Application of C-H Activation to Natural Product Synthesis

描述(由申请人提供)：有效的有机合成新策略对生物医学研究具有重要价值。尽管人们经常争辩说，任何有机化合物都可以制成，但实际上，潜在药物靶标的实际可及性是药物设计的主要考虑因素。因此，新的方法学有可能为化学结构开辟新的前景，作为药物制剂的可行探索目标。过渡金属催化的反应广泛地影响了用于合成药物靶标的方法。C-H活化目前具有相当大的兴趣，因为它有可能成为一种变革性的战略反应。这一提议围绕着最近发现的一种高度立体选择性的Rh催化的C-H活化过程，即C-H活化/COPE重排相结合的过程。这种C-C键形成反应的特点是其显著的立体选择性，大多数反应在&gt；98%de和&gt；96%ee进行。对这种化学的全部范围的探索将是这项提议的重点。这种C-H官能化方法在有机合成中提供了令人兴奋的机会，但要实现这一点，该方法将需要扩展到更广泛的底物。一旦建立了基础化学，该方法学将被应用于合成具有生物医学价值的天然产物，抗结核药物elisabinC以及潜在的抗癌药物Sinulobatins B-D和三尖杉酯内酯。

DESCRIPTION (provided by applicant): Effective new strategies for organic synthesis are of great value to biomedical research. Even though it is often argued that any organic compound can be made, in reality the practical accessibility of a potential pharmaceutical target is a major consideration in drug design. Thus, new methodology has the potential of opening up new vistas of chemical structures as viable targets for exploration as pharmaceutical agents. Transition metal-catalyzed reactions have broadly impacted the methods used for the synthesis of pharmaceutical targets. C-H Activation is of considerable current interest because it has the potential of becoming a transforming strategic reaction. This proposal is centered around a recently discovered highly stereoselective rhodium-catalyzed C-H activation process, the combined C-H activation/Cope rearrangement. The hallmark of this C-C bond forming reaction is its remarkable stereoselectivity, with most reactions proceeding in >98% de and >96% ee. The exploration of the full scope of this chemistry will be the focus of this proposal. This C-H functionalization method offers exciting opportunities in organic synthesis but to achieve this, the methodology will need to be extended to a broader range of substrates. Once the foundation chemistry has been established the methodology will be applied to the synthesis of natural products of biomedical interest, the antitubercular agent elisabethin C and the potential anticancer agents sinulobatins B-D and harringtonolide.