Design and Application of Kinetically E-Selective Olefin Metathesis Catalysts

动力学E选择性烯烃复分解催化剂的设计与应用

• 批准号: 9133915
• 负责人: Daniel T Ziegler
• 金额: $ 3.66万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2017-03-10
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9133915
• 关键词: Address; Alkenes; Asthma; Biological; Chemicals; Chloride Ion; Chlorides; Cholesterol; Collaborations; Complex; Crestor; Development; Drug Prescriptions; Environment; Future; Geometry; Goals; Investigation; Kinetics; Ligands; Literature; Methods; Modeling; Modification; Molecular Conformation; National Institute of General Medical Sciences; Nature; Ocular Hypertension; Pharmaceutical Chemistry; Pharmacologic Substance; Process; Property; Reaction; Reporting; Research Design; Route; Ruthenium; Series; Stereoisomer; Structure; Testing; Therapeutic Uses; Thermodynamics; carbene; catalyst; clinical application; computer studies; design; drug development; improved; insight; novel; preference; public health relevance; symptom treatment

 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.

 描述（由申请人提供）：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剂。它们也可以作为更复杂分子的有用构建单元。内烯烃可以E或Z-立体异构体存在。烯烃的几何形状直接影响分子的整体构象，因此影响分子的物理、化学和生物学性质。因此，选择性合成E或Z-立体异构体的方法是非常重要的。烯烃复分解的最新发展揭示了能够选择性合成Z-立体异构体的催化剂。然而，目前的烯烃复分解催化剂通常依赖于复分解反应的可逆性质来选择性地形成理论上有利的E-立体异构体。这种底物控制的方法通常是不可预测的，并且存在许多实例，其中产物的热力学偏好很小，导致难以分离的E和Z-立体异构体的混合物。到目前为止，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是难以捉摸的。 该提案概述了一个详细的，系统的方法，用于开发和应用的动力学E-选择性烯烃复分解催化剂。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NHC-钌卡宾络合物的N-杂环卡宾（NHC）配体进行策略性改变以确定催化剂结构与E-选择性之间的关系。这些研究将有助于面向了解E-选择性的起源计算研究。一旦有前途的E-选择性催化剂已经确定，他们将测试对一系列基板已知进行ROCM与低E-选择性。这项调查应区分催化剂的结构和提高我们的理解的因素，控制E-选择性。最后，从ROCM研究中获得的见解将应用于设计催化剂，以实现E-选择性交叉复分解和大环闭环复分解。