Peptide cyclization via late-stage functionalization of tryptophan by sulfonium

Abstract

Cyclic peptides exhibit important biological activities and are widely found in natural products and peptide-based drugs. Therefore, the development of synthesis methods for cyclic peptides is essential. In recent years, tryptophan-mediated cyclic peptides have emerged as bioactive molecules, but current methods require unique unnatural amino acids and transition metals as catalysts. Our group recently reported a tryptophan site-selective crosslinking in the protein binding pocket by sulfonium peptide via single-electron transfer under UV irradiation. Herein, we expanded the reaction from intermolecular to intramolecular crosslinking to achieve peptide cyclization. This method enables the preparation of tryptophan-mediated cyclic peptides from peptides via two steps: transformation of Met or Cys to dimethylsulfonium followed by crosslinking under UV irradiation with tryptophan. Therefore, this method enables synthesis using only natural amino acids, without any special catalysts. We also investigated the regioselectivity of the indole ring and found that C(6) was favoured, followed by C(4) and C(7). Next, we investigated crosslinking regioselectivity in the reader CBX1 protein binding pocket and found that C(7) was favoured, which was quite distinct from peptide cyclization. The collected data indicated that indole regioselectivity is determined by local interactions between the indole and sulfonium. Overall, this study demonstrated a feasible method for peptide cyclization using sulfonium and tryptophan. Although yield and regioselectivity are not great at the moment, we believe that this study will pave the way for future improvements based on mechanistic insights.