Synthesis of the Phormidolide A Macrocycle Supports the Proposed Configurational Reassignment

We describe the successful synthesis of the phormidolide A macrocycle as a crucial step toward its total synthesis and configurational assignment. Exhaustive exploration of macrocyclization strategies revealed the detrimental effects of a bulky protecting group on the C17 hydroxyl function, leading to the successful use of a C17 <i>p</i>-methoxybenzyloxymethyl (PMBM) ether in the macrolactonization reaction. Further elaboration of the macrocycle with a truncated C18-C23 side chain afforded an advanced C1-C23 fragment of phormidolide A. Detailed comparison of spectroscopic data with those of phormidolide A supports the proposed configurational reassignment.