Total Synthesis of Laulimalide: Assembly of the Fragments and Completion of the Synthesis of the Natural Product and a Potent Analogue

In this manuscript, we report the full account of our efforts to couple the northern and the southern building blocks, whose synthesis were described in the preceding paper, along with the modifications required which ultimately lead to a successful synthesis of laulimalide. Key highlights include an exceptionally efficient and atom-economical intramolecular ruthenium-catalyzed alkene-alkyne coupling to build the macrocycle followed by a highly stereoselective 1,3-allylic isomerization promoted by a rhenium complex. Interestingly, the designed synthetic route also allowed us to prepare an analogue of the natural product that possesses significant cytotoxic activity. We also report in this paper a second generation route which provided a more concise synthesis of the natural product.