Cyclopentannelation in Total Synthesis

描述（由申请人提供）：对天然产物作为新药先导物来源的效用有了新的认识。合成在大小和复杂性方面的实际限制往往使有希望的天然产物无法考虑作为药物。我提出的研究在三种天然产物的背景下解决了这个问题。Madindoline B来源于链霉菌，是一种选择性白细胞介素6 （IL-6）抑制剂。在肿瘤细胞中，IL-6刺激细胞增殖，并与恶病质有关。选择性抑制IL-6可能为癌症提供一种新的治疗方法。madindoline的原始来源不再产生这些化合物，因此只能通过合成来获得材料。从Illicium merrillanum中分离出的Merrilactone A具有强大的神经营养活性（在胎鼠皮质神经元中为0.1 mol/L），可用于治疗帕金森病和阿尔茨海默病等神经退行性疾病，由于其仅占果皮干重的0.004%，因此只能通过合成来解决供应问题。Terpestacin是一种真菌代谢物，可抑制与HIV感染相关的合胞体（大型多核细胞）的形成（ID50 0.46 ug/mL），因此对艾滋病的治疗有很大的兴趣。抗血管生成活性与特培他星有关，这使其作为抗癌先导物引起了人们的兴趣。这三种天然产物在结构上都是独特的，因此它们可能通过新的机制发挥各自的作用。

DESCRIPTION (provided by applicant): There is a renewed realization of the utility of natural products as sources for new drug leads. The practical limits on synthesis in terms of size and complexity often preclude promising natural products from consideration as drugs. The research that I propose addresses this problem in the context of three natural products. Madindoline B is derived from Streptomyces and is a selective interleukin 6 (IL-6) inhibitor. In tumor cells IL-6 stimulates cell proliferation and is also associated with cachexia. Selective inhibition of IL-6 could offer a new treatment for cancer. The original source for the madindolines no longer produces these compounds, therefore material can only be secured through synthesis. Merrilactone A, isolated from Illicium merrillianum, has potent neurotrophic activity (0.1 ¿mol/L in fetal rat cortical neurons), and is of interest as a treatment for neurodegenerative diseases such as Parkinson's and Alzheimer's, Since it constitutes only 0.004% of the dry weight of the pericarps, the supply problem can only be solved through synthesis. Terpestacin is a fungal metabolite that inhibits the formation of syncytia, large multinucleated cells that are associated with HIV infection (ID50 0.46 ug/mL) and is therefore of great interest in the treatment of AIDS. Anti angiogenic activity has been associated with terpestacin, making it interesting as an anticancer lead. All three natural products are structurally unique, therefore they may exert their respective activities through novel mechanisms. Progress in this area occurs at two levels, by discovering improved methodologies and by using them to develop new strategies for total synthesis. In parallel with the total syntheses I will continue to improve and expand the scope of the methodology. Each of the natural product total syntheses referred to above uses a cyclization reaction in the key step that my research group developed.