Synthesis of Macroheterocycles through Intramolecular Oxidative Coupling of Furanoid β‐Ketoesters

Furanocembranoids are an intriguing class of marine diterpenoids characterized by a C14 cembrane skeleton with an embedded furan heterocycle.[1] Derived from these structures are various more advanced secondary metabolites arising through biooxidation of their furan moieties into more complex cembranoids which often undergo transannular transformations involving carbon–carbon and/or carbon–oxygen bond formations.[1] Bielschowskysin (1),[2] verrillin (2),[3] and plumarellide (3)[4] are three such molecules (Figure 1a). Their origins can be traced back to exo-enol ether/cyclic hemiacetal precursors 4, 5, and 6, respectively, as shown in Figure 1a. Methods for the synthesis of the latter precursors are, therefore, crucial to testing such biosynthetic hypotheses and to synthetic strategies toward these natural products. In addition to the cytotoxic and antimalarial properties that many furanocembranoids exhibit,[1a] these macrocyclic exo-enol ether/cyclic hemiacetal structural motifs (see A, Figure 1b) may be of interest to chemical biology and medicinal chemistry as novel molecular diversity whose biological properties remain largely unexplored.