Synthesis of Epidithiodiketopiperazine Natural Products

University Of California Irvine, Irvine CA

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Abstract

Nature has provided an array of structurally complex epidithiodiketopiperazine (EDKP)-containing alkaloids that exhibit potent cytotoxicity and antitumor activity. The preliminary reports of the biological activities of several representative EDKP alkaloids suggest that compounds within this class hold significant potential for development into useful chemotherapeutic anti-cancer agents. For example, the EDKP-containing natural product leptosin D displays comparable cytotoxicity against P388 lymphocytic leukemia to that of the known anticancer chemotherapeutic agent mitomycin C. Synthetic organic chemistry is uniquely suited to providing compounds for a comprehensive study of the anticancer activity of EDKP alkaloids because appreciable quantities of both natural products and non-natural analogues can be obtained using synthetic methods. Leptosin D represents an intriguing synthetic target because of its potent cytotoxicity, natural scarcity, and structural complexity. The synthetic challenges involved in an enantioselective total synthesis of this natural product include establishment of the quaternary carbon stereocenter, stereocontrolled installation of the hydroxyl functionality, and incorporation of the EDKP system. A convergent approach to leptosin D that addresses each of the critical synthetic issues is proposed. Synthetic studies toward leptosin D will present opportunities for exploring the use of the asymmetric intramolecular Heck reaction for construction of quaternary carbon stereocenters. Additionally, the proposed study will examine the use of metallated thioacetal-diketopiperazines for nucleophilic addition to complex aldehyde substrates. The methodological innovations required for the synthesis of leptosin D can be readily applied to the synthesis of other cytotoxic and antitumor EDKP alkaloids, including the chaetocins and verticillin A. Synthetic access to these unique alkaloids will be useful for further biological studies that may provide insight into the control of cellular proliferation and assist in the development of new anticancer therapies.