Synthetic studies toward the cytotoxic norditerpene (+)-harringtonolide: setting up key-stereogenic centers of the cyclohexane ring D

The pivotal stereogenic centers of the asymmetric cycle D of (+)-harringtonolide were installed by functionalization of an enantiomerically pure IMDA cycloadduct, constructed from the chiral pool. The chiral 1,3-dioxane template used to direct the IMDA reaction was unraveled in an acidic medium, through spectacular hydrolysis of the acetal and concomitant lactone ring contraction. The central cyclohexene was selectively epoxidized either on the β- or on the α-side depending on the substitution pattern. The reactivity of several epoxide intermediates was challenged toward the construction of the oxygenated bridges of harringtonolide. We found one of them suitable for an access to another natural product, tetrodecamycin, which shares a similar substitution pattern as harringtonolide. Alternatively, functionalization led to set up key-stereocenters, en route to the asymmetric total synthesis of harringtonolide. The reactivity of the epoxide intermediates gave helpful insight for future work on this total synthesis.