HETEROCYCLES

■ Viridobrunnines A and B, Antimicrobial Phenoxazinone Alkaloids from A Soil Associated Streptomyces sp.

Xiu Mei Zhang, Xu Liu, Zhe Wang, Zhen Hua Tian, and Wei Dong Xie*

*Department of Pharmacy, Marine College, Shangdong University at Weihai, Wenhua Xilu 180, Weihai 264209, China

Abstract

Chemical investigation of a Streptomyces sp. strain designated A1302 isolated from soil sample led to the discovery of two new phenoxazinone alkaloids, viridobrunnines A and B (1 - 2), along with two known analogues exfoliazone (3) and chandrananimycin D (4). Their structures were established by means of spectroscopic methods. The antibacterial and antifungal activity of isolated compounds was assayed. Viridobrunnine B (2) exhibited potent antibacterial activity against Bacillus subtilis with inhibition zone from 13 mm to 15 mm.

■ Recent Developments of Free-Radical Substitutions of Heteroaromatic Bases

Francesco Minisci,* Elena Vismara, and Francesca Fontana

*Dipartimento di Chimica, Politecnico di Milano, Piazza Leonardo da Vinci 32, 20133 Milano, Italy

Abstract

The most recent mechanistic and synthetic aspects of the substitution of protonated heteroaromatic bases by nucleophilic carbon-centered radicals are reviewed. From mechanistic point of view the following aspects are discussed; i ) Structurereactivity relationship; i i ) Rearomatization of the radical adducts; iii) Solvent and isotope effects; iv) Overlap area with ionic reactions. The synthetic developments concern the following topics: i) Selectivity with carbonyl radicals; ii) Alkyl iodides as sources of alkyl radicals; iii) Alkylation by carboxylic acids; iv) Vinylation by olefins; v) Oxyalkylation by ethers; vi) Catalytic processes; vii) Substitution with strongly nucleophilic radicals.

■ Survey of Oxygenated 2,11-Cyclized Cembranoids of Marine Origin

Patrick Bernardelli and Leo A. Paquette*

*Evans Chemical Laboratories, The Ohio State University, Columbus, OH 43210, U.S.A.

Abstract

The structure, source, and biological activities of the many known members of the four classes of oxygenated 2,11-cyclized cembranoid natural products are compiled in tabular form. The cladiellins, briarellins, asbestinins, and sarcodictyins have been purposefully organized to highlight biological activity interrelationships.

■ Brevisulcatic Acids from a Marine Microalgal Species Implicated in a Toxic Event in New Zealand

Raku Irie, Rina Suzuki, Kazuo Tachibana, Patrick T. Holland, D. Tim Harwood, Feng Shi, Paul McNabb, Veronica Beuzenberg, Fumiaki Hayashi, Huiping Zhang, and Masayuki Satake*

*Department of Chemistry, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan

Abstract

Ladder-frame polyethers, known as brevisulcatic acids (BSXs) -1 (1), -2 (2), -4 (3), -5 (4) and -7 (5), were isolated from the dinoflagellate Karenia brevisulcata as potential causative toxins of a harmful algal event in New Zealand in 1998. The structures of 2, 4, and 5 were elucidated in this study. Brevisulcatic acids possessed a common fused nine ether-ring backbone, with a size and sequence determined to be 8/6/8/9/7/7/6/6/6. Rings B, C, H, I and J of the brevisulcatic acids were similar to those of brevetoxin A, a well-known polyether toxin. BSX-5 (4) had a γ-lactone as the 5-membered A-ring, analogous to brevetoxin A, while in BSX-2 (2) and BSX-7 (5) the lactone was present in its seco-acid form. In addition to this backbone variation, there were also some structural difference in side-chain substituents, with 2 and 4 having a 2-methylenepropionic acid unit, and 5 a 2-methylenepropanol unit. Cytotoxicity of 4 against neuroblastoma cells indicated that not only the structures but also activity of brevisulcatic acids are similar to those of brevetoxin A. This indicates that brevisulcatic acids potentially played a significant role in the toxicity observed during the only documented Karenia brevisulcata bloom to date.

