Evolution of the Total Synthesis of (−)-Okilactomycin Exploiting a Tandem Oxy-Cope Rearrangement/Oxidation, a Petasis−Ferrier Union/Rearrangement, and Ring-Closing Metathesis

An effective, asymmetric total synthesis of the antitumor antibiotic (−)-okilactomycin (1), as well as assignment of the absolute configuration, has been achieved exploiting a convergent strategy. Highlights of the synthesis include a diastereoselective oxy-Cope rearrangement/oxidation sequence to install the C(1) and C(13) stereogenic centers, a Petasis−Ferrier union/rearrangement to construct the highly functionalized tetrahydropyranone inscribed within the 13-membered macrocycle ring, employing for the first time a sterically demanding acetal, an intramolecular chemoselective acylation to access an embedded bicyclic lactone, and an efficient ring-closing metathesis (RCM) reaction to generate the macrocyclic ring.