Total Synthesis and Biological Assessment of Mandelalide A.

Abstract

A new convergent total synthesis of the marine macrolide mandelalide A (1) has been developed that is based on macrocyclic ring closure by a Shiina-type macrolactonization and the construction of the requisite precursor seco acid by a highly efficient Sonogashira cross-coupling reaction between two fragments of comparable complexity. Key steps in the elaboration of the acid building block were the enantioselective, catalytic addition of a protected acetylene to crotonaldehyde and the construction of the tetrahydropyran unit that is embedded in the macrocycle by means of an acid-catalyzed Prins reaction. The synthesis of the alcohol fragment features the formation of the trisubstituted tetrahydrofuran ring through an acetal cleavage/epoxide opening cascade reaction and a rarely used radical alkynylation of a primary alkyl iodide. Intriguingly, the dihydroxylation of a terminal double bond as part of the synthesis of this building block gave the same major product for both the α- and β-AD-mix reagents, albeit with moderate or low selectivity. Synthetic mandelalide A (1) was a potent proliferation inhibitor of A549, HT460, and H1299 human lung cancer cells in vitro, but not of SK-N-SH neuroblastoma cells. However, in no case did we observe complete cell kill even at the highest compound concentration tested (5 μm).