Total and semi-syntheses of antimicrobial thuggacin derivatives

Abstract

The total and semi-synthesis of 13 new macrolactones derived from thuggacin, which is a secondary metabolite from the myxobacterium Sorangium cellulosum, are reported. The thuggacins have attracted much attention due to their strong antibacterial activity, particularly towards Mycobacterium tuberculosis. This study focuses on 1) thuggacin derivatives that cannot equilibrate by transacylation between the three natural thuggacins A-C, 2) the roles of the thiazole ring, and 3) the hexyl side chain at C2. Semi-synthetic O-methylation at C17 suppressed the transacylations without a substantial loss of antibacterial activity. Exchanging the C17-C25 side chain for simplified hydrophobic chains led to complete loss of antibacterial activity. Exchange of the thiazole by an oxazole ring or removal of the hexyl side chain at C2 had no substantial effect on the biological properties.

Keywords: antibiotics; lactones; natural products; synthesis design; total synthesis.