Synthesis and structure-activity relationship of vicenistatin, a cytotoxic 20-membered macrolactam glycoside

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. An enantioselective total synthesis of vicenistatin (1) was accomplished by using an intermolecular Horner-Wadsworth-Emmons reaction and a ring-closing metathesis as key steps. This strategy made it possible to prepare synthetic analogues of vicenistatin, including the C20- and/or C23-demethyl vicenistatins. Evaluation of their cytotoxicity indicated the importance of the fixed conformation of aglycon in determining biological activity.