HETEROCYCLES

■ Preface

Steven V. Ley

*University of Cambridge, UK

■ Biographical Data

Leo A. Paquette*

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

■ Publications of Leo A. Paquette

Leo A. Paquette*

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

■ Regioselectivity of Intramolecular Nitrile Oxide-Allene Cycloadditions

David G. J. Young* and Dongxiang Zeng

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

Abstract

Studies on the intramolecular nitrile oxide–allene cycloaddition are reported. The reaction shows a preference for reaction of the more remote π–bond.

■ Acid-mediated Cyclization of 3-Benzoyl-2-cyanobutyronitrile to 2-Amino-4-methyl-5-phenylfuran-3-carbonitrile

Susumu Watanuki,* Shuichi Sakamoto, Hironori Harada, Kazumi Kikuchi, Takahiro Kuramochi, Ken-ichi Kawaguchi, Toshio Okazaki, and Shin-ichi Tsukamoto

*Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., 21, Miyukigaoka, Ibaraki 305-8585, Japan

Abstract

Cyclization of 3-benzoyl-2-cyanobutyronitrile to 2-amino-4-methyl-5-phenylfuran-3-carbonitrile was effected under acidic conditions, rather than the basic conditions previously reported. Since treatment with trifluoroacetic acid (TFA) at room temperature is very mild, 2-amino-4-methyl-5-phenylfuran-3-carbonitriles containing various functional groups can be accessed via this route.

■ Solid-Phase Synthesis of Cyclic Glycopeptides Related to Mannopeptimycin Derivatives

Ting-Zhong Wang,* Karen L. Wheless, Alan G. Sutherland, and Russell G. Dushin

*Chemical Development, Wyeth Research, Middletown Rd. Pearl River, NY 10965, U.S.A.

Abstract

The mannopeptimycins comprise a novel series of glycopeptide antibiotics that display activity against susceptible and resistant forms of gram-positive bacteria. Low isolated yields of these products from fermentation make the synthesis of easily accessible analogs attractive. A simplified hexapeptide is synthesized using a combination of solid-phase and solution-phase techniques.

■ Synthesis of the Key Intermediates for the Core 3,4-Dihydroisocoumarin Structures of AI-77-B and Apicularen from ortho-Metallated Dianions of t-Butylbenzamides and Functionalized Epoxides

Bo-Sung Kwon and Jinsung Tae*

*Department of Chemistry, Yonsei University, 134 Shinchon-Dong, Seodaemun-Ku, Seoul 120-749, Korea

Abstract

3,4-Dihydroisocoumarins functionalized with alkoxy substituents were efficiently synthesized from dianions generated by ortho-metallation of t-butylbenzamides with alkoxy substituted epoxides.

■ Reactions of Arylhalocarbenes with Vinyl Isocyanates

James H. Rigby* and Mona Aasmul

*Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, MI 48202, U.S.A.

Abstract

A variety of aryhalocarbenes were reacted with 1-cyclohexene-1-isocyanate to provide insight into the factors that control [4+1] versus [2+1] cycloaddition reactivity.

■ Synthesis and Mercurophilic Properties of 5,8,14,17-Tetraoxa-2,11,20-trithiabicyclo[19.4.1]hexacosa-21,23,25-trien-26-one

Kanji Kubo,* Akira Mori,* and Tatsuya Nishimura

*Graduate School of Engineering Sciences, Kyushu University, 6-1, Kasuga-koen, Kasuga 816-8580, Japan

Abstract

Base-mediated condensation reaction of 2,7-dibromotropone with 3,6,12,15-tetraoxa-9-thiaheptadecane-1,17-dithiol afforded 1:1 and 2:2 condensates (4 and 5). Troponoid trithiocrown ether (4) was used as a carrier through a chloroform liquid membrane. However, the guest selectivity of 4 was lower than that of the corresponding dithiocrown ether derivative (1e).