■ Cyclic Carboxylic Imide Structures as Structure Elements of High Stability. Novel Developments in Perylene Dye Chemistry

Heinz Langhals

*Institut für Organische Chemie, Universität München, Karlstrasse 23, D-80333 München, Germany

Abstract

Cyclic carboxylic imides are structure elements in aromatic heterocycles with high persistency. Their attachment to perylene leads to the perylene dyes; the synthesis and unique properties of the dyes are reported and discussed. An extension of the principle to other aromatics is made.

■ A Highly Efficient Synthetic Route to (-)-Furaquinocin C

Amos B. Smith, III*, José Pérez Sestelo, and Peter G. Dormer

*Department of Chemistry, University of Pennsylvania, 231 South 34th Street Philadelphia, PA 19104, U.S.A.

Abstract

The first total synthesis of (-)-furaquinocin C, a member of the furaquinocin family of cytotoxic antibiotics, has been achieved. Central features of the successful synthetic strategy include Diels-Alder construction of the furanonaphthoquinic skeleton and sequential cuprate-mediated conjugate additions to an α,β-unsaturated lactone. The synthetic route proved remarkably efficient requiring only six steps from (R)-(+)-angelicalactone, and utilizing a mere four reaction vessels. This stereospecific construction of (-)-furaquinocin C confirms earlier assignments of absolute and relative stereochemistry for the furaquinocins and also constitutes completion of a formal synthesis of (-)-furaquinocin F.

■ Curriculum Vitae

Ekkehard Winterfeldt

*Institute of Organic Chemistry, University of Hannover, Schneiderberg 1B, D-30167 Hannover, Germany

■ Tuning the Solubilities of Bis-triazinylphenanthroline Ligands (BTPhens) and Their Complexes

Dominic M. Laventine, Ashfaq Afsar, Michael J. Hudson, and Laurence M. Harwood*

*Department of Chemistry, University of Reading, Reading RG6 6AD, U.K.

Abstract

A series of bis-triazinylphenanthroline ligands (BTPhens) was synthesized by modifying the triazine substituents. It was found that varying these substituents altered the solubilities of the ligands in a number of non-polar solvents. Thus C5-BTPhen showed significantly higher solubility in octanol than C1-BTPhen. The high solubility of C5-BTPhen and its complexes was exploited to facilitate the NMR titration experiments. These experiments shown that the dominant species in solution were the 1:2 complexes [Ln(III)(BTPhen)2], even at high Ln concentrations, and that the relative stability of the 2:1 to 1:1 BTPhen-Ln complexes varied with different lanthanides. C5-BTPhen therefore shows considerable promise for a once-through selective actinide separation process.

■ A New Type of Oxidation-Reduction Condensation by the Combined Use of Phenyl Diphenylphosphinite and Oxidant

Teruaki Mukaiyama,* Kiichi Kuroda, and Yuji Maruyama

*Tokyo Chemical Industry Co., Ltd., 6-15-5 (TCI) Toshima, Kita-ku, Tokyo 114-0003, Japan

Abstract

A new type of oxidation−reduction condensation of alcohols with sulfur, nitrogen, and oxygen nucleophiles by the combined use of phenyl diphenylphosphinite (PhOPPh2) and oxidants such as azides or diethyl azodicarboxylate (DEAD) are described. In these reactions, chiral secondary and tertiary alcohols are converted into the corresponding chiral sulfides, azides, esters and ethers under mild and neutral conditions with almost complete inversion of stereochemical configuration.

■ Multigram-Scale and Column Chromatography-Free Synthesis of L-Azetidine-2-carboxylic Acid for the Synthesis of Nicotianamine and Its Derivatives

Tomohiro Takaishi, Kyosuke Wakisaka, Christopher J Vavricka, Hiromasa Kiyota, and Minoru Izumi*

*Graduate School of Environmental and Life Science, Okayama University, 1-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530, Japan

Abstract

Multigram-scale synthesis of L-azetidine-2-carboxylic acid from L-aspartic acid was achieved in 13 conventional synthetic steps, without the need for purification by silica-gel column chromatography and expensive reagents. Nicotianamine and its fluorescence-labeled derivatives could be obtained from this synthetic strategy.

