ORGN 346

^"

Linker strategies lie at the heart of solid phase synthesis and combinatorial chemistry. We have recently developed a new class of linkers known as HASC (a-Hetero-Atom Substituted Carbonyl) linkers cleaved using SmI₂. A sulfur-based HASC linker has the advantage that the sulfur atom not only links the substrate to resin but also ‘enables’ additional chemistry to be performed at the point of attachment to the resin. Specifically, generation of sulfonium ions allows Pummerer chemistry to be carried out. Pummerer cyclisations are a powerful method for generating carbocycles and heterocycles.A traceless sulfur HASC linker has been developed and applied to the solid phase synthesis of oxindoles.

The oxindole framework is a recurring structural motif in many biologically active compounds. We have carried out the first Pummerer cyclisations on resin in a convenient route to oxindoles. a-Bromoacetamides are immobilised using a benzyl thiol resin. Oxidation, Pummerer cyclisation and cleavage with SmI₂ gives the desired oxindole products. A variety of oxindoles bearing neutral, electron rich and electron deficient aromatic systems have been synthesised in good yields and high purity using our approach. Crucially, the sulfur link to the resin remains intact through the cyclisation thus allowing further on-resin modification of the product heterocyclic framework before cleavage.