Total synthesis of laulimalide: Assembly of the fragments and completion of the synthesis of the natural product and a potent analogue

Abstract

Herein, we present a full account of our efforts to couple the northern and the southern building blocks, the synthesis of which were described in the preceding paper, along with the modifications required to 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 a second generation route that provides a more concise synthesis of the natural product. All in one piece: Efforts to couple the northern and southern building blocks, synthesized in the preceding paper, along with modifications required to lead to a successful synthesis of laulimalide are discussed. Interestingly, the designed synthetic route also allowed the preparation of an analogue of the natural product that possesses significant cytotoxic activity (see scheme). A more concise, second-generation route to the natural product is also described. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.