Synthesis of Anticancer Pyran Natural Products

研究抗肿瘤天然产物的化学反应性和生物活性对于理解其作用机制和开发用于治疗和/或预防癌症的新疗法至关重要。该研究计划旨在通过开发和随后应用有机合成的新策略和方法，开发具有六元氧杂环的生物活性天然产物的有效合成。将追求产生目标天然产物结构的策略，同时为合成相关化合物家族提供广泛的解决方案。为这些研究选择的靶标具有有趣和新颖的分子结构，缺乏重要的先前合成研究，并且在癌症背景下具有有希望的生物活性。计划的合成方法的设计特点催化立体选择性吡喃形成反应，黄烷酮的对映选择性合成，并纳入多键形成序列。 本研究的具体目标是：（1）天然产物色乳霉素和奥克拉霉素的合成。这些抗肿瘤抗生素具有独特的高度氧化的三环核心。我们将使用一种新的丁烯二醇大环化/共轭加成方法作为关键的战略序列。(2)（3）黄烷酮类天然产物阿比西林酮II和苦参素的合成。我们将采用一种新的手性硫脲催化的对映选择性黄烷酮合成方法来合成这些化合物。(4)评价这些研究中所有化合物对各种人类肿瘤细胞系（包括乳腺癌、前列腺癌、结肠癌和胰腺癌）的活性。这最后一个目标将通过我们的合成知识和能力与西北大学的罗伯特·H。卢里综合癌症中心和耶鲁大学的一位生物有机化学家专家

Investigating the chemical reactivity and biological activity of anti-tumor natural products is vital to understanding their mechanism of action and developing new therapeutics for the treatment and/or prevention of cancer. This research program aims to develop efficient synthesis of biologically active natural products possessing six-membered oxygen heterocycles through the development and subsequent application of new tactics and methodologies for organic synthesis. Strategies that generate the targeted natural products structures while providing broad solutions to synthesizing related families of compounds will be pursued. The targets selected for these investigations possess interesting and novel molecular architecture, lack significant prior synthetic studies, and have promising biological activity in the context of cancer. The planned synthetic approaches are designed to feature catalytic stereoselective pyran-forming reactions, the enantioselective synthesis of flavanones, and incorporate multiple bond forming sequences. The specific goals of this research are: (1) Synthesis of the natural products chrolactomycin and okilactomycin. These antitumor antibiotics possess a unique and highly oxygenated tricyclic core. We will use a new butenolide macrocyclization/conjugate addition approach as the key strategic sequence. (2) Total synthesis of exiguolide (3) Syntheses of flavanone natural products abyssinone II and kurarinone. We will employ a new enantioselective flavanone synthesis catalyzed by chiral thioureas for the syntheses of these compounds. (4) Evaluate all compounds in these studies for their activity against various human tumor cell lines including breast, prostate, colon, and pancreatic cancer. This last aim will be accomplished in a collaboration combining our synthetic knowledge and capabilities acquired in Aims 1-3 with two expert cancer researchers at Northwestern’s Robert H. Lurie Comprehensive Cancer Center and one expert bioorganic chemist at Yale University