Design and Application of Kinetically E-Selective Olefin Metathesis Catalysts

 描述(申请人提供)：内烯烃存在于大量生物活性化合物中，包括用于各种临床应用的治疗药物。它们也是更复杂的分子的有用的积木。内烯烃可以作为E或Z-立体异构体存在。烯烃的几何构型直接影响分子的整体构象，从而影响分子的物理、化学和生物性质。因此，选择性地合成E或Z-立体异构体的方法是非常重要的。烯烃歧化反应的最新进展表明，催化剂能够选择性地合成Z-立体异构体。然而，目前的烯烃歧化催化剂通常依赖于歧化反应的可逆性来选择性地生成热力学上有利的E-立体异构体。这种底物控制的方法通常是不可预测的，并且存在许多例子，其中产品的热力学偏好很小，导致E和Z-立体异构体的混合物难以分离。迄今为止，烯烃 能够在动力学控制下选择性合成(E)-烯烃的复分解催化剂仍然很难找到。 这项建议概述了一种详细的、系统的开发和应用动力学E-选择性烯烃歧化催化剂的方法。在一个有希望的初步结果的指导下，初步的研究将集中在开环交叉复分解(ROCM)。将对N-杂环卡宾(NHC)配体进行战略性改变，以确定催化剂结构与E-选择性之间的关系。这些研究将得到旨在了解E-选择性起源的计算研究的帮助。一旦确定了有前景的E-选择性催化剂，它们将在一系列已知进行低E-选择性ROCM的底物上进行测试。这项研究应该区分催化剂的结构，并加深我们对控制E-选择性的因素的理解。最后，从ROCM研究中获得的见解将被应用于催化剂的设计，以实现E-选择性交叉复分解和大环闭环复分解。

 DESCRIPTION (provided by applicant): Internal olefins are present in a large number of biologically active compounds including therapeutics that are used for a diverse range of clinical applications. They also serve as useful building blocks for more complex molecules. Internal olefins can exist as either the E or Z-stereoisomer. The geometry of the olefin directly impacts the overall conformation of the molecule and, therefore, the physical, chemical, and biological properties of the molecule. As a result, methods to selectively synthesis the E or Z-stereoisomer are of great importance. Recent developments in olefin metathesis have revealed catalysts capable of selectively synthesizing the Z-stereoisomer. However, current olefin metathesis catalysts typically rely on the reversible nature of the metathesis reaction to selectively form th thermodynamically favorable E-stereoisomer. This substrate-controlled approach is often unpredictable, and many examples exist where the thermodynamic preference of the product is small leading to a mixture of E and Z-stereoisomers that are difficult to separate. To date, olefin metathesis catalysts capable of selectively synthesize the (E)-olefin under kinetic control remain elusive. This proposal outlines a detailed, systematic approach for the development and application of kinetically E-selective olefin metathesis catalysts. Guided by a promising preliminary result, initial investigations will focus on ring-opening cross metathesis (ROCM). Strategic changes will be made to the N-heterocyclic carbene (NHC) ligand of the NHC-ruthenium carbene complex to determine the relationship between catalyst structure and E- selectivity. These studies will be aided by computational studies geared towards understanding the origin of the E-selectivity. Once promising E-selective catalysts have been identified, they will be tested against a series of substrates known to undergo ROCM with low E-selectivity. This investigation should differentiate between catalyst structures and enhance our understanding of the factors that control E-selectivity. Finally, the insights gained from the ROCM studies will be applied to designing catalysts to achieve E-selective cross metathesis and macrocyclic ring-closing metathesis.