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.

在化学系化学催化计划的支持下，特拉华州大学的唐纳德沃森教授正在研究一种镍催化的方法，用于制备一类称为轴向手性双芳烃的化合物。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，但其制备的传统方法在范围上受限和/或依赖于基于贵金属的催化剂的使用。相比之下，感兴趣的过程是相当通用的，并且其对镍（一种地球上丰富的金属）的依赖性意味着化学更环保。该过程的一个突出特征是它能够生成双芳烃，其中分子的一种扭曲形式（类似于手性的概念）占主导地位。随着沃森教授和他的同事们参与各种教育和外展活动，该奖项的更广泛影响将扩大到社会所获得的好处。最值得注意的是，学术化学家培训（REACT）计划的研究经验旨在保持那些由于学术准备不足而进入大学时处于不利地位的学生参与物理科学，因此，辍学的风险很高。REACT计划预计将特别有利于属于STEM中代表性不足的群体的学生（科学、技术、该资助项目涉及进一步研究沃森实验室最近报道的对映选择性镍催化还原芳基卤偶联，并提供了潜在的效率和范围增益超过既定的程序合成非-外消旋的轴向手性二芳烃。该研究分为三个目标，旨在开发该方法，同时更充分地实现其合成潜力。第一个目标是集中在扩展homocoupling过程的基板之前没有探索目标联萘和联苯系统从邻卤代（通常是溴）取代的芳烃，包括芳基膦/氧化膦，酯，胺，和硫醚。第二个目标涉及追求的方法，以实现对映选择性还原环化的适当栓系的双（卤代芳烃），并导致C2-对称和非对称的多环联芳基的分子内的变体。后者包括MOP和PHOX型体系的实例，其本身可用作可调手性配体框架。最后和最雄心勃勃的目标是针对实现两个不同的芳基卤底物之间的高度对映选择性的交叉偶联。在这里，将确定避免竞争性同偶联事件的必要条件，以便可能出现一个制备具有广泛适用性的联芳化合物的通用平台。特拉华州大学的高通量实验（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。这项工作的结果预计将导致影响联芳基合成的实践和对映选择性催化的更广泛领域的根本性进展。该奖项反映了NSF的法定使命，并已被认为是值得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的支持。