-gallate, 3”-O-gallate and 3,3”-di-O-gallate, is described. Condensation of the electrophile derived from (+)-catechin with the nucleophile derived from (-)-epicatechin in the presence of TMSOTf as a catalyst gave procyanidin B4 3-O-gallate and 3,3”-di-O-gallate in good yields. Procyanidin B4 3”-O-gallate and procyanidin B3 3”-O-gallate were synthesized by the DCC method. Their DPPH radical scavenging activity and DNA polymerase inhibitory activity were also investigated. The results indicated that the presence of the galloyl moiety of these compounds is very important for both activities.

■ Chiral Synthesis of (+)-Febrifugine and (-)-Isofebrifugine by Means of Samarium Diiodide-promoted Carbon-Nitrogen Bond Cleavage Reaction

Miho Katoh, Ryuichiro Matsune, and Toshio Honda*

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

Abstract

(+)-Febrifugine, a potential anti-malarial piperidine alkaloid, was synthesized from (4S)-hydroxyproline methyl ester, stereoselectively, where a samarium diiodide-promoted carbon-nitrogen bond cleavage reaction was involved as a key reaction. A stereocontrolled formal synthesis of (-)-isofebrifugine was also described.

■ From Amino Acids to Polycyclic Heterocycles - Synthesis of Enantiopure, Functionally Diverse Isopavines and Dihydromethanodibenzoazocines

Stephen Hanessian,* Clément Talbot, Marc Mauduit, Parthasarathy Saravanan, and Jayapal Reddy Gone

*Department of Chemistry, University of Montreal, 2900 Edouard-Montpetit, Montréal, Québec H3C 3J7, Canada

Abstract

The intramolecular double Friedel-Crafts condensation of N,N-dibenzyl-O-benzyl-L-threoninal affords a rearranged tetracyclic compound involving a methyl migration. N-Demethylation of tetracyclic isopavines leads to topologically unique secondary amines with potential utility in catalytic reactions as a chiral basic ligand.

■ Tandem Palladium-catalyzed Allene Arylation and Oxazoline Formation

Gregory R. Cook* and Wei Xu

*Department of Chemistry, North Dakota State University, Fargo, ND 58105-5516, U.S.A.

Abstract

The tandem palladium-catalyzed addition of aryl iodides to allenes followed by cyclization to afford oxazolines was investigated. A variety of chiral 5-vinyloxazolines were obtained in high yield with excellent stereoselectivity via equilibration of the intermediate π-allylpalladium complex.

■ Coupling of Fischer Carbene Complexes with Alkynylstyrene Oxides: Synthesis of Benzoxepinones in Competition with Internal Oxygen Atom Transfer

Lei Zhang and James W. Herndon*

*Department of Chemistry & Biochemistry, New Mexico State University, P. O. Box 30001, Las Cruces, NM 88003-2505, U.S.A.

Abstract

The coupling of Fischer carbene complexes with conjugated enyne epoxides has been examined. The reaction proceeds by carbene-alkyne coupling to afford an epoxyvinylcarbene complex, which then undergoes CO insertion and cyclization to afford a benzoxepinone or intramolecular oxygen atom transfer to afford a dienone derivative.

■ Synthesis of 4H-3,1-Benzoxazines by the Reaction of o-(N-Acylamino)benzyl Alcohols with DAST

Takehiko Nishio,* Yukiko Kurokawa, Yoshiya Narasaki, and Tatsuhiro Tokunaga

*Department of Chemistry, University of Tsukuba, 1-1-1 Ten-nodai, Tsukuba-shi, Ibaraki 305-8571, Japan

Abstract

The treatment of o-(N-acylamino)benzyl alcohols (1) with DAST afforded the dehydrative cyclization product, 4H-3,1-benzoxazines (4) and the hydroxy replacement product, o-(N-acylamino)benzyl fluorides (5). The yields of benzoxazines (4) and fluorides (5) depend on the substituents at α-position and acyl groups. The treatment of α,α-diaryl-o-(N-acylamino)benzyl alcohols (1a-c) with DAST yielded benzoxazines (4a-c) exclusively, while that of α-monosubstituted o-(N-acylamino)benzyl alcohols (1d-k) with DAST yielded benzoxazines (4d-k) and fluorides (5d-k). In the reaction of o-(N-acylamino)benzyl alcohol (1l) with DAST, the formation of fluoride (5l) became predominant and that of benzoxazine (4l) was suppressed almost completely.

■ A New Synthesis of Acenaphthobenzoporphyrin and Fluoranthobenzoporphyrin

Tetsuo Okujima,* Naoki Komobuchi, Hidemitsu Uno, and Noboru Ono*

*Department of Chemistry, Faculty of Science, Ehime University, 3 Bunkyo-cho, Matsuyama, 790-8577 Ehime, Japan

Abstract

Benzoporphyrins fused with acenaphthylene or fluoranthene (3) and (4) were prepared by the condensation of bicyclo[2.2.2]octadiene(BCOD)-fused tripyrrane (5) with appropriate pyrrole dialdehydes (13) or (14) and the subsequent retro Diels-Alder reaction. The absorptions of these new porphyrins were very intense at both Soret and Q bands, which might be useful as organic dyes for solar cells.

■ A Lewis-Acid Catalyzed Synthesis of Substituted Oxindole Derivatives

Shoko Yamazaki,* Machiko Yamamoto, and Satoshi Morikawa

*Department of Chemistry, Nara University of Education, Takabatake-cho, Nara 630-8528, Japan

Abstract

Lewis acid-catalyzed cyclization of various 2-(N-arylcarbamoyl)-methylenemalonates to give nitrogen-containing benzo-annelated heterocycles was investigated in terms of selectivity. Reaction of substrates with various alkyl groups on nitrogen proceeded to give oxindole derivatives. Cyclization reaction of diester-amides of MeO and halogen-substituted anilines in the presence of catalytic Lewis acid (ZnCl₂, SnCl₄, AlCl₃, Zn(OTf)₂, Sc(OTf)₃, etc.) gave oxindoles in high yields. Interesting regioselectivity was observed for meta-halogen substrates. Dimethoxyisoquinoline analogs were also obtained by this reaction using a catalytic Lewis acid.

