Novel Furan Cycloaddictions for Preparation of Medicinally Important Compounds

描述(由申请人提供)：本提案中的工作涉及开发新的呋喃和吡咯基环加成反应，这些反应导致从简单和容易获得的组分形成复杂的环系。环加成方式取决于合成路线和呋喃/吡咯核的取代方式。当炔烃与二烯基呋喃偶联时，会发生[8+2]-环加成反应。该反应组装了海洋衍生的实验性抗癌药物ELUTHERROIN的核心环系统(呋喃桥联的十元环)。这一反应的全部合成潜力将被开发，包括描述[8+2]-环加成反应的范围、极限和立体化学，然后研究密集官能化的[8+2]-环加成产物的反应性分布。这些化学过程将被用于设计新的抗癌剂，这些抗癌剂在结构上类似于Eleutherobin。将测试这些化合物促进微管聚合的能力，并进一步测试活性候选化合物作为抗癌剂的作用。卡宾铬配合物与邻炔基苯甲酰衍生物的偶联反应生成了活泼的呋喃/吡咯环，并与多种烯烃和炔烃进行了有效的环加成反应。这一过程的一个变种将被开发，其中高度不饱和的卡宾铬络合物在正式的[5+5]-环加成反应中提供菲咯烷环体系。这些反应是多种有效的合成方法的基石，丹参酮可用于治疗高血压，阿朴吗啡是一种用于治疗帕金森病的多巴胺受体。 本提案中的工作从简单且容易获得的组分提供了结构复杂且具有重要药用价值的化合物。该反应过程可以方便地提供化合物(或更重要的结构类似物)，这些化合物已显示出强大的抗癌活性、抗高血压活性和抗帕金森氏病等神经疾病的活性。这些都是非常常见的疾病，对很大一部分美国人口的生活质量产生了负面影响。

DESCRIPTION (provided by applicant): The work in this proposal involves the development of new furan and pyrrole-based cycloaddition reactions that result in the formation of complex ring systems from simple and readily available components. The cycloaddition mode depends upon the synthetic route and the substitution pattern for the furan/pyrrole core. The [8+2]-cycloaddition mode occurs when alkynes couple with dienylfurans. This reaction assembles the core ring system (furan-bridged ten-membered ring) of the marine-derived experimental anti-cancer agent eleutherobin. The full synthetic potential of this reaction will be developed, including delineation of the scope, limit, and stereochemistry of the [8+2]-cycloaddition followed by a study of the reactivity profile for densely functionalized [8+2]-cycloadducts. These chemical processes will be employed in the design of new anti-cancer agents that structurally resemble eleutherobin. The ability of these compounds to promote microtubule polymerization will be tested, and active candidates will be further tested as anti-cancer agents. The coupling of chromium carbene complexes with ortho-alkynylbenzoyl derivatives leads to activated furan/pyrrole rings, which undergo efficient cycloaddition with a variety of alkenes and alkynes. A variant of this process will be developed where highly unsaturated chromium carbene complexes afford phenanthroid ring systems in a formal [5+5]-cycloaddition reaction. These reactions are the cornerstone for versatile and efficient synthetic approaches to tanshinones, useful for the treatment of hypertension, and to apomorphine, a dopamine receptor useful for the treatment of Parkinson's disease. Work in this proposal provides structurally complex and medicinally important compounds from simple and readily available components. The reaction process can conveniently provide compounds (or more importantly structural analogs) that have shown potent anti-cancer activity, anti-hypertension activity, and activity against neurologic disorders such as Parkinson's disease. These are all very common ailments that negatively impact the quality of life a large portion of the U.S. population.