Current Topics in Medicinal Chemistry

ISSN: 1568-0266

Current Topics in Medicinal Chemistry
Volume 5, Number 15, 2005

Contents

Metathesis Reactions in the Synthesis of Biologically
Active Compounds and Medicinal Chemistry
Guest Editor: Janine Cossy


Editorial Pp.1459


Metathesis Reactions. General Considerations Pp.1461
Pierre Van de Weghe, Jacques Eustache and Janine Cossy
[Abstract]


Recent Applications of Olefin Ring-Closing Metathesis (RCM) in the Synthesis of Biologically Important Alkaloids, Terpenoids,Polyketides and Other Secondary Metabolites Pp.1473
Tanja Gaich and Johann Mulzer
[Abstract]


The Application of Olefin Metathesis to the Synthesis of
Biologically Active Macrocyclic Agents Pp.1495
Pierre Van de Weghe and Jacques Eustache
[Abstract]


Ring Closing Metathesis in the Synthesis of Biologically
Interesting Peptidomimetics, Sugars and Alkaloids Pp.1521
William H. C. Martin and Siegfried Blechert
[Abstract]


Olefin Metathesis Route to Antiviral Nucleosides Pp.1541
Luigi A. Agrofoglio and Steven P. Nolan
[Abstract]


Application of Olefin Cross-Metathesis to the Synthesis of
Biologically Active Natural Products Pp.1559
Joëlle Prunet
[Abstract]


Cross-Metathesis: Efficient Preparation of Trialkyl-Substituted Isoprenoid Olefins as Key-Intermediates for Tocopherol Synthesis Pp.1579
Thomas Netscher
[Abstract]




Abstracts

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Editorial

Metathesis Reactions in the Synthesis of Biologically Active Compounds and Medicinal Chemistry
In the last decades, among the many types of transition-metal catalyzed carbon-carbon bond forming processes, the palladium-catalyzed cross-coupling reactions and the olefin-metathesis reactions have probably played major roles in organic synthesis. Olefin metathesis is now widely considered as one of the most powerful synthetic tools. This reaction, where the carbon-carbon double bond of an alkene is broken and reformed in the presence of an organometallic catalyst, was discoverd 50 years ago and used to synthesize polymers. The elucidation of the mechanistic pathways took at least 20 years and the accepted mechanism of alkene metathesis, proposed by Prof. Chauvin in 1971, invokes metal carbene intermediates as key propagating intermediates in the catalytic cycle. Due to Prof. Schrock and Prof. Grubbs, who designed catalysts which are stable, easily handled, tolerant to most functional groups and commercially available, the alkene metathesis reaction became one of the most powerful carbon-carbon forming reactions currently available to the synthetic chemist and, more and more researchers are employing the metathesis reactions. The synthetic transformations that can be achieved with one catalyst when applied to appropriate substrates is astonishing. Metathesis reactions have a variety of applications including ring-opening metathesis polymerization (ROMP), ring-closing metathesis reactions (RCM), acyclic dienes metathesis polymerization (ADMET), ring-opening metathesis (ROM) and cross-metathesis reaction (CM). The sequential transformation of the alkene obtained in metathesis reactions (domino process) is an attractive application of this synthetic method and can be used in the synthesis of complex molecules in a single catalytic step. Furthermore, tandem metathesis coupled with other alkene reactions (Diels-Alder, Heck…) is a fascinating area of research.
In October 2005, the Nobel Committee has recognized the importance and utility of the metathesis reaction as it has awarded Prof. Chauvin (France), Prof. Grubbs (USA) and Prof. Schrock (USA) «for the development of the metathesis method in organic synthesis».
In this review, we do not want to duplicate any of the reviews dealing with metathesis and, rather than presenting an exhaustive coverage of the litterature, all the authors have limited themselves to applications in the field of biologically active relevant molecules (natural and non natural) with emphasis on methods that will be of interest to medicinal chemists.
I would like to thank all authors for contributing to this special issue.

