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，特拉华大学的唐纳德·沃森教授正​​在研究一种镍催化工艺，用于制备一类被称为轴向手性联芳烃的化合物。此类化合物是具有一系列社会相关应用的有用材料，例如作为药剂或作为化学制造过程的调节剂，但其传统的制备方法在范围上受到限制和/或依赖于贵金属基催化剂的使用。相比之下，我们感兴趣的过程非常通用，而且它对镍这种地球上丰富的金属的依赖意味着该化学过程在环境上更具可持续性。该过程的一个显着特点是它能够生成双芳烃，其中分子的一种扭曲形式（类似于旋向性的概念）优于另一种。该奖项的更广泛影响将延伸到沃森教授和他的同事参与各种教育和推广活动为社会带来的利益。最值得注意的是，学术化学家培训研究经验（REACT）项目旨在维持学生对物理科学的参与，这些学生在进入大学时最初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 计划预计对 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特别有益。该资助项目涉及对沃森实验室最近报道的对映选择性镍催化还原芳基卤化物偶联的进一步研究，与非外消旋轴向手性合成的既定程序相比，它在功效和范围上有潜在的提高 比亚芳烃。该研究分为三个目标，旨在开发该方法，同时更充分地发挥其合成潜力。第一个目标是将自偶联过程扩展到以前未探索过的底物，以一系列邻位卤代（通常是溴代）取代的芳烃（包括芳基膦/氧化膦、酯、胺和硫醚）中的联萘和联苯系统为目标。第二个目标涉及寻求该方法的分子内变体，以实现适当束缚的双（卤代芳烃）的对映选择性还原环化，并产生 C2 对称和非对称多环联芳基。后者包括 MOP 和 PHOX 型系统的例子，它们本身可用作可调节的手性配体框架。最终也是最雄心勃勃的目标是实现两种不同的芳基卤化物底物之间的高度对映选择性交叉偶联。在这里，将确定避免竞争性自偶联事件的必要条件，以便可能出现用于制备具有广泛适用性的联芳基化合物的通用平台。特拉华大学的高通量实验 (HTE) 实验室将在上述研究过程中得到广泛使用，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。这项工作的结果预计将带来对联芳合成实践和更广泛的对映选择性催化领域产生影响的根本性进展。该奖项反映了 NSF 的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。