Total synthesis of (+)-spirastrellolide A methyl ester: Challenges and discoveries

This review focuses on recent synthetic efforts by our group towards spirastrellolide A methyl ester, a complex marine macrolide containing two spiroacetal ring systems that shows promising anticancer properties. The evolution of a flexible, modular strategy leading to the first total synthesis of (+)-spirastrellolide A methyl ester, and the associated challenges overcome, are highlighted, particularly in dealing with the initial structural ambiguities. This work enabled the development of an improved second-generation synthesis, which revealed a critical dependence of the key macrolactonization step on the nature of the protecting groups in the linker region between the spiroacetal motifs.