HETEROCYCLES

■ Contents

■ Preface — A Life Dedicated to Chemistry in Nature

Yuichi Kanaoka*

*Toyama College, Toyama, Toyama-city Gankaiji, Japan

■ Memorial Preface for Dr. John W. Daly: A Retrospective on Our Collaboration on Batrachotoxin Chemistry

Takashi Tokuyama*

*Daido 2-8-16, Tennouji-Ku, Osaka, 543-0052, Japan

■ Biographical Data

John W. Daly*

*Laboratory of Bioorganic Chemistry, Bldg. 8, 1A-15, National Institute of Health, 8 Center Drive MSC 0820, Bethesda, MD 20892, U.S.A.

■ List of Publications

John W. Daly*

*Laboratory of Bioorganic Chemistry, Bldg. 8, 1A-15, National Institute of Health, 8 Center Drive MSC 0820, Bethesda, MD 20892, U.S.A.

■ John W. Daly – An Appreciation

Kenneth A. Jacobson* and Kenneth L. Kirk

*Section of Medicinal Chemistry, Laboratory of Bioorganic Chrmistry, NIDDK, National Institute of Health, Bethesda, MD 20892, U.S.A.

Abstract

John W. Daly was engaged in groundbreaking basic research for nearly 50 years at NIH in Bethesda, Maryland. A primary focus of his research included the discovery, structure elucidation, synthesis and pharmacology of alkaloids and other biologically active natural products. However, he earned further acclaim in other areas that included the investigation of the structure-activity relationships for agonists/antagonists at adenosine, adrenergic, histamine, serotonin, and acetylcholine receptors. In addition he was a pioneer in studies of the modulation and functional relationships for systems involving calcium, cyclic nucleotides, ion channels and phospholipids and in the mechanism of actions of caffeine and other xanthines.

■ Adenosine Receptors: The Contributions by John W. Daly

Bertil B. Fredholm* and Kenneth A. Jacobson

*Department of Physiology and Pharmacology, Karolinska Institute, S-171 77 Stockholm, Sweden

Abstract

John Daly played an important role in defining adenosine receptors as an important target for drug discovery. His systematic work characterized the effects of adenosine analogues on cyclic AMP in the brain that were antagonized by methylxanthines. He also played a decisive role in establishing these receptors as bona fide biochemical entities and contributed to the discovery of receptor heterogeneity. This brief review will cover some of his important early discoveries in the pharmacology and medicinal chemistry of adenosine receptors.

■ John W. Daly: The Early Years. The NIH Shift and Cyclic-AMP Assays: Early Pharmacological Breakthroughs

Kenneth L. Kirk* and Fabian Gusovsky

*Section of Medicinal Chemistry, Laboratory of Bioorganic Chrmistry, NIDDK, National Institute of Health, Bethesda, MD 20892, U.S.A.

Abstract

Although trained as an organic chemist, John Daly embarked in his early years at NIH on several research projects that involved a significant and sophisticated application of biochemistry and pharmacology. He was able to work with impressive leaders in these fields, including the late Nobel Laureate, Julius Axelrod. In this report, we highlight two aspects of this work—his involvement in the discovery of the NIH shift and the development of a method to quickly assay cyclic AMP biosynthesis. The strong pharmacological component of his research career evolved from these and other early seminal discoveries.

■ The John Daly I Knew in Madagascar: November 1989 – December 1993 / January 1994 – December 1998 – February 2003

Nirina R. Andriamaharavo*

*Laboratory of Bioorganic Chemistry, NIDDK, NIH, DHHS, Bethesda, MD 20892, U.S.A.

■ Epibatidine Analogs Synthesized for Characterization of Nicotinic Pharmacophores—A Review

F. Ivy Carroll*

*Organic and Medicinal Chemistry, Research Triangle Institute, Research Triangle Park, NC 27709, U.S.A.

Abstract

In 1992 Daly and co-workers reported the isolation of a new natural product, epibatidine. Future studies showed that epibatidine was an nAChR ligand with analgesic potency 200-400 times greater than that of morphine. However, its potential as a new drug was limited by its toxic side effects, probably resulting from its activity at a number of nAChR subtypes. Epibatidine's unique structure and potent activity made it an ideal lead structure for the development of nAChR ligands with reduced side effects and better nAChR subtype selectivity. This review presents the synthetic methods we have used to synthesize a number of epibatidine agonists, antagonists, and mixed agonists/antagonists to better characterize the α4b2 nAChR pharmacophore and hopefully provide compounds that have potential for treating nicotine addiction.

