Palladium catalysis directed towards the synthesis of natural products: The total synthesis of (-)-showdomycin

Palladium catalysis is a powerful tool for simplifying the synthesis of complex molecules. In the interest of preparing medicinally relevant natural products, we undertook expanding the scope of two palladium catalyzed reactions, an asymmetric allylic alkylation and an isomerization on reaction.; (–)-Showdomycin was chosen as a synthetic target because it structurally resembles several anti-HIV drugs. Using carbon nucleophiles in palladium(0) catalyzed asymmetric allylic alkylation reactions, the enantioselectivity was exceptionally high for either a maleimide synthon or a hydroxymethyl synthon ($\ge$90%ee). A second allylic alkylation was used to introduce the other group with efficient chirality transfer. A diastereoselective dihydroxylation formed the diol selectively. By unmasking the maleimide moiety and the hydroxymethyl, (–)-Showdomycin was prepared in 10 synthetic steps. The synthesis of (–)-Showdomycin was short, highly enantioselective, and provides access to either enantiomer of (–)-Showdomycin as well as a variety of analogs.; Galanthamine is an acetylcholine esterase inhibitor that is being investigated for the treatment of Alzheimer's disease. Galanthamine is also an ideal synthetic target for exploring a palladium(0) catalyzed allylic alkylation. reaction to differentiate between enantiotopic olefins. To prepare an advanced achiral intermediate, a phenyl coupling was efficiently accomplished using the Suzuki protocol; however, the formation of a seven-membered spirodienone was unsuccessful. Future directions in this project would include using the known low-yielding bisphenol coupling to prepare the desired substrate or the use of a different system to explore the palladium chemistry.; Mitomycin C is a cytotoxic chemotherapeutic agent that is used for a variety of cancers. A palladium(II) catalyzed enyne cycloisomerization reaction was envisioned as a concise approach to the fully functionalized ring system of mitomycin. A succinct six step sequence (45% yield) was developed to form the A and C rings of the enyne substrate from a known bromoquinone; the thioketeneaminal was formed instead of the keteneaminal due to its additional stability. Unfortunately, we were unable to find conditions to effect the cycloisomerization reaction, and difficulties associated with making alternative substrates hindered these investigations. Future studies towards the synthesis of FR-900482, a mitomycinoid, are currently being investigated by Michael Ameriks in our laboratory.