New Catalytic Methods to Prepare Axially Chiral Compounds

在化学系化学催化计划的支持下，特拉华大学的唐纳德·沃森教授正在研究一种镍催化工艺，以制备一类被称为轴向手性联芳烃的化合物。这类化合物是一种有用的材料，具有广泛的社会应用，例如，用作医药制剂或作为化学制造过程的调节剂，但传统的制备方法范围有限，和/或依赖贵金属催化剂的使用。相比之下，感兴趣的过程相当多才多艺，而且它对镍的依赖，意味着这种化学更具环境可持续性。镍是一种富含地球的金属。这一过程的一个显著特征是，它使联芳烃的生成成为可能，在这种联芳烃中，分子的一种扭曲形式(类似于左旋手的概念)主导另一种分子。该奖项的更广泛影响将延伸到沃森教授和他的同事从事各种教育和外展活动时为社会带来的好处。最值得注意的是，培训中的学术化学家研究经验(REACT)计划旨在保持学生对物理科学的参与，这些学生最初进入大学时由于学业准备不足而处于不利地位，因此有很高的辍学风险。REACT计划预计将特别有益于STEM(科学、技术、工程和数学)工作队伍中代表性较低的群体的学生。该资助项目涉及Watson实验室最近报道的对映体选择性镍催化的还原芳基卤化物偶联的进一步研究，该项目在效率和范围方面比现有的非外消旋轴手性联芳烃的合成方法具有潜在的优势。这项调查分为三个目标，旨在允许开发该方法，同时更充分地实现其合成潜力。第一个目标是将均相偶联过程扩展到以前没有探索过的底物，以从一系列邻位卤代(通常是溴)取代的芳烃，包括芳基膦/膦氧化物、酯、胺和硫醚中靶向联萘和联苯体系。第二个目标涉及寻求该方法的分子内变体，以实现适当系留的双(卤代芳烃)的对映选择性还原环化反应，并导致C2对称和非对称多环联芳基。后者包括MOP和PHOX类型的系统的例子，它们本身作为可调谐的手性配体骨架可能是有用的。最终也是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的交叉偶联。在这里，将确定避免竞争性同质偶联事件的必要条件，以便可能出现制备具有广泛适用性的联芳烃的一般平台。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基结构、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对联芳基合成的实践和对映体选择性催化剂的更广泛领域产生根本性的影响。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

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.