Synthesis of Amino Acid α-Thioethers and Late-Stage Incorporation into Peptides

The accelerating discovery of structurally distinct peptide natural products bearing alpha-thioether cross-links, such as the family of sactipeptide natural products, highlights the need for strategies to synthesize this underexplored functional motif. Herein, we describe the preparation of orthogonally protected, cross-linked amino acid alpha-thioether building blocks and probe their stability toward conventional solid-phase peptide synthesis. We overcome challenges with linkage lability by developing a late-stage, on-resin approach to alpha-thioethers, providing important proof-of-principle for sactipeptide synthesis.

Automated summary

This paper describes the preparation of cross-linked amino acid alpha-thioether building blocks and their stability towards conventional solid-phase peptide synthesis, overcoming challenges with linkage lability by developing a late-stage, on-resin approach to alpha-thioethers, providing important proof-of-principle for sactipeptide synthesis.