Fig. 4 Synthesis of artemisinin from R-(+)-pulegone.
Fig. 6 Synthesis of artemisinin from dihydroartemisinic acid.
One defining feature of terpenoid metabolites is their stereochemical complexity. In order to arrive at an efficient synthesis, the number of stereogenic steps must be minimized, and the level of stereocontrol at each of these steps must be maximized. A logical way to achieve these goals is to prioritize retrosynthetic transforms that efficiently set multiple stereocenters at once (see also ‘Pumilaside aglycon’ section). Furthermore, stereochemical relay from the substrate can be an effective tool to rapidly increase complexity, as long as the appropriate choreography of bond disconnections can be determined. Below, we document several recent examples of terpenoid synthesis and we focus on the stereochemical decisions made during retrosynthetic analysis. In many cases, the actual stereocontrol achieved is not perfect, even though the logic is good and reduces the length of the route. The lessons learned from these syntheses should inform future work in the same or related molecules.
Fig. 2 Synthesis of artemisinin from (-)-isopulegol.
Chain executes his strategy by first reacting the enolate of 6 with citronellal-derived enal 7. A modest 2:1 ratio of 8 to all other isomers is obtained, but this mixture can be subjected to samarium (II) iodide in hexamethylphosphoramide to effect carbonyl-alkene cyclization in 43% yield (maximum 66% yield based on 2:1 diastereomeric mixture of starting material). Keto-alcohol 9 is then elaborated to englerin A in four steps, completing a synthesis of only eight steps from commercial materials in a remarkable 20% overall yield.