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 thiazolinerich 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 threestep synthesis of an uncommon hydroxy acid and the oxidation-free elimination of a phenylselenide to form a dehydroalanine moiety. The exploitation of the acidlabile 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.