■ Endoperoxidation of 9,10-Bis(1-hydroxyalkyl)anthracenes and Successive Formation of 9,10-Anthraquinone under Grignard Reaction Conditions

Shigeyasu Kuroda,* Mitsunori Oda,* Hiroki Syumiya, Shah M. I. Shaheen, Ryuta Miyatake, Teruhiko Nishikawa, Akiko Yoneda, Tokiko Tanaka, Masaru Mouri, and Mayumi Kyogoku

*Department of Applied Chemistry, Faculty of Engineering, Toyama University, Gofuku 3190, Toyama 930-8555, Japan

Abstract

The reaction of anthracene-9,10-carboaldehyde with various Grignard reagents under ambient conditions gave 9,10-bis(1-hydroxyalkyl)anthracene-9,10-peroxides and 9,10-anthraquinone as the first example. The endoperoxidation of 9,10-bis(1-hydroxyalkyl)anthracenes was assisted by the lone paired electron of oxygen in the side chain, and the endoperoxides were transformed to anthraquinone by the Grignard reagents.

■ Total Syntheses of Natural Pseurotins A and F₂ and Azaspirene

Shin-ya Aoki, Takahiro Oi, Kazuya Shimizu, Ryota Shiraki, 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

Total syntheses of natural pseurotins A (1) and F₂ (8-O-demethylpseurotin A) (2) and structurally related azaspirene (3), each possessing a novel heterospirocyclic system, i.e., 1-oxa-7-azaspiro[4.4]non-2-ene-4,6-dione skeleton, have been accomplished starting from D-glucose.

■ Aldol Reactions of Unsubstituted β-Lactams. Studies of a β-Glycine Enolate Equivalent

David R. Williams,* Andrew F. Donnell, and David C. Kammler

*Department of Chemistry, Indiana University, 800 E. Kirkwood Avenue, Bloomington, IN 47405-7102, U.S.A.

Abstract

Aldol reactions of the lithium enolate of N-(4-methoxybenzyloxy)azetidin-2-one (1) were examined. High diastereoselectivity favoring the anti adduct was observed with achiral aldehydes. Modest α-stereocontrol with chiral aldehydes was realized. Application of this method for the efficient synthesis of novel β-amino esters is also described.

■ Synthesis in the Plakortone Series: Plakortone E

Patricia Y. Hayes and William Kitching*

*Department of Chemistry, School of Molecular and Microbial Sciences, The University of Queensland, St. Lucia, Brisbane, Queensland 4072, Australia

Abstract

A Pd(II)-mediated hydroxycyclisation-carbonylation-lactonisation sequence has operated efficiently with racemic enediol (8) to furnish (four) separable diastereomers of the bicyclic lactone system assigned to the sponge-derived, bioactive plakortone E. All four are cis ring-fused, and one is identical, on the basis of ¹H and ¹³C NMR spectroscopic comparisons, with plakortone E, thus confirming its constitution and relative stereochemistry about the bicyclic lactone core. This synthetic approach, when applied to stereoisomer (13), will establish the absolute stereochemistry of plakortone E, likely to be that shown for (14).

■ A Unified Approach to the Enantioselective Synthesis of 2,6-cis and trans Disubstituted Tetrahydropyranones

Michael T. Crimmins,* Caroline J. Diaz, and Kyle A. Emmitte

*Department of Chemistry, University of North Carolina, Chapel Hill, NC 27599-3290, U.S.A.

Abstract

A stereoselective construction of cis- and trans-2,6-disubstituted tetrahydropyranones, based on strategy which combines an asymmetric alkylation and ring closing metathesis for the formation of a cyclic enol ether, is reported.

