Total Synthesis of (−)‐Zampanolide and Structure–Activity Relationship Studies on (−)‐Dactylolide Derivatives

A new total synthesis of the marine macrolide (−)‐zampanolide ( 1 ) and the structurally and stereochemically related non‐natural levorotatory enantiomer of (+)‐dactylolide ( 2 ), that is, ent ‐ 2 , has been developed. The synthesis features a high‐yielding, selective intramolecular Horner–Wadsworth–Emmons (HWE) reaction to close the 20‐membered macrolactone ring of 1 and ent ‐ 2 . The β‐keto phosphonate/aldehyde precursor for the ring‐closure reaction was obtained by esterification of a ω‐diethylphosphono carboxylic acid fragment and a secondary alcohol fragment incorporating the THP ring that is embedded in the macrocyclic core structure of 1 and ent ‐ 2 . THP ring formation was accomplished through a segment coupling Prins‐type cyclization. Employing the same overall strategy, 13‐desmethylene‐ ent ‐ 2 as well as the monocyclic desTHP derivatives of 1 and ent ‐ 2 were prepared. Synthetic 1 inhibited human cancer cell growth in vitro with n M IC 50 values, while ent ‐ 2 , which lacks the diene‐containing hemiaminal‐linked side chain of 1 , is 25‐ to 260‐fold less active. 13‐Desmethylene‐ ent ‐ 2 as well as the reduced versions of ent ‐ 2 and 13‐desmethylene‐ ent ‐ 2 all showed similar cellular activity as ent ‐ 2 itself. The same activity level was attained by the monocyclic desTHP derivative of 1 . Oxidation of the aldehyde functionality of ent ‐ 2 gave a carboxylic acid that was converted into the corresponding N‐hexyl amide. The latter showed only μ M antiproliferative activity, thus being several hundred‐fold less potent than 1 .