In 1987, Hashimoto and co-workers isolated an unprecedented compact diterpene, vinigrol (1, Scheme 1), from the fungal strain Virgaria nigra F-5408, found at the foot of Mount Aso in the Kumamoto Prefecture in Japan. [1] The relative stereochemistry of the natural product was established by NMR and X-ray crystallographic analysis of the oxidized derivative 2. Its tricyclic core is comprised of a cis-fused [4.4.0] system with a four-carbon bridge between C1 and C5 and features eight contiguous stereocenters. The rare boat half chair conformation of the eight-membered ring (highlighted in Scheme 1 in bold) makes vinigrol a unique structure among diterpenoids.
Biological testing of vinigrol (1) has revealed a number of interesting properties, including an influence on platelet aggregation [2] and tumor necrosis factor (TNF) antagonism. [3] These results prompted investigations into the application of vinigrol in medicine. [4,5] Not surprisingly, the impressive biological activities of vinigrol (1), combined with its unique and synthetically challenging structure, have resulted in considerable attention from the synthetic community. [6,7] In 1993, Hanna et al. unveiled the first synthesis of the tricyclic core of vinigrol featuring an anionic oxy-Cope ring expansion. [6a] Subsequent investigations by our group and others, [6d,e,h,l-n] focused on a direct cyclization of the eightmembered ring (the ansa belt) of vinigrol from functionalized decalin precursors. Unfortunately, all such approaches were thwarted by an inability to find reaction conditions for the cyclization. The failure of these approaches can be attributed