Versatile Post‐synthetic Modifications of Helical β‐Peptide Foldamers Derived from a Thioether‐Containing Cyclic β‐Amino Acid

Abstract

AbstractWe introduce a novel cyclic β‐amino acid, trans‐(3S,4R)‐4‐aminotetrahydrothiophene‐3‐carboxylic acid (ATTC), as a versatile building block for designing peptide foldamers with controlled secondary structures. We synthesized and characterized a series of β‐peptide hexamers containing ATTC using various techniques, including X‐ray crystallography, circular dichroism, and NMR spectroscopy. Our findings reveal that ATTC‐containing foldamers can adopt 12‐helical conformations similar to their isosteres and offer the possibility of fine‐tuning their properties via post‐synthetic modifications. In particular, chemoselective conjugation strategies demonstrate that ATTC provides unique post‐synthetic modification opportunities, which expand their potential applications across diverse research areas. Collectively, our study highlights the versatility and utility of ATTC as an alternative to previously reported cyclic β‐amino acid building blocks in both structural and functional aspects, paving the way for future research in the realm of peptide foldamers and beyond.