Strategy Evolution in the Total Synthesis of (−)-Leiodermatolide

Abstract

This review highlights the various challenges overcome during our recent synthetic campaign towards (−)-leiodermatolide, a potent cytotoxic and antimitotic macrolide isolated from the marine sponge $\textit{Leiodermatium}$ sp. This structurally unprecedented macrocyclic chemotype represents a promising lead for anticancer drug discovery, provided a sustainable supply can be realised by an efficient chemical synthesis. Faced with the stereochemical ambiguities arising from our structural assignment work, a flexible and modular synthetic strategy was adopted for the construction of various key fragments, as a prelude to the controlled assembly of the two diene moieties. Installation of the nine stereocentres was achieved by the strategic use of boron-mediated aldol reactions of chiral ketone building blocks. Following the exploratory construction of the macrocyclic core, we revised our strategy to circumvent some problematic steps, enabling a highly convergent total synthesis of (−)-leiodermatolide.