■ Constituents and Bioactivities of Clausena excavata

Ngampong Kongkathip* and Boonsong Kongkathip

*Department of Chemistry, Faculty of Science, Kasetsart University, 50 Phahonyothin Road, Chatuchak, Bangkok 10903, Thailand

Abstract

Clausena excavata Burm. f. (Rutaceae) is a medicinal plant which is used in folklore medicine for treatment of cold, malaria, AIDS, dermatopathy, abdominal pain, and snake-bite. This plant is a rich source of coumarins and carbazole alkaloids. So far, fifty-three coumarins and fifty-eight carbazole alokaloids were isolated from C. excavata. Furthermore, a small group of tetranortriterpenoids, steroids, flavonoids, and essential oils were also obtained from this plant. C. excavata showed diverse therapeutic activities which are antibacterial, antifungal, antiplatelet, antiplasmodial, antitumor, antinociceptive, immunomodulatory, antimycobacterial, and anti-HIV-1 activities. The incidence of HIV-1 infection leading to AIDS has increased every year, and fungal and bacterial infections, particularly TB-causing mycobacteria are prevalent in HIV-infected patients. So Clausena excavata which showed inhibition of these diseases, is very promising to be developed for treatment of AIDS.

■ Synthesis of 1α,25-Dihydroxy-2β-(3-hydroxypropoxy)vitamin D3 (Eldecalcitol) and Related Compounds by the Trost Convergent Methodology

Noboru Kubodera* and Susumi Hatakeyama

*Chugai Pharmaceutical Company, Ltd., 2-1-1, Nihonbashi-Muromachi, Chuo-ku, Tokyo 103-8324, Japan

Abstract

Using Trost convergent methodology, the synthesis of 1α,25-dihydroxy-2β-(3-hydroxypropoxy)vitamin D3 (eldecalcitol) for the improved and industrial scale production and related putative metabolites of eldecalcitol is summarized. In addition, A-ring diastereomers at the 1- and 3-positions of eldecalcitol are described. The synthesis centers on a key palladium-catalyzed alkylative cyclization and coupling of ene-ynes that constitute the A-ring fragment to bromomethylenes comprising the C/D-ring fragment which affords the requisite triene framework of vitamin D3 analogs.

■ Reactions and Uses of Artificial Ketoses

Takashi Yamanoi* and Sho Matsuda

*The Noguchi Institute, 1-8-1, Kaga, Itabashi-ku, Tokyo 173-0003, Japan

Abstract

Some artificial ketoses having a naturally occurring aldose backbone can be readily prepared by the addition of RLi or RMgX to aldonolactone derivatives. They are expected to be a novel class of carbohydrate reagents for synthesizing valuable compounds. In order to utilize these ketoses completely, we must elucidate the reaction characteristics influenced by the ketose’s specific structures. In particular, it is important to understand the reaction specificities of the nucleophilic substitutions at the anomeric carbons of these ketoses to produce various ketosides. This review describes the nucleophilic reactions to form the ketosidic linkages from the artificial ketoses, focusing mainly on our recent research results.

■ Discovery of Batrachotoxin: The Launch of the Frog Alkaloid Program at NIH

H. Martin Garraffo* and Thomas F. Spande

*Laboratory of Bioorganic Chemistry, Bldg. 8, 1A-15, National Institute of Health, 8 Center Drive MSC 0820, Bethesda, MD 20892, U.S.A.

Abstract

The determination of the structures of the batrachotoxins (BTXs), extremely toxic steroidal alkaloids found in the skins of the dart-poison frogs of the genus Phyllobates from Colombia in the 1960s is reviewed. The BTXs function by locking open sodium-ion channels of nerve and muscle, thereby depolarizing them. The structures and pharmacology of the BTXs were determined by a team led by John W. Daly. This research started a 40 year long study of alkaloids from frog skin, whereby John and his team identified and/or characterized more than 800 such alkaloids. The source of the BTXs, not synthesized but sequestered from diet by the frogs, is briefly discussed, in the context of the occurrence of BTXs in birds of Papua New Guinea and in a small melyrid beetle found there. Emphasized is the critical importance of maintaining and safe-guarding the large collection of frog-skin extracts and data accumulated since.

■ Epibatidine: From Frog Alkaloid to Analgesic Clinical Candidates. A Testimonial to “True Grit”!

H. Martin Garraffo, Thomas F. Spande, and Michael Williams*

*Discovery Research, Cephalon Inc., 145 Brandywine Parkway, West Chester, PA 19380, U.S.A.

