Total Synthesis of Thiamyxins A–C and Thiamyxin E, a Potent Class of RNA‐Virus‐Inhibiting (Cyclo)depsipeptides

Abstract

We present the first total synthesis of the thiamyxins A–C and the now fully characterized thiamyxin E, an interesting class of thiazole‐ and thiazoline‐rich depsipeptides with diverse antiviral activity. The synthesis features a parallel closing of two methyl thiazoline units, with low epimerization of the very labile adjacent stereocenter. It also includes the three‐step synthesis of an uncommon hydroxy acid and the oxidation‐free elimination of a phenylselenide to form a dehydroalanine moiety. The exploitation of the acid‐labile stereocenter at the isoleucine moiety and the reopening of the macrolactones gave access to the four thiamyxins with good yields and diastereomeric purities from a single precursor. The modular total synthesis allows further testing of the biological activity and gives opportunities to explore the pharmacophore and antiviral target through derivatization.

Recent advances in discovery and biosynthesis of natural products from myxobacteria: an overview from 2017 to 2023

“…In light of the pronounced bioactivity, Kevin Bauer and Uli Kazmaier performed the total synthesis of the cyclic depsipeptides thiamyxins A and B as well as the open-chain derivatives thiamyxins C and E, setting the stage for studying the pharmacophore of thiamyxins or elucidating the antiviral target. 149 …”