Total Synthesis of (-)-Brevenal: A Streamlined Strategy for Practical Synthesis of Polycyclic Ethers

We describe a streamlined strategy for the practical synthesis of trans-fused polycyclic ethers and its application to a concise total synthesis of (-)-brevenal, a new pentacyclic polyether natural product with intriguing biological activities. The B-, D-, and E-rings were constructed by TEMPO/PhI(OAc)2-mediated oxidative lactonization of the corresponding 1,6-diols, with minimal need for manipulation of oxygen functionalities. The B- and E-ring lactones were appropriately functionalized by SuzukiMiyaura coupling of lactone-derived enol phosphates and subsequent stereoselective hydroboration. The A-ring was formed by our mixed thioacetalization methodology. The AB- and DE-ring fragments were assembled through SuzukiMiyaura coupling, and the C-ring was forged in the same manner as that for the A-ring. More than two grams of the pentacyclic polyether core of (-)-brevenal have been synthesized by the synthetic route developed in this study.