HETEROCYCLES

■ Frontispiece Drawing

Adam McCubbin*

*Department of Chemistry, The University of Winnipeg, 515 Portage Avenue, Winnipeg, Manitoba, R3B 2E9, Canada

■ Contents

■ The Halogen/Magnesium-Exchange Using iPrMgCl·LiCl and Related Exchange Reagents

Nadja M. Barl, Veronika Werner, Christoph Sämann, and Paul Knochel*

*Department of Chemistry, Institute of Organic Chemistry, Ludwig-Maximilians-University of Munich, Butenandtstr. 5-13 Haus F, D-81377 Munich, Germany

Abstract

We have described the regio- and chemoselective preparation of various (hetero)aryl-Grignard reagents via halogen/magnesium-exchange along with applications of these organometallics in various reactions. The LiCl-mediated halogen/magnesium-exchange proceeds readily under mild conditions and offers the opportunity to convert not only organic iodides, but less activated organic bromides, as well. Furthermore, this exchange tolerates a broad spectrum of sensitive functionalities such as triazenes, methyl esters, silylated cyanohydrins, alcohols and acrylates. Electron-rich aryl derivatives can be converted into the corresponding Mg-species by using more activated bis-alkylmagnesium compounds. Subsequent functionalization reactions such as cross-couplings, allylations, acylations, addition reactions to ketones, cyclization reactions, fluorinations, disulfenylations, aminations as well as sulfoxide/magnesium-exchange reactions have been performed, readily furnishing highly functionalized derivatives as well as biologically active heterocycles.

■ Syntheses of Chiral Heterocyclic Compounds via Zirconium-Catalyzed Asymmetric Carboalumination of Alkynes (ZACA Reaction)

Shiqing Xu and Ei-ichi Negishi*

*Herbert C. Brown Laboratories of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, Indiana 47907-2084, U.S.A.

Abstract

Shortly after the Zr-catalyzed carboalumination of alkynes was discovered in 1978, we sought expansion of the scope of this reaction so as to develop its alkene version for catalytic asymmetric C–C bond formation, namely the ZACA (Zr-catalyzed asymmetric carboalumination of alkenes). However, the discovery of such an asymmetric reaction proved to be quite challenging. The ZACA reaction was finally discovered in 1995 by suppressing three unwanted side reactions, i.e., (i) cyclic carbometalation, (ii) β-H transfer hydrometalation, and (iii) alkene polymerization, represented by the Ziegler-Natta polymerization. Three mutually complementary procedures for the enantioselective synthesis of methyl-substituted 1-alkanols have been developed, which allow highly flexible designs for the syntheses of chiral organic compounds. This review summarizes the syntheses of chiral heterocyclic compounds of biological and medicinal interest via ZACA reaction, which provides a widely applicable, efficient and selective method for catalytic asymmetric C–C bond formation.

■ Electrochemical Behaviour of Alkaloids: Detection and Interaction with DNA and Proteins

Martina Zatloukalová, Jan Vacek, and Vilím Šimánek*

*Department of Medical Chemistry and Biochemistry, Faculty of Medicine and Dentistry, Palacký University, Hnevotínská 3, 77515 Olomouc, Czech Republic

Abstract

Electroanalysis can provide valuable information on the molecular interactions, biological activity and pharmacological potential of alkaloids. This article summarizes current knowledge on the electrochemical properties of a broad spectrum of alkaloids using polarography and voltammetry. Alkaloid interactions with DNA and proteins using electrochemical techniques are also described. More than 100 references published in the last 70 years are reviewed.

■ Synthesis of the ABCD Ring System of Vinca Alkaloids Using Tandem Intramolecular [2+2]Photocycloaddition-Retro-Mannich Fragmentation

James D. White* and Yang Li

*Department of Chemistry, Oregon State University, Gilbert Hall 153, Corvallis, Oregon 97331, U.S.A.