■ Stereoselective Aza-Henry Reaction of 3-Nitro-dihydro-2(1H)-quinolones with N-Boc-Aldimines under the Catalysis of Chiral Ammonium Betaines

Daisuke Uraguchi, Masahiro Torii, Kohsuke Kato, and Takashi Ooi*

*Institute of Transformative Bio-Molecules (WPI-ITbM) and Department of Applied Chemistry, Graduate School of Engineering, Nagoya University, Nagoya 464-8601, Japan

Abstract

A highly enantioselective aza-Henry reaction between 3-nitro-dihydro-2(1H)-quinolones and N-Boc-aldimines was developed by using a chiral ammonium betaine as a catalyst. This protocol provides a direct synthetic method for accessing hydroquinoline derivatives possessing a tetrasubstituted stereogenic center at the C3 position and casts light on the utility of the α-functionalization of dihydroquinolones.

■ Stereoselective Synthesis of 1-Substituted 1,2,3,4-Tetrahydro-β-carbolines by Asymmetric Electrophilic α-Amidoalkylation Reactions

Ulrich Weber, Cornelia Hoesl, W. Ponikwar, M. Suter, Heinrich Nöth, and Klaus T. Wanner*

*Department of Pharmacy, Ludwig-Maximilians-University of Munich, Butenandtstr. 5-13 Haus C, D-81377 Munich, Germany

Abstract

An efficient procedure for the asymmetric synthesis of 1-substituted 1,2,3,4-tetrahydro-9-methyl-β-carbolines based on asymmetric electrophilic α-amidoalkylation reactions is described. Stereoselective addition of various organometallic reagents to a chiral N-acyl-β-carbolinium ion gave the corresponding 1-substituted 1,2-dihydro-β-carbolines in high yields and very good to excellent diastereomeric ratios. Catalytic hydrogenation followed by the removal of the chiral auxiliary via reductive cleavage of the amide bond proceeded with complete conservation of the absolute configuration at the newly created stereocenter leading to 1-substituted 1,2,3,4-tetrahydro-9-methyl-β-carboline derivatives in high yields. Their absolute stereochemistry was proven by X-Ray analysis. The 1-phenyl-substituted 1,2,3,4-tetrahydro-β-carbolines were evaluated for their affinity to the PCP binding site of the NMDA receptor.

■ Asymmetric Synthesis of 1-Substituted 1,2,3,4-Tetrahydroisoquinolines by Asymmetric Electrophilic α-Amidoalkylation Reactions

Matthias Ludwig,* K. Polborn, and Klaus T. Wanner*

*Department Pharmazie, Zentrum für Pharmaforschung, LMU München, Butenandtstr. 5-13 D-81377 München, Germany

Abstract

An efficient method for the asymmetric synthesis of 1-substituted 1,2,3,4-tetrahydroisoquinolines via chiral N-acyliminium ions is presented. The N-acyl-1,2-dihydroisoquinolines (8) and (9) underwent smooth oxidation reactions with Ph₃C⁺BF₄^- to give the chiral N-acylisoquinolinium ions (10) and (13), respectively. Stereoselective addition of organomagnesium and organozinc compounds to intermediates (10) and (13) provided the corresponding 1-substituted N-acyl-1,2-dihydroisoquinolines (11/12) and (14/15) in good yields. The diastereoselectivity of these reactions appeared to be dependent on the structure of the N-acyliminium ion intermediates (10) and (13) and on the nature of the trapping reagent with the zinc reagents in general leading to markedly improved stereoselectivities. Pure diastereomers were obtained by preparative HPLC and readily transformed into enantiopure 1-substituted 1,2,3,4-tetrahydroisoquinolines by catalytic hydrogenation and reductive removal of the chiral auxiliary.

■ Asymmetric α-Amidoalkylation. Synthesis of α-Substituted Piperidines of High Enantiomeric Purity

Klaus Th. Wanner and Annerose Kärtner

*Institut für Pharmazie und Lebensmittelchemie, Universität München, Sophienstraße 10, D-80333 München, Germany

Abstract

A stereoselective α-amidoalkylation was performed employing the chiral and cyclic enamide 1. The resulting amides 6 were employed in the synthesis of the title products.

