Metathesis Reactions in Solid-phase Organic Synthesis

Metathesis Reactions in Solid-phase Organic Synthesis 

Sofa Barluenga, Pierre-Yves Dakas, RajamallesivarammaJogireddy, Ga ele Valot, and Nicolas Winssinger 

Metathesis in Natural Product Synthesis Strategies, Substrates and Catalysts. Edited by Janine Cossy, Stellios Arseniyadis, and Christophe Meyer 

Copyright 2010 WILEY-VCH Verlag GmbH Co. KGaA, Weinheim ISBN 978-3-527-32440-8 

This chapter is divided into six subsections which cover the most prominent applications of the metathesis reaction in solid-phase organic chemistry RCM for cleavages from the resin synthesis of small rings to macrocycles on the resin via RCM the use of the metathesis reaction for dimerization of polymer-bound small molecules RCM to constrict peptide conformations (while this is formally an RCM, it is treated separately because of the unique considerations of peptide chemistry) CM between a polymer-bound alkene and an alkene in solution and ene-yne metathesis. As the field evolved relatively rapidly with major advances in the catalysts, each subsection is organized in chronological order for the sake of clarity. 

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I 73 Metathesis Reactions in Solid-phase Organic Synthesis... 

The functional group tolerance of the ruthenium-based metathesis catalysts has had a tremendous impact on solid-phase organic synthesis. The efficacy of the reaction in solution generally translates directly to solid-phase transformation and its potential has been harnessed in a number of library syntheses, solid-phase syntheses of natural products, or diversity-oriented syntheses. It enables the use of chemically robust alkenes as linkers which can be cleaved by RCM or CM. It, of course, provides new manifolds of diversification in diversity-oriented synthesis as has been elegantly shown in landmark examples by Schreiber and Nelson. Another metathesis application of paramount importance is in peptide chemistry where solid-phase synthesis is omnipresent. The ability to stabilize secondary structures in short peptide motifs and replace pharmacologically unsuitable disulfide bonds or simply restrict the conformation of a peptidic library has already been successfully implemented in a number of important examples. The orthogonality of the metathesis reaction to peptide chemistry provides a really powerful tool in this regard. 

The olefin metathesis reaction has been proven to be an extremely useful tool for carbon-carbon bond formation in organic synthesis. Owing to the prevalence of this reaction in the synthetic organic literature, it is not surprising that it has been translated to the solid phase. Several metathesis catalysts, for example, A-C, have been developed and employed on the solid support for various applications (Figure 6.1)." Moreover, in several examples, the solid support affords a mechanism for the differentiation of the olefins, allowing the rapid removal of undesirable side products. 

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