Application of C-H Activation to Natural Product Synthesis

描述（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造，但实际上，潜在药物靶点的实际可及性是药物设计的主要考虑因素。因此，新的方法有可能为化学结构开辟新的前景，作为药物制剂探索的可行目标。过渡金属催化反应广泛地影响了用于合成药物靶点的方法。碳氢化合物活化目前引起了相当大的兴趣，因为它有可能成为一种转化战略反应。这个提议是围绕最近发现的高立体选择性铑催化的碳氢活化过程，结合碳氢活化/Cope重排。这种C-C键形成反应的标志是其显著的立体选择性，大多数反应在>98% de和>96% ee中进行。探索这种化学的全部范围将是本提案的重点。这种碳氢功能化方法为有机合成提供了令人兴奋的机会，但要实现这一目标，该方法将需要扩展到更广泛的底物范围。一旦基础化学建立，该方法将应用于生物医学天然产物的合成，如抗结核药物elisabeth ethin C和潜在的抗癌药物sinulobatins B-D和harting tonolide。

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.