Heronamides are biosynthetically related metabolites isolated from marine-derived actinomycetes. Heronamide C shows potent antifungal activity by targeting membrane phospholipids possessing saturated hydrocarbon chains with as-yet-unrevealed modes of action. In spite of their curious hypothesized biosynthesis and fascinating biological activities, there have been conflicts in regard to the reported stereochemistries of heronamides. Here, we describe the asymmetric total synthesis of the originally proposed and revised structures of heronamide C, which unambiguously confirmed the chemical structure of this molecule. We also demonstrated nonenzymatic synthesis of heronamides A and B from heronamide C, which not only proved the postulated biosynthesis, but also confirmed the correct structures of heronamides A and B. Investigation of the structure–activity relationship of synthetic and natural heronamides revealed the importance of both long-range stereochemical communication and the 20-membered macrolactam ring for the biological activity of these compounds.

The total synthesis of the proposed structure of heronamide C was accomplished through a Sato–Micalizio reductive alkyne–alkyne coupling strategy and remote-amine controlled stannylcupration. However, the physical data for the synthetic and natural samples differ from each other, which suggests that the proposed structure should be reinvestigated.

We have developed two syntheses of vicenistatin and its analogues. Our first-generation strategy included the rapid and sequential assembly of the macrocyclic lactam by using an intermolecular Horner–Wadsworth–Emmons reaction between the C3–C13 fragment and the C1–C2, C14–C19 fragment, followed by an intramolecular Stille coupling reaction. The second-generation strategy utilized a ring-closing metathesis of a hexaene intermediate to generate the desired 20-membered macrolactam. This second-generation strategy made it possible to prepare synthetic analogues of vicenistatin, including the C20- and/or C23-demethyl analogues. Evaluation of the cytotoxic effect of these analogues indicated the importance of the fixed conformation of aglycon for determining the biological activity of the vicenistatins.