Asymmetric Syntheses and Wnt Signal Inhibitory Activity of Melleumin A and Four Analogues of Melleumins A and B

Guided by nature : A flexible and epimerization‐free approach for the asymmetric syntheses of melleumin A and four analogues of melleumins A and B was developed, which allowed confirming the stereochemistry at C‐4 of melleumin A, and revealed that the unnatural 4‐ epi ‐melleumin B possesses a modest inhibitory activity on Wnt signaling.The first total synthesis of melleumin A and four analogues of melleumins A and B is described. The N ‐acyl L ‐Thr‐Gly/β‐hydroxy‐γ‐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 ‐β‐hydroxy‐γ‐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 ‐β‐hydroxy‐γ‐amino acids, and hence analogues of melleumins A and B. Among them, unnatural 4‐ epi ‐melleumin B ( 2 a ) exhibits a modest inhibitory activity on Wnt signaling. The total synthesis of melleumin A allowed confirmation of its full structure.