■ Synthesis of 4-Silyl-substituted Methyl Nicotinates via Silylcupration of N-Acylpyridinium Salts

Cornelia E. Hösl and Klaus Th. Wanner*

*Institut für Pharmazie, Universität M&uuuml;nchen, Sophienstrasse 10, D-80333 München, Germany

Abstract

A general synthetic method for the preparation of 4-silyl-substituted methyl nicotinates (5) is described. The reaction sequence includes a silylcupration of the N-acylated 3-methoxypyridinium salts (2) followed by oxidation of the resulting dihydropyridines (3) to give 5.

■ Asymmetric Electrophilic α-Amidoalkylation 5: Improved Stereoselectivities through New Chiral Auxiliaries

Klaus Th. Wanner,* Annerose Kärtner, and Elmar Wadenstorfer

*Institut für Pharmazie und Lebensmittelchemie, Universität München, Sophienstraße 10, D-80333 München, Germany

Abstract

Enamides of type 2 were employed in asymmetric α-amidoalkylation reactions with silyl enol ether 4 as nucleophile. Depending on the chiral auxiliary used, (R)-5/(S)-5 stereoselectivities up to 95/5 could be reached. Based on the obtained results a model for the transient acyliminium ion is proposed.

■ Rearrangement of Dialkyl-2-(azetidin-3-yl)propane-1,3-dioates - A Structural Revision

Mark R. Faust, Cornelia E. Hoesl, and Klaus T. Wanner*

*Department of Pharmacy - Center for Drug Research, LMU Munich, Butenandtstr. 5-13, D-81377 Munich, Germany

Abstract

The rearrangement reaction of dialkyl 2-[1-diphenylmethyl)azetidin-3-yl]propane-1,3-dioates during saponification was studied. Contrary to a previous report postulating the formation of a 4-(hydroxy-methyl)-2-oxo-pyrrolidine-3-carboxylic acid derivative, our analytical data showed that the rearrangement reaction led to a lactone ring. This structural revision is based on elemental analysis, IR and two-dimensional NMR studies.

■ Isomerization of N-Acly-1,2,5,6-tetrahydropyridines to N-Acyl-enamines by Palladium on Carbon

Klaus Th. Wanner and Annerose Kärtner

*Institut für Pharmazie und Lebensmittelchemie, Universität München, Sophienstraße 10, D-80333 München, Germany

Abstract

Allylic amides 1 were rearranged to enamides 2 using palladium on carbon as catalyst.

■ Asymmetric Electrophilic α-Amidoalkylation 6: Syntheses of Tetrahydroisoquinolines of High Enantiomeric Purity

Klaus Th. Wanner* and Ilona Praschak

*Institut für Pharmazie, Universität München, Sophienstraße 10, D-80333 München, Germany

Abstract

Syntheses of 1-substituted tetrahydroisoquinolines of high enantiomeric purity are described. As key step a diastereoselective trapping reaction of a chiral acyliminium ion with silyl enol ethers is involved. The starting acyliminium ion can be prepared by hydride abstraction with triphenylcarbonium tetrafluoroborate.

■ Addition of Phthalimidonitrene to Substituted Indoles

Perumal Raja Kumar

*Department of Chemistry, University of Madras, Madras 600 025, India

Abstract

The aziridine 2a obtained by the addition of phthalimidonitrene to N-phenylsulphonylindole was treated with methanolic potassium hydroxide to give desulphonated indole and quinazoline. The aziridine 2b and 2c derived from phthalimidonitrene and 2-methylindole or 2-phenylindole were treated with dimsyl anion to give 2-methylquinazoline and 2-phenylquinazoline. However the nitrene adducts 2d and 2e derived from 1,2,3,4-tetrahydrocarbazole and 1-oxo-1,2,3,4-tetrahydrocarbazole afford carbazole and 1-hydroxycarbazole under similar conditions. Hydrazinolysis of the nitrene adducts-2a, b, c, d and e regenerated the parent indole.