Collective total syntheses of cytochalasans and merocytochalasans

Abstract

Cytochalasans are an important class of fungal metabolites displaying remarkable structural diversity and significant biological activity. Historically, considerable effort has been devoted toward the synthesis of cytochalasans. Comparably, merocytochalasans, an array of more complicated molecules biosynthetically derived from cytochalasans and epicoccine through hetero-dimerization, -trimerization or -tetramerization, have been less explored. In recent years, our group has shown keen interest on cytochalasans and merocytochalasans, which has culminated in the collective syntheses of a variety of representative molecules of this family. To this end, we first developed a highly concise, efficient and modular approach to access 11/6/5 tricyclic cytochalasans, featuring an intermolecular Diels-Alder reaction and a ring-closing metathesis reaction as key steps. Based on this synthetic route, several cytochalasan monomers, including aspochalasin B, aspochalasin P, aspochalasin D and aspergillin PZ, have been synthesized within 11–14 longest linear steps. Subsequently, a couple of hetero-dimeric and -trimeric merocytochalasans, including asperchalasines A-E and asperflavipine B, have been accessed from aspochalasin B and the suitable epicoccine precursors through a series of intriguing bio-inspired transformations such as Diels-Alder reaction and formal [5 ​+ ​2] cycloaddition. Moreover, the full profile of the regio- and endo/exo selectivity of the Diels-Alder heterodimerization has been explored through computational study. The present study not only notably enriches the synthetic chemistry of cytochalasans and merocytochalasans, but also affords venerable clue to decipher the biosynthetic origins of the newly identified merocytochalasans.