Studies directed towards the total synthesis of a jatrophane diterpene



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It has been found that certain cancer cells naturally become resistant to chemotherapeutic drugs when exposed to the drug over a period of time. Most cancer deaths (around a half million people) in the United States are caused by the failure of chemotherapy. It has been revealed that the overexpression of permeability glycoprotein (Pgp) in cancer cells extrude the chemotherapeutic drug from inside the cancer cell ultimately leading to the failure of the chemotherapy. The developed resistance of disease-causing microbes or cells against varying drugs is commonly known as multidrug resistance (MDR). In the past few decades extensive research has been conducted towards designing potent inhibitors of permeability glycoprotein (Pgp), the result of which would cause the reverse of MDR. A number of potential Pgp inhibitors are currently under clinical trials. The milky latex produced from E. peplus is known to be used for treating certain skin cancers. Jatrophane diterpenes have been identified as effective lead compounds for the reversal of MDR. A number of attempts were made to finish the total synthesis of jatrophane diterpenes. In this dissertation we propose a reterosynthetic strategy to construct our target jatrophane diterpene by means of ring-closing metathesis (RCM) and a nucleophilic addition reaction of a lithiated vinyl species on an aldehyde. Along with conducting efforts towards the synthesis of the jatrophane skeleton, a synthetic route for the synthesis of a chiral vinyl iodide has also been developed. An NOE experiment was performed to confirm the absolute stereochemistry at C7 to validate the result obtained from the Mosher ester analysis.



Permeability glycoprotein (Pgp), Multidrug resistance (MDR), Retrosynthesis