Abstract
Parallel synthesis of peptides and peptidomimetics has been an important approach to search for biologically active ligands. A novel systematic synthesis of different size bicyclic dipeptide mimetics was developed on solid‐phase supports. By taking advantage of the enantioselective synthesis of ω‐unsaturated amino acids and their N‐methylated derivatives, the hemiaminal problem was prevented in the pathway to thiazolidine formation. The bicyclic dipeptide was generated on the solid‐phase support in three steps by an unconventional method. By inserting this bicyclic scaffold into the synthesis of a larger bioactive peptide, 11 different sizes of bicyclo^[2,3]^‐Leu‐enkephalin analogues were synthesized in a fast and efficient way. Modeling studies show that a reversed turn structure at positions 2–3 was favored when an L‐ and L‐bicyclic scaffold was used, and that an extended conformation at the N‐terminal was favored when a D‐ and L‐bicyclic scaffold was inserted. Binding affinities and bioassay studies show ligands with micromolar binding affinities and antagonist bioactivities for the [6,5]‐ and [7,5]‐bicyclo‐Leu‐enkephalin analogues. © 2005 Wiley Periodicals, Inc. Biopolymers (Pept Sci), 2005