Modular Approaches to Lankacidin Antibiotics

Abstract

Lankacidins are a class of polyketide natural products isolated from <i>Streptomyces spp.</i> that show promising antimicrobial activity. Owing to their complex molecular architectures and chemical instability, structural assignment and derivatization of lankacidins are challenging tasks. Herein we describe three fully synthetic approaches to lankacidins that enable access to new structural variability within the class. We use these routes to systematically generate stereochemical derivatives of both cyclic and acyclic lankacidins. Additionally, we access a new series of lankacidins bearing a methyl group at the C4 position, a modification intended to increase chemical stability. In the course of this work, we discovered that the reported structures for two natural products of the lankacidin class were incorrect, and we determine the correct structures of 2,18-<i>seco</i>-lankacidinol B and <i>iso</i>-lankacidinol. We also evaluate the ability of several <i>iso</i>- and <i>seco</i>-lankacidins to inhibit the growth of bacteria and to inhibit translation in vitro. This work grants insight into the rich chemical complexity of this class of antibiotics and provides an avenue for further structural derivatization.