Chloromethyl Polystyrene

The Merrifield resin has in the past been the standard support for the synthesis of peptide acids by Boc strategy. Originally, the cesium salt of a protected amino acid was anchored to the chloromethyl support via nucleophilic displacement of chlorine. Although, Me4N salts, sodium salts in THF with Bu4NF catalysis and more recently zinc salts in EtOH have also been used. Cleavage is normally effected by treatment with HF or trifluoromethanesulfonic acid or by hydrogenolysis, alcohols can be released by using diisobutylaluminium hydride or LiBH4. For cleavage scavengers may be required. New isomeric trialkoxybenzylamine resins have been developed by coupling phthalimidomethyl-3,5-dimethoxyphenols to this resin followed by subsequent treatment with hydrazine, that allows DCC coupling with the carboxyl function of amino acids or peptides. The addition of alcohols can be performed by heating the corresponding potassium or sodium alkoxide and the resin in DMF. Reductive cleavage of the anchoring ester linkage was also accomplished. Attachment of sodium dihydrocinnamate to this resin and treatment with a solution of lithium diisopropylamide (LDA) in THF formed a resin-bound zinc enolate for aldol condensations. Reductive cleavage with diisobutylaluminium hydride afforded a 1,3-diol library. The removal of ß-lactams has been achieved by using aluminium chloride. Another application of this support to nonpeptides involved anchoring the cesium salts of bromo or iodobenzoic acids followed by subsequent transformation into biaryl derivatives using Suzuki coupling conditions. The products were released from the resin via nucleophilic attack with methoxide ion to give methyl esters.