Approaches to the enantioselective total synthesis of the natural product neoliacinic acid

The target molecule for chemical synthesis, neoliacinic acid, is a germacranolide sesquiterpene lactone that occurs naturally in the leaves of Neolitsea acciculata Koidz. A related compound from the same species, neoliacine, shows moderate in vitro cytotoxicity in Hela cell culture, an immortalized culture of cancer cells, and similar activity is expected of neoliacinic acid. A synthesis of this highly oxygenated, structurally unique 6-5-8 ring system has yet to be realized and offers an excellent challenge to a chemist's toolbox of reagents and tactical designs.;A convergent synthetic strategy was employed where two scalemic segments were coupled and this product was elaborated to the pyran ring level of neoliacinic acid. Scalemic segment 26 was accessed via chiral reduction of an ynone. The epoxy aldehyde 101 was constructed via a Sharpless epoxidation of the corresponding allylic alcohol and subsequent oxidation. To access a linear framework, C-3 of segment 26 was linked to C-4 of segment 101. The pyran ring was formed via an intramolecular 6-exo-tet attack of the C-1 hydroxyl at C-5 of the epoxide to provide three series of pyrans. Acid-catalyzed cyclizations were studied in detail to determine the requirements for pyran formation. It was found that cyclization was prevented by substitution at C-7 to C-13, whereas substitution at C-4 and C-1 had no effect. Future directions will involve construction of the pyranolactone stage and further elaboration of this intermediate to arrive at the eight-membered ring of neoliacinic acid.