E- and Z-Trisubstituted macrocyclic alkenes for natural product synthesis and skeletal editing

Many therapeutic agents are macrocyclic trisubstituted alkenes, and yet, preparation of these structures is typically inefficient and nonselective. A possible solution would entail catalytic macrocyclic ring-closing metathesis, but these transformations require high catalyst loading, conformationally rigid precursors, and are often low yielding and/or non-stereoselective. Here, we introduce a ring-closing metathesis strategy for synthesis of trisubstituted macrocyclic olefins in either stereoisomeric form, regardless of the level of entropic assistance. The goal was achieved by addressing several unexpected difficulties, including complications arising from pre-ring-closing metathesis alkene isomerization. The power of the method is highlighted by two examples. One being the near-complete reversal of substrate-controlled selectivity in the formation of a macrolactam related to an anti-fungal natural product. The other is a late-stage stereoselective generation of a E-trisubstituted alkene in a 24-membered ring, en route to cytotoxic natural product dolabelide C.