Abstract

Irradiation of 3-alkyl indole 20 gave spiropyrroline 22 via [2+2]-photocycloaddition and subsequent in situ retro-Mannich fragmentation of fused cyclobutane 21. N-Alkylation of 22 followed by treatment of the resulting pyrrolinium salt with sodium hydride and lithium diisopropylamide generated a dienolate dianion, e.g. 24, which underwent cyclization to afford tetracyclic products 25, 27 and 30. The configuration of 25 was proven by a series of NMR experiments which established that ring C in the major stereoisomer resides in a boat conformation. Tetracycles 25, 27, and 30 contain structural features including the ABCD ring system and substituents found in certain alkaloids of the Vinca family.

■ Synthesis of p-tert-Butylcalix[4]thiacrowns Exhibiting Sulfur Number-Dependent Complexation with Mercury(II) Ion

Tatsuya Takimoto,* Hirohito Tsue, Hiroki Takahashi, Rui Tamura, and Hideaki Sasaki

*Faculty of Pharmaceutical Sciences, Kobe Gakuin University, 1-1-3 Minatojima, Chuo-ku, Kobe 650-8586, Japan

Abstract

A novel synthetic pathway to calix[4]thiacrowns 3 and 4 has been developed. NMR studies revealed that the complexation behavior of 3 and 4 with mercury(II) ion was controlled by the number of sulfur atoms involved in the thiacrown moiety.

■ A Catalytic C-C Bond-Formation with Minimal Use of Protecting Groups: Construction of Functionalized Isotetronic Acid Derivatives

Yohei Shimizu,* Kouji Yasuda, and Motomu Kanai*

*Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan

Abstract

A catalytic method to construct multi-functionalized isotetronic acids was developed using cyclic hemiacetals and pyruvic acid derivatives as substrates. The key to success was the combination of catalytic amounts of iron(III) trifluoroacetate and 2-mercaptopyridine. A catalytic asymmetric variant was also developed using 6,6’-dimethoxy-binaphthyl phosphate instead of 2-mercaptopyridine.

■ 1,3-Dipolar Cycloaddition of Pyridynes and Azides: Concise Synthesis of Triazolopyridines

Nozomi Saito,* Ken-ichi Nakamura, and Yoshihiro Sato*

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

Abstract

1,3-Dipolar cycloaddition of pyridynes and organic azides was investigated. Thus, 3,4-pyridynes and 2,3-pyridynes were reacted with various organic azides under mild conditions to afford the corresponding [1,2,3]triazolo[4,5-c]pyridines and [1,2,3]triazolo[4,5-b]pyridines, respectively. In the case of the reaction of 3,4-pyridyne, it was also found that a substituent on the pyridine ring affected the regioselectivity of the cycloaddition.

■ Biomimetic Synthesis of Antrodia Maleimides and Maleic Anhydrides

John Boukouvalas* and Vincent Albert

*Pavillon Alexandre-Vachon, Department of Chemistry, Laval University, 1045 Avenue de la Médecine, Quebec City, Quebec G1V 0A6, Canada

Abstract

A simple and efficient biomimetic synthesis of Antrodia maleimides and maleic anhydrides, including the HCV protease inhibitor antrodin A, is described. The key step is a Perkin-type condensation performed under exceptionally mild conditions.

■ Chiral Memory Units Based on Dynamic Redox Systems with a Dibenzoxepinone Skeleton: Drastic Change in Racemization Barrier and Electrochemical Bistability

Kazuhisa Wada, Yuna Chiba, Takashi Takeda, Hidetoshi Kawai, Ryo Katoono, Kenshu Fujiwara, and Takanori Suzuki*

*Division of Chemistry, Graduate School of Science, Hokkaido University, Kita 10 Nishi 8, Kita-ku, Sapporo, Hokkaido 060-0810, Japan

Abstract

The configuration of helical dicationic dyes 22+ with a dihydrodibenzoxepinone unit is stable, whereas the corresponding neutral electron donors 1 with a tetrahydrophenanthroxepinone skeleton easily undergo ring-flip. Thanks to their electrochemical bistability, electron exchange between 1 and 22+ is prohibited. Thus, the above electrochromic pairs 1/22+ can serve as new members of less well-explored redox-based chiral-memory units.