■ New Routes to Clavine-type Ergot Alkaloids. Part 1. First Total Synthesis of Three Natural Products: (+)-Setoclavine, (+)-Isosetoclavine, (-)-9,10-Dihydroisosetoclavine, and Structure Correction of the Latter

István Moldvai,* Eszter Temesvári-Major, Eszter Gács-Baitz, Mária Incze, Gábor Dörnyei, and Csaba Szántay*

*Institute of Chemistry, Chemical Research Center, Hungarian Academy of Sciences, H-1525 Budpest II, Pusztaszeri ut 59-67, P.O. Box 17, Hungary

Abstract

The double bond in ring D of (+)-9,10-didehydro-6-methylergolin-8-one (2) was reduced selectively by catalytic hydrogenation to yield (-)-6-methylergolin-8-one (6). Grignard reaction of 6 has been performed with methylmagnesium iodide to afford two isomers (5 and 7). The main isomer having an 8α-methyl group at C8 with a C/D-trans junction (5; (-)-dihydro-isosetoclavine) proved to be identical with the natural product, hence its name and structure should be corrected. As a minor isomer (7) a C/D-cis clavine derivative was also isolated which can be regarded as unnatural (+)-8α-hydroxy-costaclavine. (+)-Setoclavine (8) and (+)-isosetoclavine (9) have also been prepared from 2, thus achieving the first total synthesis of these natural products. Detailed structure elucidation of 5-9 has been carried out as well.

■ An Efficient Synthesis of 2’-O-(β-D-Glucopyranosyl)- and 2’-O-(2-Acetamido-2-deoxy-β-D-glucopyranosyl)-L-biopterins

Tadashi Hanaya,* Kazuyuki Soranaka, Koichiro Harada, Hiroshi Yamaguchi, Ryo Suzuki, Yusumi Endo, Hiroshi Yamamoto, and Wolfgang Pfleiderer

*Department of Chemistry, Faculty of Science, Okayama University, 3-1-1 Tsushima-naka, Okayama 700-8530, Japan

Abstract

N²-(N,N-Dimethylaminomethylene)-3-[2-(4-nitrophenyl)ethyl]-1’,2’-di-O-trimethylsilyl-L-biopterin (6) was prepared from L-biopterin in 5 steps. Glycosylation of 6 with 2,3,4,6-tetra-O-benzoyl-α-D-glucopyranosyl trichloro-acetimidate (9) and 1,3,4,6-tetra-O-acetyl-2-phtalimido-β-D-glucopyranose (10) respectively afforded the corresponding 2’-O-(β-D-glucopyranosyl) derivatives (12b, 12c) as major products. Removal of protecting groups of 12c provided naturally occurring limipterin (2).

■ Synthesis and 2α-Modification of 24-Phenylvitamin D₃ Lactones: Effects on VDR Antagonistic Activity

Nozomi Saito, Toshihiro Matsunaga, Hiroshi Saito, Miyuki Anzai, Kazuya Takenouchi, Daishiro Miura, Seiichi Ishizuka, Hiroaki Takayama, and Atsushi Kittaka*

*Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Teikyo University, 1091-1 Suarashi, Sagamiko-machi, Tsukui-gun, Kanagawa 199-0195, Japan

Abstract

Novel vitamin D receptor (VDR) antagonists, 1α-hydroxy-24-phenylvitamin D₃-26,23-lactones were synthesized by Trost’s methodology. The biological evaluation revealed that both the binding affinity for VDR and antagonistic activity were affected by the orientation of the phenyl group on the lactone ring. The modification of the 2α-position of the 24-phenylvitamin D₃ lactones improved the antagonistic activity up to 41 times higher than that of TEI-9647.

■ Reactions of 2-Triphenylphosphoimino-1-azaazulenes with Aryl Isocyanates and Aryl Isothiocyanates

Kentaro Nagamatsu, Ai Serita, Jun-Hau Zeng, Hiroyuki Fujii, Noritaka Abe,* and Akikazu Kakehi

*Department of Chemistry, Faculty of Science, Yamaguchi University, 1677-1 Yoshida, Yamaguchi 753-8512, Japan

Abstract

Reaction of 2-triphenylphosphoimino-1-azaazulenes (4a-c), prepared from 2-amino-1-azaazulenes, with some aryl isocyanates gave 2-arylimino-3-aryl-2,3,4,4a-tetrahydro-1,3,4a-triazabenz[a]azulen-4-one (6) as major products. Reaction of aryl isothiocyanates gave 2-arylimino-3-aryl-2,3,4,4a-tetrahydro-1,3,4a-triazabenz[a]azulene-4-thiones (10).

■ Platinum Catalyzed H-D Exchange Reaction of Various Aromatic Compounds under Hydrothermal Condition

Mitsuru Yamamoto, Koichiro Oshima, and Seijiro Matsubara*

*Department of Material Chemistry, Graduate School of Engineering, Kyoto University, Kyoudai-katsura, Nishikyo, Kyoto 615-8510, Japan

Abstract

Various aromatic compounds were treated with deuterium oxide under hydrothermal conditions in the presence of a catalytic amount of platinum (IV) oxide. An efficient H-D exchange reaction was observed, which gave various deuterium labeled aromatic compounds.