Studies toward the total synthesis of (+)‐neopeltolide using N‐heterocyclic carbene‐catalyzed oxo‐acyloxylation/reductive oxa‐Michael addition strategy

This article describes a concise synthesis of two important fragments (tetrahydropyran [THP] and ketone moieties) of the cytotoxic macrolide (+)‐neopeltolide in 10 long linear steps in enantiomerically pure form. Asymmetric Keck allylation to install the required C11 and C13 stereocenters, N‐heterocyclic carbene (NHC)‐catalyzed oxoacyloxylation to functionalize alkenes, and reductive oxa‐Michael addition to construct 2,6‐difunctionalized THP unit intramolecularly are the important steps in synthetic efforts. Finally, Keck asymmetric allylation and Lewis acid‐catalyzed diastereoselective allylation of the aldehyde were sequentially employed to establish the stereocenters at C11 and C13 positions, respectively. The synthesis of two key fragments of (+)‐neopeltolide, a marine macrolide with potent antiproliferative activity, is reported in 10 long linear steps in enantiomerically pure form. The synthetic protocol employs N‐heterocyclic carbene (NHC)‐catalyzed oxo‐acyloxylation/reductive oxa‐Michael addition as the key reaction.