The Total Synthesis of Thapsigargin

• Applicant: Dr. Frank Georg Wierschem
• Subject Area: Organic Molecular Chemistry - Synthesis and Characterisation
• Term: Funded in 2005
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 5449385

The focus of our investigation is the first total syntheses of Annomuricin C and E, members of the Annonaceous acetogenin family. The Annonaceous acetogenins, which were only isolated from the plant family Annonaceae, are promising new antitumor and pesticidal agents. These natural products of diverse, but still closely related compounds exhibit a broad range of potent biological activities in a widespread area of interests, such as in vivo antitumor activity and cytotoxic, antibacterial, antimalarial, antiparasitic, immunosuppressive and pesticidal effects. The Annonaceous acetogenins have emerged as promising new leads against the resistance of multidrug resistant tumors and of pesticide resistant insects. Our specific interest in Annomuricin C and E is based on the fact, that these natural products show cytotoxicities against sic types of human tumors, with selectivities to the pancreatic carcinoma (PACA-2) and colon adenocarcinoma (HT-29) cell lines. Annomuricin C as well as Annomuricin E with their characteristic central 2,5-disubstituted, a, a'-dihydroxylated mono-THF moiety are representatives of the most important subclass of the mono-THF acetogenins. The intended synthetic strategy utilizes and develops innovative and efficient synthetic methodologies as well as reagents established by the Ley group to achieve a general synthetic and above all modular approach towards this important subgroup of the Annonaceous acetogenin family. As the use of the BDA protecting group renders for example the enantiopure synthesis of the central 2,5-disubstituted THF moiety, the application of a variety of polymer supported reagents, e.g. PSP, PS-triphenylphosphine, etc. will reduce the number of purification procedures to guarantee straight forward and efficient enantioselective total syntheses of Annomuricin C and E based on a modular synthetic strategy.

• DFG Programme: Research Fellowships
• International Connection: United Kingdom
• Cooperation Partner: Professor Dr. Steven V. Ley