Abstract

A routine toxicity test of the alkaloid extract from the Ecuadoran poison frog Epipedobates anthonyi gave a Straub-tail (S-T) response on sub-cutaneous (sc) injection in mice, a phenomenon never seen before from any poison frog alkaloid. It is characteristic of opioids; however, in this instance it was not blocked by a morphine-antagonist, naloxone. Its site of action was soon shown to be a nicotinic receptor. The determination of the structure of this novel analgesic named epibatidine has led to a renaissance of research into controlling pain via nicotinic pathways (thereby minimizing the risk of tolerance/addiction) and the synthesis of many analogs, some of which are discussed.

■ (-)-Indolizidine 167B via 4-Pyrrolylbutanals: Two Synthetic Methodologies at Comparison

Roberta Settambolo*

*ICCOM-CNR, Pisa Section, Department of Chemistry and Industrial Chemistry, University of Pisa, Via Risorgimento 35, 56126 Pisa, Italy

Abstract

This review relates the results that we obtained in the field of the total synthesis of (-)-indolizidine 167B, based on the intramolecular cyclodehydration of a 4-pyrrolylbutanal to a 5,6-dihydroindolizine core, according to “oxo” or “non oxo” methodology. In the former pathway the butanal was (R)-4-(pyrrol-1-yl)heptanal and originated from (R)-3-(pyrrol-1-yl)but-1-ene via rhodium-catalyzed hydroformylation. In the latter one the proper (R)-4-carboxyethyl-4-(pyrrol-1-yl)butanal intermediate was obtained from diethyl-2-(pyrrol-1-yl)pentanedioate via chemo- and regioselective reduction of the sole distal ester group. In both cases a diastereoselective hydrogenation of the final 5-n-propyl-5,6-dihydroindolizine gave the target compound.

■ Enantioselective Radical Cyclization for the Synthesis of Cyclic Compounds

Eito Yoshioka, Shigeru Kohtani, and Hideto Miyabe*

*Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-shimoadachi-machi, Sakyo-ku, Kyoto 606-8501, Japan

Abstract

This review highlights the enantioselective radical cyclization reactions catalyzed by chiral Lewis acid as well as organocatalyst. The results of the radical cyclization controlled by chiral Al, Ti, Mg, Yb and Zn reagents, the oxidative cyclization using chiral amine, the chiral complexing agent-catalyzed reductive cyclization, transfer of chirality in radical cyclization, and so on are summarized.

■ 3-Methyl-2,5-dihydro-1-benzoxepins and 3-Methyl-2,5-dihydrooxepins

Seiji Yamaguchi*

*Department of Chemistry, Graduate School of Science and Engineering, Toyama University, Gofuku 3190, Toyama 930-8555, Japan

Abstract

Three preparative procedures of seven-membered O-heterocyclic 3-methyl-2,5-dihydro-1-benzoxepin derivatives are summarized. For the Z-selective formation of C=C double bond, the first approach used the Grubbs ring-closing methathesis, the second approach used the intramolecular Mitsunobu cyclization of corresponding Z-diols prepared using Stille coupling of the benzyl bromide with (Z)-vinylstannane, and the third approach used the revised synthesis of the Z-diols using Z-selective Ando-Horner-Emmons condensation and the following DIBAL-H reduction. Some naturally occurring 3-methyl- 2,5-dihydro-1-benzoxepin derivatives were synthesized using these procedures. In these studies, some preparations of 3-methyl-2,5-dihydrooxepin derivatives were also developed.

■ Unconventional Activators in the Synthesis of Oligonucleotides and Their Structural Analogues

Wojciech Dabkowski and Jan Michalski*

*Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza 112, 90-363 Lodz, Poland

Abstract

Activation of phosphoramidites as phosphitylating reagents in the synthesis of biophosphates and their structural analogues is of great importance. Tetrazole a customary activator can be conveniently replaced by trimethylchlorosilane (TMCS) or 2,4-dinitrophenol. Advantages of use of these reagents in the synthesis of biophosphates and their mechanism of action are discussed. Phosphites containing 4-nitrophenoxy leaving group are activated by DBU which role is revealed. Readily accessible P(III)-F structures, can be “activated” by their facile transformation into the corresponding bromides using trimethylbromosilane (TMBS). Application of phosphoramidites in synthesis of phosphates of biological interest and their activation by azolides and acids salts, including and stereochemical aspects was described in 'Topics in Current Chemistry'.

