The first total synthesis of melleumin A and four analogues of melleumins A and B is described. The N-acyl L-Thr-Gly/beta-hydroxy-gamma-amino acid coupling/macrolactamization strategy allowed the efficient assembly of the three segments being free of epimerization. While the Jouin-Castro method with minor modification allows a rapid entrance to the key syn-beta-hydroxy-gamma-amino acid segment, required for the synthesis of melleumin A, an extension of our malimide-based methodology using a changed N-protecting group affords a flexible access to several anti-beta-hydroxy-gamma-amino acids, and hence analogues of melleumins A and B. Among them, unnatural 4-epi-melleumin B (2a) exhibits a modest inhibitory activity on Wnt signaling. The total synthesis of melleumin A allowed confirmation of its full structure. ; NSFC [20572088, 20832005]; Innovative Research Team in Science & Technology (University) in Fujian Province