Formal total synthesis of the myxobacteria metabolite apicularen A via a transannular oxy-Michael addition

The formal total synthesis of the myxobacteria metabolite (−)-apicularen A (1) is described. The key step utilized to construct the 2,6-trans-disubstituted tetrahydropyran ring was the transannular oxy-Michael addition of enone (+)-48 to form trans-pyranone (+)-50. Cyclisation of the C13 epimer (−)-49 also gave the same trans-pyranone (+)-50 demonstrating that the stereochemistry of the apicualren ring system can be controlled only by the C15 asymmetric centre. Reduction of the ketone in (+)-50 and demethylation gave the advanced apicularen intermediate 4 completing the formal total synthesis of the natural product 1.