■ A Simple Route to Functionalized Δ1-Pyrrolenines

Matilda Bingham, Cécile Moutrille, and Samir Z. Zard*

*Department of Chemistry, Ecole Polytechnique, CNRS UMR 7652, 91128 Palaiseau, France

Abstract

Treatment of γ-unsaturated oxime esters with cupric acetate or ferric chloride in acetic acid / t-butanol or in t-butanol alone leads to the formation of vinyl- or chloroalkyl- substituted Δ1-pyrrolines in moderate to good yield.

■ No Catalyst, Radical Initiator and Photochemical Irradiation Approach to Direct α-Trifluoromethylation of Lithium Enolates

Yuichi Tomita, Toshiaki Iida, Ryota Hashimoto, Yoshimitsu Itoh, 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

Heterocyclic lactam lithium enolates exploit an access to the electrophilic radical α-trifluoromethylation without catalyst/radical initiator/photochemical irradiation.

■ Improved Synthesis of the A-E Ring Segment of Ciguatoxin CTX3C

Kengo Shiroma, Hiroki Asakura, Tokihiro Tanaka, Hiroyoshi Takamura, and Isao Kadota*

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

Abstract

The improved synthesis of the A-E ring segment of ciguatoxin CTX3C was performed via a highly convergent approach based on intramolecular allylation-RCM methodology.

■ Development of Method for the Efficient α-Oxidation of tert-Alkylamines Using bis(2,2,2-Trichloroethyl) Azodicarboxylate

Shinobu Honzawa,* Mitsuaki Uchida, and Takumichi Sugihara*

*Department of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, 265-1, Higashi-jima, Akiha-ku, Niigata 956-8603, Japan

Abstract

An efficient α-oxidation of amines can be accomplished using bis(2,2,2-trichloroethyl) azodicarboxylate, which is more electrophilic than diethyl azodicarboxylate, often used in synthetic chemistry. N-Acetyl and N-tert-butoxycarbonylamines are good substrates for this α-oxidation, and in the case of N-phenylpyrrolidine an interesting dimerization reaction is followed by α-oxidation. The α-oxidation product can be transformed in the presence of nucleophiles and a Lewis acid to α-modified amines, presumably via an iminium intermediate.

■ Asymmetric Synthesis of Tertiary 2-Substituted 5-Oxotetrahydrofuran-2-carboxylic Acids

Anne Paju, Karolin Oja, Katharina Matkevitš, Priit Lumi, Ivar Järving, Tõnis Pehk, and Margus Lopp*

*Department of Chemistry, Tallinn University of Technology, Akadeemia tee 15, Tallinn, Estonia

Abstract

3-Substituted 1,2-cyclopentanediones 1 were transformed to 2-substituted 5-oxotetrahydrofuran-2-carboxylic acids 2 using a catalytic process with 0.2-0.3 equivalent of Ti(OiPr)4/tartaric ester/tBuOOH complex in up to 72% isolated yield and up to 94% ee. Different functional groups in the 3-alkyl substituent of 1 like, hydroxy, ether, Boc-amino and ester groups are tolerated. Boc-aminomethyl substituents lead to β-amino acid analogues and Boc-aminoethyl substituent to γ-amino acid analogues as well as spiro-lactone-lactams. A direct, two-step procedure for homocitric acid synthesis is described.

■ Synthesis of 2-Substituted 1,3-Cycloheptanedione via a Lewis Acid Mediated Ring Expansion Reaction

Kohei Inomata* and Yasuyuki Endo*

*Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan

Abstract

We have established a new route to provide 2-substituted 1,3-cycloheptanediones via a Lewis acid mediated ring expansion reaction of cyclobutanones as the key step. The ring expansion reactions were mediated by a series of Lewis acids. Among the used Lewis acids, ZnI2 was the most practical mediator. This route has succeeded in providing the title compounds even on a multi-gram scale. During the research, the Baeyer-Villiger oxidation of the cyclobutanones to obtain the new bicyclic lactones was also examined. The regioselective oxidation was observed in the case of chlorinated cyclobutanones.

