New Catalytic Methods to Prepare Axially Chiral Compounds

制备轴向手性化合物的新催化方法

• 批准号: 2247330
• 负责人: Donald Watson
• 金额: $ 60万
• 依托单位: University of Delaware
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2247330&HistoricalAwards=false
• 关键词: New; Catalytic; Methods; Prepare; Axially

With the support of the Chemical Catalysis Program in the Division of Chemistry, Professor Donald Watson of the University of Delaware is studying a nickel-catalyzed process for the preparation of a class of compounds know as axially chiral biarenes. Such compounds are useful materials with a range of societally relevant applications, for example, as pharmaceutical agents or as modulators for chemical manufacturing processes, but traditional methods for their preparation are limited in scope and/or dependent on the use of precious metal-based catalysts. By contrast, the process of interest is quite versatile and its dependence on nickel, an earth abundant metal, means that the chemistry is more environmentally sustainable. A prominent feature of the process is that it enables the generation of biarenes in which one twisted form of the molecule (analogous to the concept of handedness) predominates over the other. The broader impacts of the award will extend to the benefits accrued to society as Professor Watson and his coworkers engage in a variety of education and outreach activities. Most notably, the Research Experiences for Academic Chemists in Training (REACT) program which is designed to maintain engagement in the physical sciences from students who are initially disadvantaged upon entering college due to poor academic preparation and consequently, of high risk of dropping out. The REACT program is anticipated to be particularly beneficial to students belonging to groups underrepresented in the STEM (science, technology, engineering and mathematics) workforce.The funded project involves further study of the enantioselective Ni-catalyzed reductive aryl halide coupling recently reported by the Watson laboratory and which offers potential gains in efficacy and scope over established procedures for the synthesis of non-racemic axially chiral biarenes. The investigation is divided across three objectives designed to allow for development of the method while more fully realizing its synthetic potential. The first objective is focused on extending the homocoupling process to substrates not previously explored to target binaphthyl and biphenyl systems from a range of ortho-halo- (typically bromo-) substituted arenes including aryl phosphines/phosphine oxides, esters, amines, and thioethers. The second objective involves pursuit of an intramolecular variant of the method to achieve enantioselective reductive cyclizations of suitably tethered bis(haloarenes) and leading to both C2-symmetric and non-symmetric polycyclic biaryls. The latter include examples of MOP and PHOX type systems which may be useful in their own right as tunable chiral ligand frameworks. The final and most ambitious objective is directed at the realization of a highly enantioselective cross-coupling between two distinct aryl halide substrates. Here, the necessary conditions to avoid competing homocoupling events will be identified to allow for the potential emergence of a general platform for the preparation of biaryls with broad applicability. The High Throughput Experimentation (HTE) laboratory at the University of Delaware will be used extensively during the course of the outlined studies to facilitate the rational screening campaigns needed to evaluate and optimize factors such as ligand structure, additive and solvent effects, temperature, and other reaction variables. The findings of this work are anticipated to lead to fundamental advances impactful to the practice of biaryl synthesis and to the wider field of enantioselective catalysis.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

在化学系化学催化项目的支持下，特拉华大学的Donald Watson教授正在研究一种镍催化的工艺，以制备一类被称为轴向手性双芳烃的化合物。这些化合物是具有一系列社会相关应用的有用材料，例如，作为药物剂或化学制造过程的调节剂，但其制备的传统方法范围有限和/或依赖于贵金属基催化剂的使用。相比之下，我们感兴趣的过程是相当多样的，而且它依赖于镍这种地球上丰富的金属，这意味着这种化学反应更环保。该过程的一个突出特征是，它使双芳烃的生成成为可能，其中分子的一种扭曲形式（类似于手性的概念）占主导地位。由于沃森教授和他的同事从事各种教育和外展活动，该奖项的更广泛影响将扩大到为社会带来的利益。最值得注意的是，在培训中的学术化学家研究经验（REACT）项目，该项目旨在保持学生对物理科学的参与，这些学生在进入大学时由于学术准备不足而处于不利地位，因此退学的风险很高。REACT计划预计将特别有利于那些在STEM（科学、技术、工程和数学）劳动力中代表性不足的群体的学生。该资助项目涉及对镍催化的对映选择性还原芳酰卤化物偶联的进一步研究，该偶联最近由沃森实验室报道，与合成非外消旋轴手性双芳烃的既定程序相比，它在功效和范围上有潜在的收益。调查分为三个目标，旨在允许方法的发展，同时更充分地实现其综合潜力。第一个目标是将均偶联过程扩展到以前未探索的底物，以从一系列邻halo-（通常是溴-）取代芳烃（包括芳基膦/膦氧化物，酯，胺和硫醚）中靶向联萘和联苯体系。第二个目标涉及追求该方法的分子内变体，以实现适当拴住的双卤代芳烃的对映选择性还原环化，并导致c2对称和非对称多环双芳基。后者包括MOP和PHOX型体系的例子，它们可以作为可调的手性配体框架。最后和最雄心勃勃的目标是在两个不同的芳基卤化物底物之间实现高度对映选择性交叉偶联。在这里，将确定避免竞争性均偶联事件的必要条件，以允许潜在的通用平台的出现，以制备具有广泛适用性的双芳烯。特拉华大学的高通量实验（HTE）实验室将在概述的研究过程中广泛使用，以促进评估和优化配体结构、添加剂和溶剂效应、温度和其他反应变量等因素所需的合理筛选活动。这项工作的发现预计将导致影响联芳基合成实践和对映选择性催化更广泛领域的根本性进展。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。