Silanol: a bifunctional group for peptide synthesis and late-stage functionalization

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Peptide Chemistry

Background:

• Chemical modification of peptides improves pharmacokinetics and enables post-synthetic diversification.
• Late-stage functionalization is crucial for efficient peptide modification.

Purpose of the Study:

• To develop a novel palladium-catalyzed late-stage ortho-olefination of tyrosine (Tyr) residues on peptides.
• To achieve high chemo- and site-selectivity in peptide modification.
• To establish orthogonal protection strategies for Tyr residues applicable to solid-phase peptide synthesis (SPPS).

Main Methods:

• Utilized a palladium-catalyzed reaction for C(sp2)-H functionalization.
• Employed a silanol group as a bifunctional protecting and directing group for Tyr residues.
• Investigated the compatibility with various peptide sequences, Tyr residue locations, and olefins.
• Developed orthogonal protection strategies for Tyr residues.

Main Results:

• Achieved the first Pd-catalyzed late-stage ortho-olefination of Tyr residues on peptides with high selectivity.
• Demonstrated compatibility with hexapeptides containing varied amino acid sequences and Tyr positions.
• Showcased the utility of the developed orthogonal protection strategies for SPPS.

Conclusions:

• The developed protocol expands the chemical toolbox for late-stage peptide modification via C(sp2)-H functionalization.
• The method offers a versatile approach for enhancing peptide properties and enabling diversification.
• Orthogonal protection strategies are compatible with solid-phase peptide synthesis, facilitating broader applications.