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

项目摘要 含羰基底物的刘易斯酸活化广泛应用于有机合成。铁（III）- 催化的羰基-烯烃闭环复分解反应使用了在刘易斯酸中通常观察不到的反应性， 促进反应。利用我们对铁催化剂在羰基- 烯烃复分解，该建议旨在将这些知识应用于新的复分解催化剂的合理设计中。 我们的假设是，通过适当的配体支持，反应可以在优选的溶剂中进行， 生产的药物，自然，抑制机制可以防止，化学家将 能够在所述限流步骤中选择特定的过渡状态。为了促进催化剂设计，合成， 光谱学、动力学和计算技术将被用来观察所产生的化学空间 通过掺入配体，测量它们对催化循环的静止状态的影响，以及 切换限制步骤。此外，底物本身充当反应性导向配体。因此，简单 对羰基和烯烃复分解配偶体的改性不仅可以改变操作机理， 极大地改变了反应结果。总的来说，这些严格的合成和机理研究将采用 到目前为止，我们已经列举的因素提供了改进的反应结果，提高了羰基的使用， 烯烃复分解在医学上重要的分子的建设。

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.