Solid‐Supported Synthesis of Bicyclic Peptides Containing Three Parallel Peptide Chains

Four homodetic bicyclic peptides 9a − d , containing three parallel peptide chains, were synthesized on a hydroxymethyl‐functionalized polystyrene support. α,α‐Bis(aminomethyl)‐β‐alanine, bearing orthogonal protections (Alloc, Boc, Fmoc) on the three amino groups ( 1 ), was attached to the support through an H 2 N‐Leu‐Leu‐Gly‐OH spacer, and the peptide chains were assembled on the amino groups of 1 by either a stepwise coupling or coupling of a segment, keeping the amino protection within each chain unchanged. N ‐(4‐Allyloxy‐4‐oxobutanoyl)iminodiacetic acid ( 2 ) was then coupled to the Fmoc‐protected chain. The Boc protecting group was removed, and the exposed amino group was coupled with the remaining free carboxylic acid function of 2 . Finally, the Alloc and allyl ester protections were removed from the carboxylic and amino functions, and a second cyclization was performed. Release from the support gave 9a − d as free carboxylic acids. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)