Solid‐phase synthesis of functionalized bis‐peptides

We demonstrate the first solid‐phase synthesis of highly functionalized bis‐peptides. Bis‐peptides are ladder oligomers composed of stereochemically pure, cyclic bis‐amino acids joined by substituted diketopiperazine linkages. They have a shape‐programmable backbone that is controlled by controlling the stereochemistry and sequence of the monomers within each oligomer. Functionalized bis‐peptides are assembled using a new amide bond forming reaction (acyl‐transfer coupling) that we have previously developed and a novel activation strategy that allows the sequential formation of penta‐ and hexa‐substituted diketopiperazines from extremely hindered N ‐alkyl‐α,α‐disubstituted amino acids. We present mechanistic evidence that acyl‐transfer coupling is competitive with direct acylation in the formation of hindered amide bonds. We also detail the synthesis of four functionalized bis‐peptides, and that by combining bis‐peptides with amino acids through diketopiperazine linkages, bis‐peptides can mimic the display of residues i, i+4, i+7 of an α‐helical peptide. © 2011 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 96: 578–585, 2011.