Concise Enantioselective Total Synthesis of (+)-Punctaporonin U

We report herein the first enantioselective total synthesis of (+)-punctaporonin U, a cage-like pentacyclic sesquiterpene bearing eight contiguous stereocenters. The synthesis features three key transformations: a) a rare <i>cis</i>-selective Mukaiyama-Michael addition of the silyl enol ether derived from 2,2-dimethylcyclobutan-1-one to 4-[(<i>tert</i>-butyldimethylsilyl)oxy]cyclopent-2-en-1-one; b) a domino oxa-Michael addition/aldol reaction/bromination sequence that constructs both a fused five-membered ring and a 1,4-bridged 7-membered ring; c) an intramolecular S_N2 displacement to install the 1,3-bridged tetrahydrofuran ring. The synthesis is accomplished in six steps from 4-[(<i>tert</i>-butyldimethylsilyl)oxy]cyclopent-2-en-1-one, which itself is accessible in five steps from cyclopentadiene.