The First Total Synthesis of (±)-Ingenol

Abstract

The first total synthesis of (+/-)-ingenol has been achieved. The key features of the synthesis include the use of a highly diastereoselective Michael reaction to fix the C-11 methyl stereochemistry and the incorporation of the dimethylcyclopropane via diastereoselective carbene addition to the Delta13,14 olefin. The intramolecular dioxenone photoaddition-fragmentation sequence leads to the establishment of the critical C-8/C-10 trans intrabridgehead stereochemistry, a central challenge in the synthesis of ingenanes. The completion of the synthesis proceeds using the C-6alpha hydroxymethyl group as the sole handle for oxidation of seven contiguous carbon centers.

Synthesis of Medicinally Relevant Terpenes: Reducing the Cost and Time of Drug Discovery

“…The limited quantities of 59 available from plant extraction (390 mg, 59 , from 2 kg dried seeds) [59] and the diverse phenotypic responses of cells to ingenol analogs indicate that the development a practical, diversifiable synthetic route to this metabolite might enable significant contributions to medicine and biology [59]. Three previous total syntheses of ingenol have been published, all requiring between 37 and 45 steps [60–63]. Although these exercises have made important contributions to understanding the reactivity of ingenanes, they are impractical for analog exploration or large-scale production.…”

Preparation and Applications of 4-Methoxybenzyl Esters in Organic Synthesis

“…This route was able to provide ample material for subsequent studies on the biological activity of ingenol analogues that focused on their binding to protein kinase C; 110 the route was also eventually adapted to a total synthesis of ingenol ( 170 ). 111 …”

Sources for Leads: Natural Products and Libraries

“…While the first total synthesis was published in 2002 (Winkler et al 2002), a highly efficient total synthesis was published recently, which could possibly be more favorable than the current biotechnological production methods (McKerrall et al 2014). …”