Evolution of a Protecting-Group-Free Total Synthesis: Studies en Route to the Neuroactive Marine Macrolide (−)-Palmyrolide A

A full account of our synthetic work toward the first total synthesis of the neuroactive marine macrolide (−)-palmyrolide A is described. Our first-generation approach aimed to unlock the unknown C(5)–C(7) stereochemical relationship via the synthesis of four diastereomers of palmyrolide A aldehyde, a known degradation product. When these efforts provided inconclusive results, recourse to synthesizing all possible stereocombinations of the 15-membered macrolide was undertaken. These studies were critical in confirming the absolute stereochemistry, yielding the first total synthesis of (+)-ent-palmyrolide A. Subsequent to this work, the first protecting-group-free total synthesis of natural (−)-palmyrolide A is also reported.