Development of olefinic ester and diene ring-closing metathesis using a reduced titanium alkylidene; synthesis of AB ring subunit of brevenal and efforts towards the synthesis of psymberin

Cyclic enol ethers are useful precursors to a variety of cyclic ether containing, biologically active natural products such as marine ladder toxins, polyether antibiotics, nucleoside antibiotics and carbohydrate derivatives. Among the variety of methods that have been reported for their synthesis, a highly efficient and useful strategy would involve a direct conversion of an olefinic ester to cyclic enol ether. Described here is the use of a reduced titanium ethylidene reagent to effect one-step olefinic ester cyclization reactions and diene ring closing metathesis reactions.;Psymberin is a potent cytotoxic molecule that was isolated from the marine sponge Psammocinia sp. by Crews and co-workers. It demonstrated potent cytotoxicity against several melanoma, breast and colon cancer cell while being considerably inactive against leukemia cell lines. Such differential cytotoxic activity makes it a promising lead for therapeutic development. Described here is our effort towards the total synthesis of psymberin by utilizing an intermolecular oxymercuration - C-allylation strategy towards the pyran core.;Brevenal is a pentacyclic polyether natural product isolated from laboratory cultures of the dinoflagellate Karenia brevis by Baden, Bourdelais and co-workers. Brevenal competitively displaces brevetoxins from voltage gated sodium channels in rat brain synaptosomes in a dose dependent manner and thus can act as brevetoxin antagonists. Brevenal also increased the tracheal mucus velocity at concentrations one million-fold lower than the sodium channel blocker, amiloride, which is used in the treatment of cystic fibrosis. Thus, brevenal can potentially be used for the development of novel therapeutic agents for the treatment of cystic fibrosis and other lung disorders. In our effort towards the total synthesis of brevenal, described here is the synthesis of AB ring subunit of brevenal by utilizing our iterative C-glycoside/metathesis strategy.