The first total synthesis of (+)-clavilactone B, a potent antifungal agent and novel tyrosine kinase inhibitor, is described. The absolute configuration of clavilactones has been unambiguously established by using Sharpless asymmetric epoxidation to generate the enantiomerically pure substrate. The strategy highlights the use of a powerful and convergent three-component benzyne coupling with a methylallyl Grignard and a chiral epoxy-aldehyde to generate two C-C bonds and install the carbon skeleton of clavilactone. Oxidative lactonization, ten-membered ring construction by ring closing metathesis, and oxidation gave clavilactone B.