HETEROCYCLES

■ Some Recent Progress in Natural Product Chemsitry

Derek H. R. Barton and William B. Motherwell

*Institut des Chimie des Substances Naturelles, C.N.R.S., 1 avenue de la Terrasse, Bat. 27, 91198 Gif-sur-Yvette Cedex, France

Abstract

It is only in recent years that radical reactions have become part of the general practise of Organic Synthesis. Dehalogenation, deoxygenation and deamination are three processes advantageously carried out under radical conditions. In studying the radical decarboxylation of acids a new and convenient method of formation of carbon radicals has been developed. The application of this new radical reaction in Natural Product Chemistry will be discussed.

■ Synthesis and Ring a Conformation of New Anthracyclines

Sergio Penco, Francesco Angelucci, Marzia Ballabio, Giovanna Barchielli, Antonino Suarato, Ermes Vanotti, Aristide Vigevani, and Federico Arcamone

*Ricerca&Sviluppo Chimico, Farmitalia Carlo Erba SpA, Via dei Gracchi 35, 20146 Milano, Italy

Abstract

Our continuing interest in the development of new anticancer agents structurally related to daunorubicin and doxorubicin has led us to synthesize analogues modified in the sugar or in the aglycone moieties. Among the latter, 4-demethoxy analogues,obtained by total synthesis, display outstanding antitumor activity and potency. Recently new synthetic procedures have been developed aiming to new classes of analogues characterized by the presence of only one phenolic group on ring B. Such new approaches have allowed the synthesis of 6-deoxy and 11-deoxy derivatives of the antitumor anthracyclines. Interestingly, the absence of the 6-hydroxyl results in an increased conformational flexibility of ring A as shown by nmr measurements on 4-demethoxy-6-deoxydaunorubicin and its derivatives. Changes in ring A conformation had also been recorded in derivatives substituted on ring A including 10-(S)-methoxydaunorubicin [S. Penco et al., Heterocycles 13, 281 (1979)]. Correlations between ring A conformation and structure of a number of derivatives will be discussed.

■ Synthetic Carbapenem Antibiotics. I. 1-β-Methylcarbapenem

David H. Shih, Florence Baker, Lovji Cama, and Burton G. Chrisrtensen

*Merck Sharp and Dohme Research Laboratories, Rahway, NJ 07065, U.S.A.

Abstract

A total synthesis of a novel 1-β-methylcarbapenem antibiotic, (—)-(1R,5S,6S)-2-(2-N,N-dimethylamino-2-iminoethylthio)-6-(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid 1, is reported. Compound 1 is highly resistant to renal dipeptidase-I yet retains the excellent antibacterial activities of N-formimidoylthienamycin.

■ Organic Synthesis Utilizing Thiazolidine and the Related Heterocycles

Eiichi Fujita

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

Abstract

A highly selective asymmetric induction into symmetrical molecules having prochirality has been developed by utilizing 4(R)-methoxycarbonyl-1,3-thiazolidine-2-thione. In the model experiments of total synthesis of viginiamycin M2, the derivatives of 1,3-oxoazolidine-2-thione and 1,3-thiazolidine-2-thione were utilized effectively.

■ Total Synthesis of Bicyclomycin

Shin-ichi Nakatsuka and Toshio Goto

*Laboratory of Organic Chemistry ,Faculty of Agricultures, Nagoya University, Chikusa, Nagoya, Aichi 464-8601, Japan

Abstract

Total synthesis of (±)-bicyclomycin was achieved in 19 steps from diketopiperazine by applying mainly the following two newly developed reactions: (1) regiospecific cyclization of the terminal hydroxy group of the side-chain on the diketopiperazine ring into the bicyclo[4.2.2] ring system; and (2) stereospecific aldol condensation of the aldehyde and the carbanion on the bridge-head position of the bicyclo[4.2.2] ring; two chiral centers in the side chain being controlled by double stereodifferentiation with mutual kinetic resolution to afford preferentially the product having the stereochemistry same to natural bicyclomycin.

■ 2’-Substituted 2’-Deoxypurinenucleotides Their Conformation and Properties

Morio Ikehara

*Faculty of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Toyonaka, Osaka 560-0043, Japan

Abstract

In order to investigate the structure-function relationship of DNA and RNA, a number of nucleotide analogs having various substituents in the 2’-position of purine nucleoside moieties were synthesized and their physical and biological properties investigated.

■ New Tactics in Heterocycles Synthesis

Andrew S. Kende, Frank H. Ebetino, Robert Battista, Rodney J. Boatman, Dennis P. Lorah, and Eric Lodge

*Department of Chemistry, University of Rochester, Rochester, NY 14627, U.S.A.

Abstract

Recent approaches from our laboratories directed toward the total syntheses of the antitumor quinones streptonigrin and lavendamycin and the alkaloid selagine are described.

■ Recent Advances in Stereochemical Control: Multiple Asymmetric Induction

Satoru Masamune

*Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, U.S.A.

