Solid-Phase Synthesis of Peptide Thioureas and Thiazole-Containing Macrocycles through Ru-Catalyzed Ring-Closing Metathesis

摘要

N-Terminally modified a-thiourea peptides can selectively be synthesized on solid support under mild reaction conditions using N,N'-di-Boc-thiourea and Mukaiyama's reagent (2-chloro-1-methyl-pyridinium iodide). This N-termi- nal modification applies to the 20 proteinogenic amino acid residues on three commonly used resins for solid-phase synthesis. Complementary methods for the synthesis of a- guanidino peptides have also been developed. The thiourea products underwent quantitative reactions with a-halo ketones to form thiazoles in excellent purities and yields. When strategically installed between two alkene moieties, said thiazole core was conveniently embedded in peptide macrocycles via Ru-catalyzed ring-closing metathesis reactions. Various 15—17 membered macrocycles were easily accessible in all diastereomeric forms using this methodology. The developed "build/ couple/pair" strategy is well suited for the generation of larger and stereochemically complete screening libraries of thiazole- containing peptide macrocycles.