An Alkanesulfonamide “Safety-Catch” Linker for Solid-Phase Synthesis

An alkanesulfonamide "safety-catch" linker has been developed for tethering carboxylic acids to support. Acylation of the sulfonamide support provides a support-bound N-acylsulfonamide that is stable to both basic and strongly nucleophilic reaction conditions. At the end of a solid-phase synthesis sequence, treatment with iodoacetonitrile provides N-cyanomethyl derivatives that can be cleaved by nucleophiles under mild reaction conditions to release the target compounds. Coupling conditions have been developed to load Boc- and Fmoc-amino acids to the alkanesulfonamide resin with high loading efficiencies and minimal racemization. A number of support-bound amino acids incorporating diverse side-chain functionality have been subjected to a short synthesis sequence, followed by iodoacetonitrile activation and nucleophilic displacement to provide dipeptide products. All 20 of the proteinogenic amino acids, when suitably protected, are compatible with the loading and activation steps. Finally, displacement with various nucleophiles including amines, α-amino acid methyl esters, and α-amino acid coumarin derivatives is demonstrated.