Strategy Evolution in the Total Synthesis of Spirastrellolide A Methyl Ester

This review highlights the many challenges overcome during our recent synthetic campaign towards spirastrellolide A, a structurally unprecedented antimitotic marine macrolide that potently and selectively inhibits protein phosphatases, and represents a promising lead for anticancer drug discovery. Faced with the initial stereochemical ambiguities, a flexible and modular synthetic strategy was adopted for the construction of increasingly elaborate fragments of the architecturally complex macrolactone to enable further structural elucidation by detailed NMR analysis. A reliable and convergent synthetic route evolved to encompass the use of boron-mediated aldol reactions to install much of the required oxygenation pattern and associated stereocenters, together with a tandem double Sharpless asymmetric dihydroxylation and cyclization to efficiently access the signature DEF-[5,6,6]-bis-spiroacetal region from a linear diene precursor. A pivotal sp2-sp3 Suzuki fragment coupling, followed by a double hydroboration of the resulting diene, then provided an advanced C17-C40 aldehyde which was coupled with a suitable C1-C16 alkyne. Following BC-spiroacetalization, a high yielding Yamaguchi macrolactonization afforded the C1-C40 macrocyclic core, where the full side chain was then introduced by sequential olefin cross-metathesis and π-allyl Stille cross-coupling, culminating in the first total synthesis of spirastrellolide A methyl ester.