Synthesis and Structure–Activity Relationship of Vicenistatin, a Cytotoxic 20‐Membered Macrolactam Glycoside

Abstract

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.

Asymmetric Total Synthesis of Heronamides A–C: Stereochemical Confirmation and Impact of Long‐Range Stereochemical Communication on the Biological Activity

“…In previous studies, we and others successfully utilized ring‐closing metathesis (RCM) reactions during the total synthesis of polyene macrocyclic natural products such as vicenistatin, FD‐891, and incednam . We therefore attempted to construct a 20‐membered polyene macrolactam skeleton by using RCM as shown in Scheme .…”

A Concise and Unified Strategy for Synthesis of the C1–C18 Macrolactone Fragments of FD-891, FD-892 and Their Analogues: Formal Total Synthesis of FD-891

“…We expected that the C8–C9 epoxide could be installed stereoselectively in the late stage of the synthesis by utilizing an adjacent C7 or C10 hydroxyl group. However, the construction of the C12–C13 ( E )-olefin via the ring-closing metathesis (RCM) reaction of A could be challenging, because RCM between the C13 and C2 carbons has the potential to generate δ-lactone: However, we previously experienced a similar situation during the synthesis of polyene macrolactam glycoside, in which the RCM between terminal monosubstituted olefins was predominant over the other RCMs to deliver the desired macrocycle. Thus, we expected that selective formation of the C12–C13 olefin was also feasible in the present case.…”