■ A Stereocontrolled Synthesis of Hapalosin

Tetsuta Oshitari, Saiyinbilige, and Tadakatsu Mandai*

*Department of Chemistryand Bioscience, Kurasiki University of Science & the Arts, 2640 Nishinoura, Tsurajima-cho, Kurashiki 712-8505, Japan

Abstract

A facile synthetic method for two components of hapalosin, that is, β-hydroxy-γ-amino acid and β-hydroxy acid, has been established by utilizing chiral building blocks efficiently resolved in a lipase-catalyzed transesterification. Furthermore, the synthesis of hapalosin through macrolactamization of the seco acid derived from these two components and (S)-2-hydroxy-3-methylbutyric acid has thus been demonstrated.

■ Synthesis of Pyrrolopyrimidine CRF-R1 Antagonists Containing a Tricyclic Core via an Intramolecular Heck Reaction

Brian Dyck* and James R. McCarthy

*Department of Medicinal Chemistry, Neurocrine Biosciences, Inc., 10555 Science Center Drive, San Diego, CA 92121, U.S.A.

Abstract

A synthetic route to pharmaceutically important tricyclic pyrrolopyrimidines was developed. The method employs a palladium-mediated Heck cyclization as the critical step in the construction of the final six membered ring.

■ Synthesis of 2-Arylbenzothiazoles from 2-Aminobenzenethiol and Aryl Aldehydes Catalyzed by Scandium Triflate

Takashi Itoh, Kazuhiro Nagata, Hiroyuki Ishikawa, and Akio Ohsawa*

*School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan

Abstract

2-Aminobenzenethiol and an aryl aldehyde reacted to give a benzothiazoline via an imine intermediate, and the benzothiazoline was aromatized by oxygen or hydrogen peroxide to give a high yield of 2-arylbenzothiazole in the presence of a catalytic amount of scandium triflate Sc(OTf)₃. The intermediary benzothiazoline was isolated and allowed to react with O₂ or H₂O₂ in the presence of Sc(OTf)₃, and the Lewis acid was found to also catalyze the oxidative process other than the ring closing step.

■ Heterocycle Fused Cyclohexylglycine Derivatives as Novel Dipeptidyl Peptidase-IV Inhibitors

Anthony Mastracchio,* Emma R. Parmee, Barbara Leiting, Frank Marsilio, Reshma Patel, Nancy A. Thornberry, Ann E. Weber, and Scott D. Edmondson

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

Abstract

A new class of potent inhibitors of dipeptidyl peptidase IV (DP-IV) for the treatment of type II diabetes are described. Presented herein is the synthesis of indole-fused and thiazole-fused cyclohexylglycines. Pyrrolidine-derived amides of these novel heterocycles led to the discovery of thiazole derivatives (3f) and (11a), both low nanomolar inhibitors of DP-IV (IC₅₀ = 6 nM).

■ Synthesis of New Potentially Antiviral Furan-fused Compounds by Thermolysis of Benzocyclobutene Derivatives

Yuji Matsuya, Hongbo Qin, Mamiko Nagaoka, and Hideo Nemoto*

*Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama, Toyama 930-0194, Japan

Abstract

New potentially antiviral furan-fused tetracyclic compounds were prepared using intramolecular cycloaddition of o-quinodimethane generated by thermolysis of benzocyclobutene derivatives. It was found that the reaction course was changed depending on the length of alkyl chain connecting quinodimethane and furan ring.

■ Photo-induced C-C Bond Formation of 1,3-Dimethylthymine and Its Related Compounds with Naphthalene

Kazue Ohkura, Tetsuya Ishihara, Yasunobu Nakata, and Koh-ichi Seki*

*Central Institute of Radio Isotope Science, Hokkaido University, Kita 15 Nishi 7, Kita-ku, Sapporo, Hokkaido 060-0815, Japan

Abstract

UV-Irradiation of 1,3-dimethylthymine (1a) and naphthalene (2) resulted in C-C bond formation through 1,4-cycloaddition to give cis-ethenobenzoquinazoline (3) in high stereoselectivity and in fair yield. Similar irradiation of 1,3-dimethyluracil and its derivatives with a substituent at C-5 underwent cycloaddition to give the corresponding barrelene derivatives in fair yields.

