Total Synthesis of Damasterpenes II, IV, V, and VII

Abstract

Damasterpenes are highly oxygenated, multiply acylated dolabellane diterpenoids with anti-herpes simplex virus type 1 activity. These compounds share an 11/5-trans-fused carboskeleton with three methyl groups and one isopropyl group, but differ in their unsaturation, oxidation, and acylation patterns. Here, we present the first total synthesis of damasterpenes II, IV, V, and VII. In the first stage, a common 11/5-fused intermediate was convergently assembled using radical-polar crossover three-component coupling to install the two carbon branches onto the five-membered ring, followed by ring-closing metathesis to form the medium-sized 11-membered ring. In the second stage, this intermediate was transformed into damasterpenes II, IV, V, and two possible structures of damasterpene VII by tuning the oxidation levels and introducing three to four acyl groups. These architecturally complex molecules bearing 8 to 10 stereocenters were synthesized in 26–29 steps, and the previously unknown stereochemistry of damasterpene VII was elucidated. This work demonstrates the value of radical-polar crossover reactions for the rapid construction of densely substituted molecular frameworks and highlights the importance of controlling the three-dimensional conformations of 5- and 11-membered rings to achieve site- and stereoselective functional group manipulations.