The stereoselective total synthesis of sanctolide A, a 14‐membered polyketide‐nonribosomal peptide (PK‐NRP) hybrid macrolide, was accomplished. Sanctolide A contains a rare N‐methyl enamide and 2‐hydroxyisovaleric acid functionality embedded into the macrocycle. The synthesis relied on Yamaguchi esterification and intramolecular dehydrative cyclization reactions to construct the core skeleton of the macrolide. The two key chiral centers were generated by Maruoka's allylation and Noyori's asymmetric ketone reduction reactions. Commercially available, inexpensive 2‐hydroxyisovaleric acid and hexanaldehyde were utilized as the raw materials for the total synthesis.

An efficient and improved procedure for copper‐catalyzed coupling of vinyl iodide with amide in an intramolecular fashion is described. The protocol utilizes a combination of copper iodide, CsF and (±)‐1,2‐diaminocyclohexane as ligand. The vinyl iodide couples efficiently with the amide to generate an enamide macrolide without any alteration in the double ‐bond geometry. The developed method was applied in the synthesis of several large‐ring enamide macrolides, and for the total synthesis of natural product palmyrolide A and homologated sanctolide A.

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