■ Synthesis and Antimicrobial Evaluation of Oxazole-2(3H)-thione and 2-Alkylsulfanyl-1,3-oxazole Derivatives

Sandrina Silva,* Filipa V. M. Silva, Jorge Justino, Amélia Pilar Rauter, Patrick Rollin, and Arnaud Tatibouët

*Department of Chemistry, University of Orléans, rue de Chartres- BP 6759, F-45067 Orléans Cedex 2, France

Abstract

The preparation of oxazole-2(3H)-thiones (OXTs) by condensation of thiocyanic acid on α-hydroxycarbonyl substrates has been revisited. Extension to more complex scaffolds afforded chiral OXTs, whereas carbohydrate-fused 2-alkylsulfanyl-1,3-oxazolines led to original hemiaminal structures. A survey of the reactivity of OXTs with various electrophiles showed S- or N-chemoselectivity based on HSAB parameters. Antimicrobial evaluation of selected synthesized compounds was carried out, from which the hemiaminal 15 emerged as a promising antifungal agent.

■ A Deoxypodophyllotoxin-Based Sensor for Highly Selective Recognition of Hg2+ Ion

Juanjuan Wang, Yuanyuan Yan, and Hui Xu*

*Laboratory of Pharmaceutical Design & Synthesis, College of Life Sciences, Northwest A & F University, Xinong Road 22#, Yangling, Shaanxi, 712100, China

Abstract

A new deoxypodophyllotoxin-based probe 1 was prepared. Based on a selective and irreversible Hg2+-promoted desulfurization reaction, compound 1 exhibited high selectivity towards Hg2+ ion over other metal ions, accompanied by transformation of an arylthiocarbamate moiety (green-yellow) to an arylcarbamate one (colorless). The present study may open up a new opportunity for development of natural-product-based probes for selective detection of some specific metal ions.

■ Lewis Acid Catalyzed Diastereoselective 1,3-Dipolar Cycloaddition between Diazoacetoacetate Enones and Azomethine Ylides

Phong M. Truong, Michael D. Mandler, Charles S. Shanahan, and Michael P. Doyle*

*Department of Chemistry and Biochemistry, University of Maryland, 7950 Baltimore Avenue, College Park, MD 20742, U.S.A.

Abstract

Silver acetate catalyzed 1,3-dipolar cycloaddition reactions of diazoacetoacetate enones and azomethine ylides produce tetrasubstituted pyrrolidines bearing a diazoacetoacetate functional array in excellent yields and diastereoselectivities. The installment of the diazoacetoacetate functional array allows access to diverse hetereocyclic scaffolds.

■ Zinc-Acetic Acid Promoted Reductive Carbon-Nitrogen Bond Cleavage Reaction of α-Aminoketones

Kyoko Ishikawa, Miyuki Tomatsu, Hiroshi Nagase, and Hideaki Fujii*

*Laboratory of Medicinal Chemistry, School of Pharmacy, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan

■ Regioselective Multicomponent Domino Reactions Providing Rapid and Efficient Routes to Fused Acridines

Jin-Peng Zhang, Wei Fan, Jie Ding, Bo Jiang,* Shu-Jiang Tu,* and Guigen Li

*School of Chemistry and Chemical Engineering, Jiangsu Key Laboratory of Gree Synthetic Chemistry for Functional Materials, Jiangsu Normal University, Jiangsu 221116, China

Abstract

Regioselective three-component reactions of aromatic aldehydes with indazol-5-amine and 2-hydroxy-1,4-naphthoquinone in HOAc under microwave irradiation have been developed. In this one-pot reaction, a series of new pyrazole-fused benzo[h]acridine derivatives with 1,2-diketone unit were synthesized with high chemical yields. The resulting pyrazole-fused acridines were employed to further react with aldehydes and ammonium acetate to give polycyclic oxazole-fused pyrazolo[3,4-j]acridines. The present green synthesis shows several advantages including operational simplicity and fast reaction rates, which makes it a useful and attractive process of library generation for drug discovery.