Abstract

A new synthetic strategy based on the concept of multiple asymmetric induction is capable of constructing any new chiral center or centers on a chiral substrate as demonstrated in three major organic reactions: the aldol reaction, the Diels-Alder reaction, and epoxidation of allylic alcohols. Several natural product syntheses serve to illustrate the degree of stereoselection that has now been achieved.

■ Purines, Pyrimidines, Pteridines, and Cancer

John A. Montgomery

*Southern Research Institute, Post Office Box 55305, Birmingham, Alabama 35255, U.S.A.

Abstract

The haloadenine nucleosides 9-β-D-arabinofuranosyl-2-fluoroadenine, 2-bromo, 2-chloro-, and 2-fluoro-2’-deoxyadenosine are examples of second generation drugs resulting from structural modification of presently used drugs. These nucleosides are cytotoxic to a number of cell lines in culture and are highly active against both the L-1210 and P388 leukemias in mice, having been shown to be curative in the L-1210 system.
A new kind of agent has resulted from the attachment of a chemically reactive group to the 5’-position of nucleosides. 5’-Bromoacetamido-5’-deoxythymidine, the most active agent of this type prepared so far, is cytotoxic to both H.Ep.-2 and L-1210 cells in culture and has shown good activity against the P388 leukemia in mice. Biochemical studies have shown that this compound interferes with DNA synthesis perhaps by the inactivation of nucleoside diphosphate reductase.
Another new class of agents, the 1-deaza-7,8-dihydropteridines, has been found to be extremely cytotoxic and to be active against the P388 leukemia in mice. These agents are mitotic inhibitors and may prove superior to the standard clinical antimitotic agent, vincristine, in that they are active against a strain of the P388 leukemia resistant to vincristine and are more accessible synthetically. Based on the results to date, it would appear that further improvement in activity is possible via structural modification.

■ Highly Stereoselective Synthesis of Antitumor Antibiotics, (+)-Actinobolin and (—)-Bactobolin, by Asymmetric Cyclization

Masato Yoshioka, Hisao Nakai, and Masaji Ohno

*Faculty of Pharmaceutical Sciences, University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113, Japan

Abstract

A common skeleton of (+)-actinobolin and (—)-bactobolin was efficiently formed by an intramolecular Diels-Alder reaction of a chiral Z diene with a substituent at the pentadienylic carbon, and the following transformation completed the first total synthesis of (+)-actinobolin from L-threonine.

■ Dyestuff Lasers and Light Collectors — Two New Fields of Application for Fluorescent Heterocyclic Compounds

Roderich Raue, Horst Harnisch, and Karl H. Drexhage

*Bayer AG, D-5090 Leverkusen, Greece

Abstract

The physical principles and methods of the functioning of fluorescent solar collectors and dyestuff lasers are briefly discussed, together with the demands that have to be met by a fluorescent dyestuff.
In a summary of recent work carried out in these two fields, a report is given of perylene carboxylic ester dyes and perylene tetracarboxylic acid diimide dyes for solar collectors, bifluorophoric laser dyes, laser dyes with intramolecular triplet quenching and infrared laser dyes with pyrylium and thiapyrylium terminal systems, also from the tetra and hexamethine hemicyanine ranges.
A st the coumarin dyestuffs are compounds suitable as energy converters in light collecting systems, particularly if the amino group is fixed by ring closure to the aromatic system as high-power laser dyestuffs.

■ Monobactams: Ring Activating N-1-Substituents in Monocyclic β-Lactam Antibiotics

William A. Slusarchyk, Tamara Dejneka, Eric M. Gordon, Eugene R. Weaver, and William H. Koster

*The Squibb Institute for Medical Research, P. O. Box 4000, Princeton, N.J. 08540-4000, U.S.A.

Abstract

Several alternatives to the sulfonate residue in the naturally-occurring monobactams, 3-acylamino-2-oxoazetidine-1-sulfonates, provide new monobactams having potent activity against aerobic gram-negative bacteria. The monobactams compared here include: (a) those where the anionic activating group (sulfonate or phosphonate(-inate)) is attached to the β-lactam nitrogen, and (b) those where an oxygen atom is interposed between the acidic group and the β-lactam nitrogen, i.e. sulfate and phosphate(-onate) groups. Chemical and biological relationships between these classes of monobactams are presented.

■ Stereo- and Enantioselective Syntheses of 2,3-Dihydroindole Derivatives

W. Nico Speckamp

*Laboratory of Organic Chemistry, Institute of Molecular Chemistry, University of Amsterdam, Nieuwe Achtergracht 129, 1018 WS Amsterdam, The Netherlands

Abstract

2,3-Dihydroindoles (2,3-Indolines) can be obtained in a highly stereoselective fashion through 1,5-electrocyclization of ortho-substituted aminobenzenes. The scope and mechanism of this novel process are discussed and also some applications. In presence of chiral alcohols the ring closure proceeds with remarkably high enantioselectivity.

■ Macropolycyclic Compounds as Host Molecules

Ian O. Sutherland

*Department of Organic Chemistry, The Robert Robinson Laboratories, University of Liverpool, P.O.Box 147, Liverpool L69 3BX, U.K.

