Total Synthesis of Xentrivalpeptide A and Its 6α-epi Derivative

We report the first total synthesis of xentrivalpeptide A, a cyclic heptadepsipeptide natural product, through a convergent solution-phase strategy. The linear macrocyclization precursor was assembled from two peptide fragments, and a key DEPBT-mediated macrolactamization efficiently furnished the macrocyclic core despite the sterically demanding Val–Val cyclization junction. Late-stage installation of the side chain onto the common cyclic hexadepsipeptide core provides a potentially general route to other members of the xentrivalpeptide family. Additionally, switching the macrocyclization reagent from DEPBT to PyBOP enabled access to the diastereomeric congener 6α-epi-xentrivalpeptide A.