■ Photochemical Reactions of Prop-2-enyl and Prop-2-ynyl Substituted 4-Aminomethyl- and 4-Oxymethyl-2(5H)-furanones

Diego A. Fort, Thomas J. Woltering, André M. Alker, and Thorsten Bach*

*Lehrstuhl für Organische Chemie, Technische Universität München, Lichtenbergstrasse 4, D-85747 Garching, Germany

Abstract

Compounds with a heterocyclic 9-oxa¬tricyclo[5.3.0.01,5]decan-8-one skeleton were synthesized by intramolecular [2+2] photocycloaddition reactions of the title compounds (λ = 254 nm, Et2O or MeCN as the solvent). Starting from various substituted 4-(prop-2-enylaminomethyl)-2(5H)-furanones, products 5, 9, 18, 21, 23, 24 were obtained, which bear a nitrogen atom in position 3 of this skeleton within a pyrrolidine ring. The Boc or Cbz groups represent suitable nitrogen protecting groups, which were compatible with the irradiation conditions and which can be easily cleaved. In an analogous fashion an oxygen (product 22) and carbon substituent (product 25) could be implemented at position 3 of the product if the starting material was appropriately chosen. The prop-2-ynyl substituted substrates did not produce a [2+2] photocycloaddition product but rather underwent a cyclization to spiro products 11 and 13.

■ The Paecilin Puzzle ‒ Enantioselective Synthesis of the Proposed Structures of Paecilin A and B

Lutz F. Tietze,* Ling Ma, Stefan Jackenkroll, Johannes R. Reiner, Judith Hierold, Boopathy Gnanaprakasam, and Sven Heidemann

*Institute of Organic and Biomolecular Chemistry, University of Göttingen, Tammannstr. 2, D-37077 Göttingen, Germany

Abstract

For the synthesis of the two diastereomers 3c and 3d of the proposed structure of paecilin B (3) phenol 19, containing an alkenyl moiety, was treated with Pd(II) in the presence of the chiral BOXAX ligand 9b to give 20 with 96% ee. A subsequent Sharpless dihydroxylation afforded two isomeric diols, which were further transformed into 31 and 32. The final steps included removal of the silyl protecting group with simultaneous lactone formation, oxidation and cleavage of the methyl ether. For the preparation of the dimeric paecilin A (1) brominated intermediate 38 was treated with (Bpin)2, S-Phos and Pd(OAc)2. The spectroscopic data of the new compounds did not match those of the isolated natural products.

■ Rotational Energy Barrier around the C1–C11 Single Bond in Lamellarins: A Study by Variable-Temperature NMR

Tsutomu Fukuda, Ryosuke Itoyama, Terufusa Minagawa, and Masatomo Iwao*

*Division of Chemistry and Materials Science, Graduate School of Engineering, Nagasaki University, 1-14, Bunkyo-machi, Nagasaki 852-8521, Japan

Abstract

In order to estimate the free energy barrier to rotation around the C1–C11 single bond in lamellarins, new lamellarin analogues (1a), (1b), (2a), and (2b) possessing diastereotopic protons or carbons at the C1 aryl moiety were synthesized. Variable-temperature 1H and 13C NMR measurements of these analogues revealed that the free energy barriers to rotation around the C1–C11 axis in 5,6-saturated and 5,6-unsaturated lamellarins were around 72–74 and 83–87 kJ/mol, respectively.

■ Formation of Unexpected Heterocyclic Products from Pyrolysis of Thiocarbonyl Stabilised Phosphonium Ylides

R. Alan Aitken,* Graeme Barker, Lee P. Cleghorn, Euan J. Reid, and Sheryl S. Roberts

*School of Chemistry, University of St. Andrews, North Haugh, St Andrews, Fife KY 16 9ST, U.K.

