Proximity-driven acceleration of challenging solid-phase peptide couplings
Abstract
Many important solid-phase synthesis reactions proceed slowly and inefficiently, for example, the coupling of an activated ester to a sterically hindered, bead-displayed amine, a critical step in the synthesis of many peptides. Forcing conditions are often required to achieve acceptable yields. We show here that such reactions can be accelerated by tethering to the bead a nucleophilic pyridine catalyst, which reacts with the activated ester, creating a high local concentration of a reactive acylpyridinium intermediate that couples efficiently to the bead-displayed amine. In many cases, the “cleanliness” of reactions carried out on resins equipped with an immobilized catalyst is substantially better than the analogous reactions in which the catalyst is added to the solution.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (6)
Joshua Parker
Department of Chemistry, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology, 120 Scripps Way, Jupiter, Florida 33458, United States
Brooke A. Farrell
Department of Chemistry and Biochemistry, University of North Carolina
Karlee A. Kohuth
Department of Chemistry and Biochemistry, University of North Carolina
Landon Parker
Department of Chemistry, The Herbert Wertheim University of Florida Scripps Institute for Biomedical Innovation and Technology
Skander A. Abboud
Department of Chemistry, The Herbert Wertheim University of Florida Scripps Institute for Biomedical Innovation and Technology
Thomas Kodadek
Department of Chemistry, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology, 120 Scripps Way, Jupiter, Florida 33458, United States