co400102v_si_001.pdf (9.83 MB)
Solid-Phase Synthesis of Peptide Thioureas and Thiazole-Containing Macrocycles through Ru-Catalyzed Ring-Closing Metathesis
journal contribution
posted on 2014-02-10, 00:00 authored by A. Emil Cohrt, Thomas E. NielsenN-Terminally
modified α-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-terminal modification
applies to the 20 proteinogenic amino acid residues on three commonly
used resins for solid-phase synthesis. Complementary methods for the
synthesis of α-guanidino peptides have also been developed.
The thiourea products underwent quantitative reactions with α-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.