Synthesis and Functionalization of Highly Biologically Active Terpene Natural Products − Total Synthesis of (+)-Darwinolide and Semisynthesis of (−)-Englerin A and Structure-Activity Relationship Studies of Analogs

Abstract

This thesis describes the successful first total synthesis of the biofilm-penetrating anti-MRSA agent (+)-darwinolide. The synthesis of this rearranged diterpenoid was achieved via a convergent strategy. One fragment was synthesized from (S)-isophorol using an Ireland-Claisen rearrangement as the key step. The synthesis of the second fragment featured a highly enantioselective organocatalytic desymmetrization of a meso-diol. Fragment coupling was achieved by Aldol addition and the central seven-membered ring was closed by olefin-metathesis. In the second project of this thesis, a concise semisynthetic access to the renal cancer inhibitor (−)-englerin A was achieved. The starting material, guaia-6,10(14)-diene was obtained by synthetic biology and was also used for the syntheses of (−)-oxyphyllol and (+)-orientalol E. Furthermore, seven new analogs of englerin A were synthesized, and their structure-activity relationship was studied.