Synthetic Approaches to the Macrocyclic Natural Product Tripartilactam

Abstract

In 2012 Oh and co-workers reported the isolation of the tricyclic macrolactam tripartilactam from a Streptomyces sp. found in the brood ball of the dung bettle Copris tripartitus. The compound proved to be a moderate inhibitor of sodium/potasium ATPase. The unique and rather complex structure embodies a cyclobutane fused, on its opposing faces, to both an 8- and an 18-membered ring. These architecturally novel features prompted the author to pursue a total synthesis of it. Chapter One provides a brief introduction to the isolation, structural elucidation and proposed biogenesis of tripartilactam. This section also provides details of selected organic reactions that played important roles in the synthetic studies of the author, in particular the Stille cross-coupling, olefin metathesis and olefination reactions. Chapter Two describes two distinct sets of manipulations of the enantiomerically pure chloro cis-1,2-dihydrocatechol, readily obtained through the whole-cell biotransformation of chlorobenzene, into a terminal allene/carbonyl-conjugated alkene and a polyoxygenated cyclooctenone embodying the Eastern Hemisphere of the non-natural enantiomeric form of tripartilactam. Attempts to elaborate these intermediates to the bicyclo[6.2.0]decane system via both intra- and inter-molecular [2+2]-cycloaddition reactions are also discussed. The research detailed in Chapters Three, Four and Five are focused on the synthesis of a macrolactam that it was thought could engage in a transannular [2+2]-cycloadditon reaction and thus mimicking the final step in the proposed biogenesis of tripartilactam. A macrolactone was identified as a potential precursor to tripartilactam and attempts to prepare the former compound are described in Chapter Six. Show more