| Cucurbitacins are naturally occurring molecules which exhibit anti-tumor, anti-cancer, and anti-prolifterative effects in cancerous cell lines. They have been shown to arrest most cell lines in GYM or S phase, and are able to induce apoptosis. All of the cucurbitacins target JAK2/STAT3 pathways, with some being more selective than others. To date, no published total synthesis for any member of the family has been published. The aim of this dissertation is to provide synthetic methodologies and strategies directed to the total synthesis of cucurbitacin I. Toward this end, a novel oxidation of 1,3-cyclic diketones has been explored. Oxidation of these compounds will only occur in polar solvents at 50 °C, presumably due to the mechanism being dependent upon the keto-enol tautomerization. Elaboration of the ene-triketone was readily achieved in a short sequence to give the A-ring precursor. The hydrindane (C/D) ring of cucurbitacin I was first modeled toward an advanced intermediate for ring-opening/ring-closing metathesis. Diels-Alder cycloaddition between citraconic anhdyride and cyclopentadiene afforded the desired adduct, which was reduced to the diol, and protected as its methyl ether. The addition of a nitrile was accomplished through chlorination of the methyl ether via the Mitsunobu reaction and nucleophilic displacement of the chloride with NaCN. Acidic hydrolysis was found to react with the strained alkene of the norbornene, while basic hydrolysis formed a tetrahydrofuran derivative. Other homologations were unable to achieve a system for the desired bicyclo[4.3.0]non-3-ene, whereas Grignard addition of 2-propenylmagnesium bromide to the methyl ether aldehyde (prepared from the hydroxy methyl ether), oxidation by Swern conditions to the alpha,beta-unsaturated ketone, and ring-opening/ring-closing metathesis afforded the bicyclo[3.3.0]oct-3-ene. The models of these two pieces will serve as a basis for the total synthesis of cucurbitacin I. |
