Development and application of new methods for chemical synthesis

化学合成新方法的开发及应用

• 批准号: RGPIN-2018-05732
• 负责人: Yudin, Andrei
• 金额: $ 15.3万
• 依托单位: University of Toronto
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=748375
• 关键词: Development; application; new; methods; chemical

Amphoteric molecules bifunctional structures equipped with orthogonal nodes of reactivity are the main focus of our research program. The main operational principle of our work has been and will remain to develop new synthetic methods and apply them toward understanding how small-to-medium sized molecules interact with biological receptors. My lab provides superb training for highly qualified personnel, who receive employment and postdoctoral offers from top companies and labs throughout the world. Over the next five years, our program will address the following strategic directions.We will develop new macrocyclization technologies and delineate the role of heterocyclic grafts on the properties of macrocycles. Building on the cooperative interplay of intramolecular hydrogen bonds and electrostatic interactions in macrocyclization mechanisms, we will develop new methods of cyclizing linear sequences with an emphasis on structural diversity of the resulting scaffolds.We will pursue “hidden” conformations of macrocycles. We hypothesize that site-selective enforcement of cis-amide bonds in macrocycles will lead to the discovery of previously uncharted conformational space. We will resort to the thioamide functionality as the tool to investigate this idea.We will develop new boron transfer processes. Encouraged by the discovery of boride/hydride analogy in polar reaction mechanisms, we will seek new reactions for the synthesis of hitherto inaccessible boron-based intermediates and endpoints of synthesis. We will modulate residence time of covalent serine protease inhibitors. We will use our recent success in co-crystal formation between small molecules and their protein targets as the foundation for the development of covalent inhibitors of proteases and will address the enduring challenge of modulating the residence time of boron-containing inhibitors. Our foundational papers are published in high impact journals (e.g. over the past year we published three key Nature Chemistry papers). The novelty and significance of our approaches is evidenced by the rapid adoption of our methods in industry and in academia. MilliporeSigma has created a special web portal exclusively dedicated to our methods of synthesis. This decision was largely based on the worldwide demand for our reagents. The ideas implemented by us and ultimately funded by NSERC over the past 5 years have led to tangible products that are on MilliporeSigma's best-selling list. These offerings include aziridine aldehydes, boryl aldehydes, acyl boronates, and Pinc technology for macrocyclization. Chemists throughout the world use our molecules, which makes it reasonable to assume that the plans outlined for 18 students in the present NSERC discovery grant will continue to provide transformative methods of synthesis with direct application to the discovery and development of biologically active compounds.

两性分子的双功能结构配备了正交节点的反应性是我们的研究计划的主要重点。我们工作的主要操作原则一直是并将继续开发新的合成方法，并将其应用于了解中小分子如何与生物受体相互作用。我的实验室为高素质的人才提供一流的培训，他们从世界各地的顶级公司和实验室获得就业和博士后机会。在未来的五年里，我们的计划将致力于以下战略方向：我们将开发新的大环化技术，并阐明杂环接枝对大环化合物性质的作用。基于大环化机制中分子内氢键和静电相互作用的协同作用，我们将开发新的线性序列环化方法，重点是所得到的支架结构的多样性。我们将追求大环的“隐藏”构象。我们推测，大环化合物中顺式酰胺键的位点选择性执行将导致以前未知的构象空间的发现。我们将以硫代酰胺官能度为工具来探讨这个想法，并开发新的硼转移过程。受到极性反应机制中硼化物/氢化物类似物发现的鼓舞，我们将寻找新的反应来合成迄今为止难以获得的硼基中间体和合成终点。我们将调节共价丝氨酸蛋白酶抑制剂的停留时间。我们将利用我们最近在小分子及其蛋白质靶点之间的共晶体形成方面的成功，作为开发蛋白酶共价抑制剂的基础，并将解决调节含硼抑制剂停留时间的持久挑战。我们的基础论文发表在高影响力的期刊上（例如，在过去的一年里，我们发表了三篇重要的自然化学论文）。我们的方法的新奇和重要性证明了我们的方法在工业界和学术界的迅速采用。MilliporeSigma创建了一个专门用于我们的合成方法的特殊门户网站。这一决定主要是基于全球对我们试剂的需求。在过去的5年里，我们实施并最终由NSERC资助的想法已经导致了在MilliporeSigma最畅销名单上的有形产品。这些产品包括氮丙啶醛、硼醛、酰基硼酸酯和用于大环化的Pinc技术。世界各地的化学家都在使用我们的分子，这使得我们有理由假设，目前NSERC发现资助中为18名学生概述的计划将继续提供直接应用于生物活性化合物的发现和开发的变革性合成方法。