Mechanism-Based Design of Iron-Mediated Carbonyl-Olefin Metathesis Protocols

项目摘要 含羰基底物的Lewis酸活化在有机合成中有着广泛的应用。然而，铁(III)- 催化的羰基-烯烃开环歧化反应采用了通常在Lewis酸中观察不到的反应活性- 促进了反应。利用我们对铁催化剂在羰基中的机理行为的详细了解- 关于烯烃复分解，这项建议旨在将这一知识应用于新复分解催化剂的合理设计。 我们的假设是，通过适当的配体支持，该反应可以在 药物的生产，自然的、抑制的机制是可以预防的，而化学家将 能够在周转限制步骤中选择特定的过渡状态。为了方便催化剂的设计，合成， 将使用光谱、动力学和计算技术来观察所产生的化学空间 通过引入配体，测量它们对催化循环静止状态的影响，以及 限制营业额的步骤。此外，底物本身也是反应的导向配基。因此，很简单 对羰基和烯烃歧化伙伴的修饰不仅可以改变操作机制，而且 极大地改变了反应结果。总体而言，这些严格的综合和机械性研究将采用 到目前为止，我们列举了一些因素，以提供更好的反应结果，提高了羰基- 医学上重要分子构筑中的烯烃歧化作用。

Project Summary Lewis acid-activation of carbonyl-containing substrates is broadly utilized in organic synthesis. However, iron(III)- catalyzed carbonyl-olefin ring-closing metathesis employs reactivity not typically observed in Lewis acid- facilitated reactions. Using our detailed understanding of the mechanistic behavior of the iron catalyst in carbonyl- olefin metathesis, this proposal intends to apply this knowledge in the rational design of new metathesis catalysts. It is our hypothesis that, via appropriate ligand support, the reaction can be performed in solvents preferred in the production of pharmaceuticals, the natural, inhibitory mechanism can be prevented, and chemists will be able to select for a specific transition state in the turnover-limiting step. To facilitate catalyst design, synthetic, spectroscopic, kinetic, and computational techniques will be employed to observe the chemical space created by the incorporation of ligands, measuring their impact on the resting state of the catalytic cycle, as well as the turnover-limiting step. Further, substrate itself acts as a reactivity-directing ligand. Therefore, simple modifications to the carbonyl and olefin metathesis partners can not only change the operating mechanism, but dramatically alter reaction outcomes. Overall, these rigorous synthetic and mechanistic studies will employ the factors we have enumerated thus far to provide improved reaction outcomes, enhancing the use of carbonyl- olefin metathesis in the construction of medicinally important molecules.