Bioinspired Syntheses of Seven Macrodiolide Analogs of Aplysiatoxin by the Late-Stage Functionalization of a Dehydroaplysiatoxin Derivative

Aplysiatoxin (ATX) is a bioactive polyketide natural product produced by cyanobacteria and characterized by macrodiolide and spiroacetal moieties. Many structurally diverse analogs of ATX have been reported but are little studied due to the minuscule quantities in which they have been isolated. We hypothesized that most of these analogs are biosynthesized from anhydroATX, a dehydrated form of ATX, and report a de novo synthesis of the phenolic OMe ether of anhydro-deBr-ATX, as well as syntheses of seven macrodiolide ATX analogs, OTX-B1, B2, M, J, and neo-deBr-ATX-A, G, and J, according to the biosynthetic hypothesis. One of the highlights is our synthesis of neo-deBr-ATX-G by a radical cascade reaction involving 1,5-HAT and an intramolecular conjugate addition to efficiently construct its novel bicyclic structure. This work resulted in revisions to the configurations of OTX-B1, B2, and neo-deBr-ATX-G, and the ring structure of OTX-M.