Peptide cyclization via late-stage functionalization of tryptophan by sulfonium

Abstract

Cyclic peptides play important biological functions in natural products and peptide drugs. Therefore, the development of synthesis methods for cyclic peptides is essential. In recent years, tryptophan-mediated cyclic peptides are being reported as bioactive molecules, but current methods require unique unnatural amino acid and transition metal as a catalyst. Our group recently reported a tryptophan site-selective crosslinking in the protein binding pocket by sulfonium peptide via single-electron transfer under UV irradiation. Here, we expanded the reaction from intermolecular to intermolecular crosslinking so as for peptide cyclization. This method allows the preparation of tryptophan-mediated cyclic peptides from peptides in two steps, transformation of Met or Cys to dimethylsufonium followed by tryptophan crosslinking under UV irradiation. Therefore, this method enables synthesis with only natural amino acid and without special catalysts. We also investigated the regioselectivity of the indole ring and found C(6) was favored, followed by C(4) and C(7). Next, we investigated crosslinking regioselectivity in reader CBX1 protein binding pocket and found C(7) was favored, that was quite distinct from peptide cyclization. The collected data indicated that the indole regioselectivity is determined by local contact between indole and sulfonium. Overall, this study demonstrated a feasible method of peptide cyclization by sulfonium and tryptophan. Although the yield and regioselectivity were not great at this moment, we believe this study paved the way for future improvement based on the mechanisms.