Synthesis of cyclic RGD derivatives via solid phase macrocyclization usingthe Heck reaction

A novel intramolecular macrocyclization reaction on a solid support using t he Heck reaction has been achieved. For head to tail cyclization on a solid support, the linear precursor was anchored to a chlorotrityl chloride resi n via an ester linkage using the P-carboxyl group of Asp. The Heck coupling of acrylic acid amide to 3-iodobenzylamine on the solid support proceeds s moothly to yield a cyclic tetrapeptide derivative, which contains a new 3-s ubstituted cinnamic acid template and Arg-Gly-Asp sequence. The macrocycliz ation reaction takes place considerably more rapidly on a solid support tha n in solution. The solid phase procedure was successfully used for the cons truction of cyclic RGD libraries having diverse side chain structures, comb ined with a variety of ring sizes. (C) 2001 Elsevier Science Ltd. All right s reserved.