13-Oxyingenol derivative 1 and ingenol (3) are diterpenoids isolated from the plants of Euphorbia sp. The main structural features of ingenols are a bicyclo[4.4.1]undecane skeleton with inside-outside intrabridgehead stereochemistry and a high degree of oxygenation. They and their analogues showed interesting bioactivities. The molecular complexity of ingenol derivatives, in conjunction with their potent bioactivities, has made them attractive synthetic targets. We have achieved the first total synthesis of (-)-13-oxyingenol (2) and its natural derivative 1. The efficient functionalization of the A- and B-ring parts was established by using C-2 and C-7 hydroxy groups as clues. This approach is highlighted by RCM for the construction of an inside-outside framework, regio- and stereoselective dihydroxylation for the functionalization of the A-ring, and [2,3]-sigmalropic rearrangement for the functionalization of the B-ring.
