The phomactin family of natural products has captured the attention of chemists due to their intriguing biological properties and unique structural architecture. The phomactins are known to be antagonists of platelet activating factor (PAF), an important phospholipid agonist that mediates many diverse cellular processes such as platelet aggregation, inflammation, and angiogenesis. Structurally, the phomactins are characterized by their bicyclo[9.3.1]pentadecane carbon framework which gives rise to their characteristic macrocyclic “strap”. Of the 18 known phomactin natural products, phomactin A is structurally the most complex, containing a sensitive hydrated furan motif and a stereochemically rich oxadecalin core. Herein, we disclose a strategy toward the synthesis of phomactin A that exploits the reactivity of a carvone-derived cyclobutanol. This strategy utilizes the strategic activation and cleavage of a strained C–C bond to generate the carbocyclic skeleton present in all the phomactin natural products. This strategy is enantiospecific, atom-economical, and constitutes a new paradigm for the utilization of carvone and C–C activation in total synthesis.

Exploiting cyclobutanol reactivity toward the total synthesis of (+)-phomactin A

251st National Meeting (2016)

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