The Total Synthesis of Thapsigargin

本研究的重点是首次全合成番荔枝内酯家族中的花青素C和E。番荔枝内酯类化合物仅从番荔枝科植物中分离得到，是一种很有前途的新型抗肿瘤和杀虫药物。这些天然产物具有广泛的生物活性，如体内抗肿瘤活性、细胞毒性、抗细菌、抗疟疾、抗寄生虫、免疫抑制和杀虫作用等。番荔枝内酯已成为对抗多药耐药肿瘤和抗药性昆虫的有希望的新线索。我们对Annouricin C和E的特别兴趣是基于这样一个事实，即这些天然产物对SIC类型的人类肿瘤具有细胞毒性，对胰腺癌(PACA-2)和结肠腺癌(HT-29)细胞株具有选择性。去甲尿酸C和去甲尿酸E以其特有的中心2，5-二取代，a，a‘-二羟基单-四氢呋喃部分是单-四氢呋喃内酯最重要的亚类的代表。计划中的合成战略利用和开发创新和有效的合成方法以及LEY集团建立的试剂，以实现对番荔枝内酯家族这一重要亚类的一般合成和最重要的模块化方法。由于BDA保护基团的使用使得例如中心的2，5-二取代四氢呋喃部分的对映体合成，各种聚合物支载试剂的应用，如PSP，PS-三苯基膦等，将减少纯化步骤的数量，以保证基于模块化合成策略直接和有效的对映选择性地全合成去诺莫利星C和E。

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.