Abstract

The complexation of guest primary alkylammonium salts by mono- and di-aza crown ethers has been studied by NMR spectroscopy and has been shown to be stereoselective in some cases. Macrotricyclic systems derived from diaza-12-crown-4 and diaza- 15-crown-5 form inclusion complexes in a highly stereoselective fashion with bisalkylammonium cations. Chiral aza crown ethers show enantiomer selectivity in complexation which is dependent upon the substituents on the nitrogen atoms. These results have been used for the design of host molecules that catalyse ester cleavage in α-amino acid esters.

■ Polyvalent Porphyrins. Ligands for Stabilization of High Valent Metals

T. G. Traylor, Kevin Nolan, Robert Hildreth, and Thomas A. Evans

*Department of Chemistry (D-006), University of California, San Diego, La Jolla, CA 92093-0682a, U.S.A.

Abstract

The iron (III) complex of tetra(3,5-di-t-butyl-4-hydroxyphenyl)porphyrin can be oxidized by two electron equivalents with peracids or dioxygen and base to form a stable complex. This complex oxidizes phenols. Alternatively, in the presence of 1-methylimidazole, the Fe (III) complex is autoreduced to the hexacoordinated Fe (II) species. These reactions bear some resemblance to the catalytic processes occurring in horseradish peroxidase and cytochrome c peroxidase.

■ The Synthesis of 2-Chloro-2-oxo-4.5-dimethyl-1.3.2.λ⁵-dioxaphospholene (CEP Chloride)

Josef Götz and Ivar Ugi

*Department of Organic Chemistry , Technische Universität München, Lichtenbergstrasse 4, D-85747 Garching, Germany

Abstract

An efficient synthesis of CEP chloride has been developed. The cyclic diethylaminophosphite ester of 2-butene-2.3-diol is converted into the clorophosphite by treatment with HCl; subsequent oxidation with N₂O₄ leads to CEP chloride.

■ Recent Developments in β-Lactam Synthesis by Four Component Condensation

Roland Obrecht, Sekou Toure, and Ivar Ugi

*Department of Organic Chemistry , Technische Universität München, Lichtenbergstrasse 4, D-85747 Garching, Germany

■ New Approaches to the Synthesis of Spermine and Spermidine Alakaloids

Harry H. Wasserman and Ralph P. Robinson

*Department of Chemistry, Yale University, P.O. Box 6666, New Haven, Connecticut 06511, U.S.A.

Abstract

New approaches to the formation of macrocyclic lactams are described involving successive ring expansion of β-lactams and other heterocyclic systems. These methods have been used in the synthesis of a number of spermine and spermidine alkaloids including homaline, celacinnine, dihydroperiphylline, chaenorhine and verbascenine.

■ Novel Ring Transformation Reactions and Their Applications to the Syntheses of Potential Anticancer Heterocyclic Compounds

K. A. Watanabe, T. -L. Su, K. W. Pankiewicz, and K. Harada

*Laboratory of Organic Chemistry, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, Sloan-Kerreing Division of Graduate School of MEdical Science, Cornell University, New York, NY 10021, U.S.A.

Abstract

Novel heterocyclic ring transformation reactions developed recently in our laboratory are described. They include pyrimidine to pyrimidine, pyrimidine to pyridine transformations. Also discussed are novel one-step procedures for conversion of 1,3-dimethyluracil derivatives into the pyrido[2,3-d]pyrimidine system. Some applications of these novel reactions to the sytheses of compounds of biological interest are also described.

■ Natural Product Synthesis via Cycloadditions with N-Sulfinyl Dienophiles

Steven M. Weinreb, Ravi S. Garigipati, and James A. Gainor

*Department of Chemistry, The Pennsylvania State University, York Campus, P1031 Edgecomb Avenue, York, Pennsylvania 17403, U.S.A.

Abstract

Diels-Alder cycloadducts derived from N-sulfinyl dienophiles have been used for stereospecific preparation of acyclic unsaturated amines and in stereospecific syntheses of threo-sphingosine (31) and erythro-sphingosine (32). Methodology based upon these cycloadducts is also currently being developed for total synthesis of the microbial metabolite staurosporine (46).

■ Indole Alkaloid Synthesis

Ernest Wenkert

*Department of Chemistry (D-006), University of California, San Diego, La Jolla, CA 92093-0682a, U.S.A.

Abstract

The lecture describes the total synthesis of pseudoyohimbine and an approach to the deserpidine group of indole alkaloids by way of the route of nucleophilic addition to a pyridinium salt followed by acid-induced ring closure.

■ Metal Porphyrin Complexes with Novel Functions

Zen-ichi Yoshida

*Faculty of Engineering, Kyoto University, Yoshida, Sakyou-ku, Kyoto 606-8501, Japan

Abstract

Porphyrins reveal novel functions by metal complex formation. In this lecture following work in our laboratories is described: (1) oxygen binding and activation function of heme (porphyrin Fe(II) complex), (2) monooxygenation function of porphyrin oxovanadium complex (cytochrome P-450 mimic), and (3) catalytic function of porphyrin cobalt complex for valence isomerization (quadricyclanes to norbornadienes).