Synthetic studies on natural products using a new approach via Diels-Alder reaction and fragmentation reaction

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Zaragozic acids (squalestatins), a family of structurally related fungal metabolites isolated from different organisms by three independent groups in 1992, have been found to be potent inhibitors of squalene synthase and farnesyl-protein transferase. These compounds share a common 2,8-dioxabicyclo[3.2.1]octane core and differ in two lipophilic side chains (e.g., zaragozic acid A). A number of reports about their synthesis reflected their unique structures and biological activities. Their most characteristic feature is the highly oxygenated hydrophilic core bearing six contiguous chiral carbon atoms. Total syntheses of zaragozic acids have been reported by several groups, however, various synthetic approaches continue to be investigated. We developed a new synthetic route for construction of the core moiety of zaragozic acids from a furan derivative. This synthesis involves two crucial steps for the regio- and stereoselective introduction of oxygen functionalities into the C(3), C(4), C(6) and C(7) positions on 7-oxabicyclo[2.2.1]hepta-2,5-diene derivative which was obtained by Diels-Alder reaction of 2,5-disubstituted furan with dimethyl, and Grob fragmentation-reduction-iodo acetalization reaction of 7-oxabicyclo[2.2.1]heptane derivative to give 2,8-dioxabicyclo[3.2.1]octane ring system. In addition, hydrolysis of symmetrical esters in 7-oxabicyclo[2.2.1]hepta-2,5-diene derivative by pig liver esterase (PLE) gave half ester in good yield (70% ee).