Prof. Janine Cossy
Laboratoire d Chimie Organique
associé au CNRS
ESPCI
10 rue Vauquelin
75231 Paris Cedex 05
France

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Metathesis Reactions. General Considerations
Pierre Van de Weghe, Jacques Eustache and Janine Cossy

General considerations on the metathesis reaction are reported and illustrated by examples in the area of natural products and/or biologically active compounds.

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Recent Applications of Olefin Ring-Closing Metathesis (RCM) in the Synthesis of Biologically Important Alkaloids, Terpenoids,Polyketides and Other Secondary Metabolites
Tanja Gaich and Johann Mulzer

With the commercial availability of well-defined ruthenium metathesis catalysts which combine high stability and broad functional group compatibility with undiminished activity, ring-closing metathesis (RCM) is now routinely integrated in the planning of natural product syntheses. Thus, ring sizes of practically any kind from five onward may be formed. The presence of heteroatoms such as oxygen and nitrogen is of minor importance. Ring-strain and the presence of additional double bonds may be overcome by judicious selection of conditions. A major drawback of macrocyclic RCM still is the lack of E/Z stereocontrol. Nevertheless, the current overview will demonstrate the overwhelming power and scope of RCM in the total synthesis of structurally demanding natural products.

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The Application of Olefin Metathesis to the Synthesis of
Biologically Active Macrocyclic Agents
Pierre Van de Weghe and Jacques Eustache

Recent developments of the metathesis reaction in the area of biologically active molecules are presented. Scope and limitations of ring-closing metathesis to form medium and large rings are discussed and illustrated by the epothilone synthesis. Applications of the metathesis reaction related to medicinal chemistry, including solid phase synthesis and combinatorial chemistry are presented.

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Ring Closing Metathesis in the Synthesis of Biologically
Interesting Peptidomimetics, Sugars and Alkaloids
William H. C. Martin and Siegfried Blechert

Olefin metathesis has rapidly established itself as an essential tool in the synthetic chemist’s armoury. The ease of operation and functional group tolerance that is obtained with the modern generation of catalysts makes the use of metathesis an extremely attractive option when preparing medicinally interesting molecules. This article will outline some of the ways in which chemists from both industry and academia have been utilising and developing metathesis in the search for novel biological probes and drug leads.

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Olefin Metathesis Route to Antiviral Nucleosides
Luigi A. Agrofoglio and Steven P. Nolan

The success of the early nucleoside agents, the toxicity and metabolic instability of many nucleoside analogues and the effects of viral pathogens on public health are driving the design, synthesis and evaluation of new nucleoside analogues. In this context, a powerful reaction has emerged over the past decade that has fundamentally changed the outlook on nucleoside chemistry: the olefin metathesis reaction. This review is designed to give an overview of the synthesis of some nucleosides of biological interest, according to their structural types (e.g., neplanocins and aristeromycin analogues, 2’,3’-unsaturated nucleoside analogues, and acyclonucleosides), using metathesis reactions by employing either the alkoxy imido molybdenum catalyst developed by Schrock and various ruthenium carbene catalysts developed by Grubbs, Hoveyda-Grubbs and Nolan.

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Application of Olefin Cross-Metathesis to the Synthesis of
Biologically Active Natural Products
Joëlle Prunet

An overview of the use of olefin cross-metathesis in the synthesis of biologically active natural products is presented. The diverse examples are organized according to the outcome of the olefin constructed by the cross-metathesis reaction: this olefin can be either present in the final product, reduced, engaged in other transformations, or involved in tandem processes.

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Cross-Metathesis: Efficient Preparation of Trialkyl-Substituted Isoprenoid Olefins as Key-Intermediates for Tocopherol Synthesis
Thomas Netscher

A summary of the application of ruthenium catalyzed olefin cross-metathesis towards the synthesis of tocopherols (vitamin E) is given. This group of biologically important fat-soluble antioxidants is synthetically available by various routes, for which key-intermediates containing trialkyl-substituted olefinic double bonds can now be prepared efficiently. The results presented may be of interest for the area of syntheses of isoprenoid natural products in general.