■ Arthropod Alkaloids in Poison Frogs: A Review of the ‘Dietary Hypothesis’

Ralph A. Saporito,* Thomas F. Spande, H. Martin Garraffo, and Maureen A. Donnelly

*Department of Biological Sciences, Old Dominion University, Norfolk, Virginia 23529, U.S.A.

Abstract

Poison frogs are chemically defended from predators and/or microorganisms by the presence of alkaloids in dermal skin glands. Over the past 40 years, more than 800 alkaloids, which are generally organized into 28 structural classes, have been identified in several lineages of poison frogs worldwide. Originally, the presence of alkaloids in frogs was thought to be the result of biosynthesis, however research led largely by John W. Daly resulted in the discovery that most of these alkaloids are sequestered unchanged from dietary arthropods. In the present paper, we review the most significant findings and studies that led to the proposal of the ‘dietary hypothesis’.

■ Claisen Ring Expansion Approach toward The CDEF Ring System of Lancifodilactone G

Leo A. Paquette* and Kwong Wah Lai

*Evans Chemical Laboratories, The Ohio State University, Columbus, OH 43210, USA

Abstract

The fused CDEF ring system of lancifodilactone G is assembled via a Nozaki-Hiyama-Kishi cross-coupling reaction and a Petasis-Claisen ring expansion sequence as the key strategic steps.

■ Palladium-catalyzed Arylation at C-H and C-C Bonds of Masked Thiazole Derivatives

Hirotoshi Furukawa, Suguru Matsumura, Atsushi Sugie, Daiki Monguchi, and Atsunori Mori*

*Department of Chemical Science and Engineering, Kobe University, 1-1 Rokkodai, Nada, Kobe 657-8501, Japan

Abstract

The differently substituted 2,5-diarylthiazole derivatives are synthesized via palladium catalyzed sequential C-H arylation at the 5-position and C-C bond activation at the 2-positon with masked thiazole.

■ Intramolecular Si-C and C-H Bond Activation in a Platinum Complex Leading to the Formation of the Platinacycles

Norihiro Tokitoh,* Masahiro Kawai, Nobuhiro Takeda, and Takahiro Sasamori

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

Abstract

Reduction of dichloroplatinum complex dl-1 bearing two bulky aromatic substituents, Bbt groups (2,6-bis[bis(trimethylsilyl)methyl]-4-[tris(trimethylsilyl)methyl]phenyl), by sodium metal gave a unique platinacycle 2, a hydridoplatinum complex of [PtH{CH₂SiMe₂CH(SiMe₃)C₆H₂-3-CH(SiMe₃)₂-5-C(SiMe₃)₃-2-P(Me)CH₂CH₂ (Me)PBbt}], which seems to be most likely formed via the initial formation of the corresponding Pt(0) complex and the subsequent intramolecular insertion of the Pt(0) center to the H-CH₂ bond of the o-bis(trimethylsilyl)methyl group of the Bbt group. On heating, the hydridoplatinum complex 2 underwent further intramolecular Si-C activation giving another type of platinacycle, [PtMe{SiMe₂CH(SiMe₃)C₆H₂-3CH(SiMe₃)₂-5-C(SiMe₃)₃-2-P(Me)CH₂CH₂(Me)PBbt}] (4), which has a (methyl)(silyl)¬platinum complex structure.

■ Palladium-Catalyzed Heteroarylamination of Ethyl 2-Chloro-1-azaazulene-3-carboxylate and Annulation of Heteroarylamino-1-azaazurenes

Kazuya Koizumi, Kunitaka Shimabara, Aya Takemoto, Shinya Yamazaki, Noriko Yamauchi, Hiroyuki Fujii, Masaki Kurosawa, Takeo Konakahara, and Noritaka Abe*

*Applied Molecular Bioscience, Graduate School of Medicine, and Department of Biology and Chemistry, Faculty of Science, Yamaguchi University, Yoshida, Yamaguchi 753-8512, Japan

Abstract

The palladium catalyzed heteroarylamination of ethyl 2-chloro-1-azaazulene-3-carboxylate was achieved using a catalyst based on Pd₂(dba)₃ / Xantphos system. Treatment of ethyl 2-(heteroarylamino)-1-aza-azulene-3-carboxylates with a PPA-POCl₃ mixture gave corresponding annulation products. 2-(2-Benzothiazolylamino)-1-azaazulene (3h) showed anticancer activity against HeLa S3 cells (IC₅₀: 6.5 μM).

