Nickel-Catalyzed Regiodivergent Approach to Macrolide Motifs.

A strategy for regiochemical reversal of reductive macrocyclizations of aldehydes and terminal alkynes has been developed. Using an advanced synthetic intermediate directed towards the methymycin/neomethymycin class of macrolides, selective endocyclization provides the natural twelve-membered ring series, whereas ligand alteration enables selective exocyclization to provide access to the unnatural eleven-membered ring series. The twelve-membered ring adduct was converted to 10-deoxymethynolide, completing an efficient total synthesis of this natural product.