Abstract

Chiral phthalimido thioxo-stabilised phosphonium ylides, prepared starting from (S)-alanine and (S)-phenylalanine, undergo intramolecular Wittig reaction upon pyrolysis leading to the previously unknown pyrrolo[2,1-a]isoindol-5-one-2-thiones, rather than the expected P to S migration of a phenyl group. Pyrolysis of thioxo-stabilised ylides with three different groups on phosphorus gave some evidence of the required migration, but led in one case to unexpected formation of a 1,4-benzoxaphosphininium salt.

■ Aminophenylpyrrole Synthesis and Application to Pyrrolo[1,2-c]quinazolinone Synthesis

Aurélie A. Dörr and William D. Lubell*

*Department of Chemistry, University of Montreal, CP 6128, Succursale-Centre-Ville
Montreal, Quebec, H3C 3J7, Canada

Abstract

Aminophenylpyrroles have been synthesized by a three-step route from methyl N-(Boc)anthranilate (2). Amine protection of commercially available methyl anthranilate (1) gave Boc-protected methyl ester 2, which reacted with vinylmagnesium bromide in the presence of a catalytic amount of copper (I) cyanide to yield 1-[2-N-(Boc)aminophenyl]pent-4-en-1-one (3) in 43% yield. Oxidation of homoallylic ketone 3 using either a mixture of OsO4•NaIO4 and 2,6-lutidine, or PdCl2-CuCl under oxygen atmosphere gave respectively aldehyde 4 and ketone 5. Treatment of 1,4-dicarbonyl compounds 4 and 5 with ammonium formate as well as primary amines under Paal-Knorr conditions afforded a set of eight 2-[2-N-(Boc)aminophenyl]pyrroles 6a-d and 7a-d. In addition, treatment of 2-[2-N-(Boc)aminophenyl]-1H-pyrrole 6a with NaH provided a novel entry to pyrrolo[1,2-c]quinazolin-5(6H)-one 8.

■ Enantioselective Synthesis of Tetrahydroquinoline Alkaloids (-)-Angustureine and (-)-Cuspareine from Chiral tert-Butanesulfinyl Imines

Juan A. Sirvent, Francisco Foubelo,* and Miguel Yus*

*Department of Organic Chemistry, Faculty of Sciences and Institute of Organic Synthesis (ISO), University of Alicante, P.O. Box 99, 03080 Alicante, Spain

Abstract

The addition of a Grignard reagent to both enantiomeric N-tert-butanesulfinyl imines derived from 3-(2-bromophenyl)propanal 8 proceeded with high diastereoselectivity. The resulting sulfinamides 9 and 12 were easily transformed into tetrahydroquinoline alkaloids (-)-angustureine (4) and (-)-cuspareine (5) after three steps: N-desulfinylation, intramolecular N-arylation and N-methylation.

■ Total Synthesis of the Proposed Structures of Eushearilide

Takayasu Yamauchi,* Jun-ichi Takidaira, Kenya Okamoto, Takaya Sugiura, Hiroki Horikoshi, Shintaro Kudo, Shigeru Sasaki, Noriko Mizushima, and Kimio Higashiyama

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

Abstract

Total synthesis of (3R,16Z,20E,23S)- and (3R,16Z,20E,23R)-eushearilide was accomplished in 15 steps, respectively. Using either enantiomer of one of the four building blocks to assemble the phosphonium salt for the latter Wittig reaction, two diastereomers of eushearilide were prepared. Shiina macrolactonization (2-methyl-6-nitrobenzoic anhydride) was a key step in production of the 24-membered lactone in high yield.

■ Cycloaddition Reactions of Azide, Furan, and Pyrrole Units with Benzynes Generated by the Hexadehydro-Diels–Alder (HDDA) Reaction

Junhua Chen, Beeraiah Baire, and Thomas R. Hoye*

*Department of Chemistry, University of Minnesota, 207 Pleasant Street S. E., Minneapolis, MN 55455, U.S.A.

Abstract

Benzynes can be generated by the intramolecular thermal cycloisomerization of triynes–the title HDDA reaction. We report here that these can be trapped by cycloaddition reaction with trimethylsilyl azide (1,3-dipolar) or a furan or pyrrole (4+2 Diels–Alder).