New Synthetic Methods for the Preparation of Highly Functionalized Heterocycles

制备高官能化杂环化合物的新合成方法

• 批准号: RGPIN-2022-03124
• 负责人: Derksen, Darren
• 金额: $ 2.11万
• 依托单位: University of Calgary
• 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=747845
• 关键词: New; Synthetic; Methods; Preparation; Highly

The goal of the Derksen group research program is to develop methods that improve access to highly functionalized heterocycles (cyclic compounds that have at least two different elements forming the ring). These molecules have many potential applications including in the pharmaceutical industry, in materials chemistry, and as ligands for catalysis. Being able to access unique structures is critical to making molecules that have novel properties for these varying applications.  Improving synthetic access to heterocycles will also allow access to more complex molecular scaffolds, while reducing waste and lowering costs which are essential for responsible development in industry. The three main aims of this proposal involve the synthesis of heterocycles and have a particular focus on catalysis and stereochemical challenges of existing methods. Aim 1 is based on the development of atropisomer-selective catalysts for nucleophilic aromatic substitution reactions. As an increasing number of pharmaceutical compounds are moving beyond flat structures, improved methods are needed to control the relative and absolute configuration of these unique scaffolds. Aim two is focused on the synthesis of functionalized azetidines, particularly benzazetidines, and those contain stereogeneic centers. Inspired by the rise of azetidine applications in the literature and the unusual natural product Taichunamide A, this proposal describes our approach to forming complex azetidines using catalytic, asymmetric methods. Aim three of the proposal describes our strategy to improve the product selectivity of cross-electrophile coupling that reduces the amount of homocoupled byproducts found in these reactions. Although significant progress has been made in the cross-electrophile coupling between aryl and alkyl halides, our strategy is to develop a modular catalyst design strategy that can be rapidly and systematically optimized to favor cross coupling. The impact of the work described in this proposal includes the development of new catalytic strategies for stereoinduction, improved access to chiral azetidines, and the development of novel modular ligands for cross electrophile coupling. This work will lead to high impact publications and train HQP, but will also lead to new partnerships with the chemical industry.

德克森集团研究计划的目标是开发方法，以改善获得高度官能化的杂环（环状化合物，至少有两个不同的元素形成的环）。这些分子具有许多潜在的应用，包括在制药工业中，在材料化学中，以及作为催化剂的配体。能够获得独特的结构对于制造具有这些不同应用的新特性的分子至关重要。改善杂环的合成途径也将允许获得更复杂的分子支架，同时减少浪费并降低成本，这对工业负责任的发展至关重要。该提案的三个主要目标涉及杂环的合成，并特别关注现有方法的催化和立体化学挑战。目标1是基于阻转异构体选择性催化剂的发展，用于亲核芳香取代反应。随着越来越多的药物化合物超越平面结构，需要改进的方法来控制这些独特支架的相对和绝对构型。目的二是合成功能化的氮杂环丁烷类化合物，特别是苯并氮杂环丁烷类化合物。受到文献中氮杂环丁烷应用的兴起和不寻常的天然产物Taichunamide A的启发，该提案描述了我们使用催化，不对称方法形成复杂氮杂环丁烷的方法。该提案的第三个目标描述了我们的策略，以提高交叉亲电偶联的产物选择性，减少在这些反应中发现的同源偶联副产物的量。虽然在芳基和烷基卤化物之间的交叉亲电偶联方面取得了重大进展，但我们的策略是开发一种模块化催化剂设计策略，该策略可以快速系统地优化以有利于交叉偶联。本提案中描述的工作的影响包括开发立体诱导的新催化策略，改善手性氮杂环丁烷的获得，以及开发用于交叉亲电偶联的新型模块化配体。这项工作将导致高影响力的出版物和培训HQP，但也将导致与化学工业的新伙伴关系。