■ Design and Synthesis of a Conformationally Restricted Analogue of the EFGH-ring System of Ciguatoxin

Nayoung Lee, Masayuki Inoue,* and Masahiro Hirama*

*1Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan

Abstract

The fused-hexahydrooxonine (F-ring) of ciguatoxin (CTX), as well as its EFGH-ring fragment, undergoes a slow conformational change between two conformers in solution. In this paper, we designed and synthesized a conformationally restricted analogue of the EFGH-ring system of ciguatoxin. Chemo- and stereoselective epoxidation of the F-ring successfully impeded the dynamic behavior without affecting the overall three-dimensional shape of the molecule.

■ High Binding Affinity of DABCO with Porphyrin in a Porphyrin-cis-Stilbene-Porphyrin Triad

Md. Wahadoszamen, Takashi Yamamura, Atsuya Momotake, Yoshinobu Nishimura, and Tatsuo Arai*

*Department of Chemistry, Graduate School of Pure and Applied Sciences, University of Tsukuba, 1-1-1 Ten-nodai, Tsukuba-shi, Ibaraki 305-0006, Japan

Abstract

Porphyrin-stilbene-porphyrin triad (mZnPst) where a central cis-stilbene unit is connected to zinc-tetraphenylporphyrin (ZnTPP) was synthesized and its binding ability with a selected guest ligand DABCO was investigated. The association constant was evaluated to be 2.47 x 108 M-1, from the iterative least squares fitting to a 1:1 binding model, which is larger than that of monomer ZnTPP/DABCO complex (3.50 x 105 M-1). In addition, when a toluene solution of mZnPst is mixed with 1 equivalent of DABCO, the color of the solution was changed abruptly to light purple from bright reddish, providing further a visual evidence of forming strong complex. Such a high association constant suggests mZnPst/DABCO to be a promising photoresponsive supramolecular system.

■ Memory of Chirality in the Electrochemical Oxidation of N-o-phenylbenzoylated Prolinols

George Ng’aNg’a Wanyoike, Yoshihiro Matsumura, and Osamu Onomura*

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

Abstract

Memory of chirality in electrochemical carbon-carbon bond cleavage of N-o-phenylbenzoylated (S)-prolinol derivatives was observed. Substituents of the α-position affected the ee of the products. The reaction of α,α-diarylated (S)-prolinol derivatives proceeded smoothly to afford optically active α-methoxylated pyrrolidine with up to 73% ee.

■ Regioselective Ring Expansion of 3,3-Dimethylaziridin-2-carboxylate and a Photochemical Entry to the Penem Nucleus

James D. White* and Takuya Furuta

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

Abstract

3,3-Dimethylaziridin-2-carboxylates undergo ring expansion with thiocyanates to give a 4,4-dimethylthiazolidin-5-carboxylate as the major product. Irradiation of a N-cysteinyl-3,3-dimethylaziridin-2-carboxylate was found to give a penem in low yield, presumably via a transient thioaldehyde which added across the aziridine N-C(3) bond.

■ Stereoselective Synthesis of 5-Substituted 2-Allyl-3-oxotetrahydrofuran-2-carboxylates Using Rhodium(II)-Catalyzed Oxonium Ylide Formation–[2,3] Shift

Takayuki Yakura,* Katsuaki Matsui, Kazumasa Matsuzaka, and Masayuki Yamashita

*Faculty of Pharmaceutical Sciences, Graduate School, Toyama University, 2630 Sugitani, Toyama, Toyama 930-0194, Japan

Abstract

Reaction of 5-allyloxy-2-diazo-3-ketoesters 1 with catalytic amount of dirhodium(II) tetraacetate in dichloromethane proceeded in high yields with excellent stereoselectivities to give methyl 5-substituted 2-allyl-3-oxotetrahydro- furan-2-carboxylates 2, which are suitable intermediates for synthesis of heliespirones and their derivatives.

■ Effective Synthesis of Optically Active 3-Phenyl-3-(3-trifluoromethyl)diazirinyl Bishomophenylalanine Derivatives

Yuta Murai, Yasumaru Hatanaka, Yuichi Kanaoka, and Makoto Hashimoto*

*Obihiro University of Agriculture and Veterinary Medicine, Inada-cho, Obihiro, Hokkaido 080-8555, Japan

Abstract

Effective incorporation of phenyldiazirine moiety on the acyl residue of L- and D- glutamic acid by Friedel-Crafts reactions with triflic acid developed simple preparation of bishomophenylalanine (bhPhe) for aromatics, which added a versatile and a reliable access to photoreactive peptide probes.