■ A Uniquely Accessible Route to the Diastereoselective Synthesis of Azetine Derivatives

Narendra B. Ambhaikar, Marike Herold, and Dennis C. Liotta*

*Department of Chemistry, Emory University, 1521 Pierce Drive Atlanta, Georgia 30322, U.S.A.

Abstract

In the diastereoselective additions of chlorotitanium enolate of N-propionylthiazolidine-2-thione (2) to nitriles via the corresponding N-metalloaldimines (Al, B, Zr as metals), thiazolidine-2-thioneazetines (3) are preferentially formed over the dihydropyrimidinones (4), with the ratios of compounds (3/4) ranging from 5:1 to 17:1 (for R = phenyl, 1-naphthyl and 2-thienyl).

■ Enantioenriched Axially Chiral β-Diketimines: Determination of the IAN-amine Barrier to Atropisomerization

Sarah B. Cortright, Ryan A. Yoder, and Jeffrey N. Johnston*

*Department of Chemistry, Indiana University, 800 E. Kirkwood Avenue, Bloomington, IN 47405-7102, U.S.A.

Abstract

Enantioenriched (>98% ee) β-diketimines derived from Isoquinoline and 2-Amino Naphthalene (‘IAN-amines’) were prepared. Thermal racemization of a series of R-IAN amines (R = NH₂, NHMe, NMe₂) revealed a high barrier to atropisomerization (~30 kcal/mol) and its relative insensitivity to substitution at the aminonaphthalene nitrogen. Molecular mechanics calculations accurately predicted the observed relative substituent effects.

■ Preferential Conformation of the Six-membered Cyclic Compounds Bearing Both Trimethylsiloxy(or Methoxymethyleneoxy) and Tributylstannyl Groups at the Geminal Position

Michimasa Goto, Yukihiro Kotani, Kiyoshi Kida, Shuji Tomoda, and Yoshimitsu Nagao*

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

Abstract

The preferential conformer and conformer ratio in the cyclohexane, oxane, and thiane derivatives bearing both trimethylsiloxy (or methoxymethyleneoxy) and tributylstannyl groups at the geminal position were determined on the basis of their ³J(¹¹⁹Sn-¹³C) coupling constants and ¹³C NMR spectral analyses at low temperature.

■ Computational Study on Conformational Features of Protonated 5H,7H-Dibenzo[b,g][1,5]dithiocin Oxides by ab initio MO Calculations

Keiji Okada, Masato Tanaka, and Katsuo Ohkata*

*Department of Chemistry, Faculty of Science, Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima, Hiroshima 739-8526, Japan

Abstract

The ab initio MO calculations with HF/6-31G* basis set were performed in the neutral 5H,7H-dibenzo[b,g][1,5]dithiocin 12-oxide (1), the mono-protonated (1-H⁺) and the di-protonated (1-2H⁺) sulfoxides. The calculations indicated that the protonation is very important process for the 1,5-oxygen shift and the oxygen atom approaches to another sulfur by protonation. The inside oxygen conformation (the TB_i or the BB_i) is important for the intramolecular oxygen shift to form the oxygen-bridged intermediate in 1-2H⁺-BB_b, and the outside oxygen conformation (the TB_o or the BB_o) is the most probable conformation to form the sulfurane intermediate in 1-2H⁺-BB_o and 2-2H⁺-BB_o, respectively.

■ Facial Selectivity in Nucleophilic Epoxidation of 3-Aryl-2-phosphonoacrylates Induced by the (-)-8-Phenylmenthyl Moiety as a Chiral Auxiliary

Shahnaz Begum, Md. Moshfiqur Rahman, Ryukichi Takagi, and Katsuo Ohkata*

*Department of Chemistry, Faculty of Science, Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima, Hiroshima 739-8526, Japan

Abstract

Stereoselectivity was investigated in the epoxidation of (-)-8-phenylmenthyl E-3-aryl-2-phosphonoacrylates (2a-d) with hydrogen peroxide and potassium carbonate to give the corresponding epoxides (3a-d). The reaction of the E-isomeres gave the corresponding trans-epoxy derivatives with the moderately higher diastereoselectivity as the major diastereomers as compared with that of the cis isomers.

