Novel thermally cleavable safety-catch linkers for combinatorial chemistry

Abstract

Two novel thermally cleavable safety-catch linkers were developed for solid phase organic synthesis, based on the sulfoxide/selenoxide pericyclic elimination reaction. The linkers were evaluated using various substrates; both peptides and small organic molecules.

Activation of the safety-catch was achieved via selective oxidation of the sulfide/selenide to the corresponding sulfoxide/selenoxide. A novel oxidation method for the solid phase oxidation of sulfides to sulfoxides was developed whereby hydrogen peroxide was used in hexafluoroisopropanol (HFIP) preventing undesirable over-oxidation to the sulfone.

Cleavage of the sulfoxide linker was only possible using high temperature (100°C) and an activated substrate. In contrast, the selenoxide elimination occurred at room temperature, hence allowing milder cleavage conditions. The selenoxide linker was synthesised with a number of substrates, both peptides and small organic molecules. Cleavage was successful at room temperature, although further optimisation is required.

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