Efficient solid-phase synthesis of peptides with tripodal side-chain bridges and optimization of the solvent conditions for solid-phase cyclizations.

Problems of cyclodimerization during the synthesis of two large-ring monocyclic peptides have allowed us to identify optimized solvent conditions for solid-phase cyclizations. These conditions combine high solvent polarity with excellent peptide-resin swelling. Using this newly optimized solvent system for the cyclizations, we have employed standard Boc/Benzyl methods and orthogonal Fmoc/OFm and Alloc/OAl protection to construct a novel type of bicyclic peptide with a tripodal side-chain bridge. The bridge, which links three amino-acid side chains to one trifunctional template, illustrates a new approach to peptide scaffolding for alpha-helix stabilization that might readily be applied to more complex structures.