An Enantioselective Synthesis of FR182877 Provides a Chemical Rationalization of Its Structure and Affords Multigram Quantities of Its Direct Precursor

The evolution of a strategy culminating in an efficient, enantioselective synthesis of the potent
microtubule-stabilizing agent FR182877 is described. Guided by a proposed biogenesis of this complex
natural product, a solution emerged that involved the first reported example of a double transannular Diels−Alder reaction to fashion the key elements of its hexacyclic structure. This pivotal transformation creates
a complex pentacycle from a 19-membered macrocyclic pentaene, forming seven new stereogenic centers
in a fully diastereocontrolled fashion. The efficiency of the approach ultimately enabled the preparation of
multigram quantities of the direct precursor of FR182877 for conversion to the relatively unstable natural
product when required. The reactivity of the strained, bridgehead olefin of this secondary metabolite with
biologically relevant nucleophiles is also described.