■ Geometrically Selective Synthesis of Sulfur-containing Heterocycles by Intramolecular Pd-catalyzed Sulfinylzincation

Naoyoshi Maezaki,* Suguru Yagi, Jun Maeda, Ryoko Yoshigami, and Tetsuaki Tanaka*

*Graduate School of Pharmaceutical Science, Osaka University, 1-6 Yamadaoka, Toyonaka, Osaka 560-0043, Japan

Abstract

A new method to synthesize cyclic sulfoxide derivatives was developed utilizing Pd-catalyzed sulfinylzincation, which proceeds with high syn-selectivity under mild conditions. The resulting vinylzinc species reacted with electrophiles such as proton, allyl bromide, and benzoyl chloride to afford a single geometric isomer.

■ Synthesis and Electrospray Ionization Mass Spectrometric Evaluation of the Metal Cation Complexation Behavior of Cage-annulated Azacrown Ethers

Alan P. Marchand,* Zilin Huang, Huiguo Lai, Artie S. McKim, Jennifer S. Brodbelt,* and Sheldon Williams

*Department of Chemistry, University of North Texas, NT Station, P.O. Box 305070, Denton, TX 76203-5070, U.S.A.

Abstract

Six new cage-annulated azacrown ethers (1 - 6) have been prepared, and their respective abilities to function as alkali metal cation and/or heavy metal cation complexants have been assessed via application of electrospray ionization mass spectrometry (ESI-MS) techniques. All of these host systems bind to H⁺; however, they also generally display a high degree of selectivity toward complexation with Ag⁺.

■ Stereoselective Zirconocene-mediated Ring Transformation of 2-Vinylheterocycles to Vinylcarbocycles

Yuji Hanzawa,* Hiromichi Kiyono, and Takeo Taguchi

*School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan

Abstract

Stereoselective ring transformation of 2-vinylheterocycles to vinylcarbocycles was efficiently carried out by the use of a zirconocene equivalent (“Cp₂Zr”). The transformation proceeded through an intramolecular allylation of Z-allylic zirconocene species to the epoxide or aziridine ring.

■ Acylation and Alkoxycarbonylation of Benzoxazoline-2-thione and Benzothiazoline-2-thione

Takehiko Nishio* and Kiyoko Shiwa

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

Abstract

Acylation of benzoxazoline-2-thione (1) and benzothiazoline-2-thione (2) with acetic anhydride (3) and acyl chlorides (4) gave N-acyl (5, 6) and/or S-acyl (7, 8) derivatives depending on the nature of acylating agents and bases used. Alkoxycarbonylation of 1 with aralkyl chlorocarbonates (9) gave N-alkoxycarbonyl derivatives (10) mainly, while that of 2 with aralkyl chloroccarbonates (9) gave S-alkoxycarbonyl derivatives (12) exclusively. Photolysis of N-acyl derivatives (5 or 6) in the presence of alcohols afforded 1 or 2, respectively, together with esters (16).

■ Oxidative Addition of Chloro- and Dichloroacetic Acid to Alkenes to Give α-Chloro- and α,α-Dichlorobutyrolactones with Manganese(III) Acetate

Barry B. Snider* and Qinglin Che

*Department of Chemistry, Brandeis University, 415 South Street, Waltham, MA 02454-9110, U.S.A.

Abstract

Oxidative addition of chloroacetic acid and dichloroacetic acid to alkenes with Mn(OAc)₃ to give α-chloro- and α,α-dichlorobutyrolactones proceeds in moderate to good yield in MeCN containing one equivalent of the sodium salt of the carboxylic acid.