Solid-Phase Synthesis of Hybrid Urea Oligomers Containing Conservative Thiourea Mutations

The introduction of a thiourea unit at a selected position in the backbone of aliphatic N,N′-linked urea foldamers can be used to locally modulate the secondary structure and physicochemical properties. To facilitate scanning the effect of thiourea introduction into biologically active oligourea helices, we have investigated the solid-phase synthesis of oligoureas containing a single oxo-to-thioxo replacement in their sequence. Several suitably protected activated monomers were considered, and conditions for their coupling and deprotection were evaluated and compared. The synthesis of oligo(thio)ureas on TFA-labile resins (i.e., Rink amide resin; TFA = trifluoroacetic acid) required careful optimization, and the choice of N-Fmoc-aminoalkyl isothiocyanates (Fmoc = fluorenylmethoxycarbonyl) as monomers for thiourea-bond formation was found to be critical.