The total synthesis of (-)-citrinadin A, a novel pentacyclic alkaloid with cytotoxicity against murine leukemia and human epidermoid carcinoma cells, will be carried out. The focus of the convergent strategy will be an enantioselective palladium-catalyzed trimethylenemethane (TMM) [3+2] cycloaddition used to construct the highly functionalized spirooxindole core. Asymmetry will be induced via coordination of the palladium center to various chiral phosphine ligands, yielding the desired natural stereoisomer. Further elaboration of this spirocyclic oxindole into the target, will rely on a novel carboxyl-substituted TMM precursor to be synthesized and subsequently employed in the cycloaddition. Development of this novel enantioselective carboxyl-substituted TMM [3+2] cycloaddition will provide rapid access to the complex pentacyclic skeletons of citrinadins A and B, minimizing the overall number of synthetic steps while introducing the stereochemistry necessary for biological activity.
To date, no total synthesis of citrinadin A has been reported;the stereochemical assignments have been made via nuclear magnetic resonance and vibrational circular dichroism studies. The proposed synthesis will confirm the absolute stereochemistry, and more importantly supply larger quantities of material needed for further biological studies. Moreover, numerous natural products such as the brevianamides, paraherquamides, marcfortines, sclerotamides, and asperparalins possess a similar spirooxindole core. This new technology could also prove highly valuable to the syntheses of these biologically active alkaloids.
| Trost, Barry M; Masters, James T; Taft, Benjamin R et al. (2016) Asymmetric synthesis of chiral ?-alkynyl carbonyl and sulfonyl derivatives via sequential palladium and copper catalysis. Chem Sci 7:6217-6231 |
| Trost, Barry M; Taft, Benjamin R; Masters, James T et al. (2011) A new strategy for the synthesis of chiral ?-alkynyl esters via sequential palladium and copper catalysis. J Am Chem Soc 133:8502-5 |
