Expedient Synthesis of Large-Ring trans-Enamide Macrolides by CuI-Mediated Intramolecular Coupling of Vinyl Iodide with Amide: Total Synthesis of Palmyrolide A

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.