Synthesis of Complex Molecular Architectures Using Strategic 1,4-Sigmatropic Rearrangements

使用战略 1,4-Sigmatropic 重排合成复杂分子结构

• 批准号: RGPIN-2017-04117
• 负责人: Derksen, Darren
• 金额: $ 2.04万
• 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: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=710029
• 关键词: Synthesis; Complex; Molecular; Architectures; Using

Organic synthesis plays an essential role in the fine chemical, agrochemical, and pharmaceutical industries. The synthesis of molecules containing multiple stereocenters in close proximity is one of the major challenges in synthetic chemistry and many classes of biologically important natural products contain stereocenters. One strategy to rapidly access these complex frameworks is through "one-pot" tandem reactions - where the product of one reaction is the substrate for the next transformation. Research in the Derksen group is focused on developing asymmetric, tandem reactions that incorporate a 1,4-sigmatropic rearrangement (1,4-SR). We have recently discovered a synthetic strategy to access important biologically active terpene natural product frameworks using a tandem photo-cyclization/1,4-SR reaction process. This work has shown that solvent effects and even the wavelength of light used to initiate the reaction play an important role in the overall yield of targeted terpene frameworks and the formation of byproducts. This research proposal aims to advance the utility of this process by identifying novel strategies of controlling the regio- and stereoselectivity of the 1,4-SR using substrate control as well as catalytic methods - reducing the overall number of steps and the cost of synthesis. This proposal also aims to expand the substrate scope of the tandem cyclization/1,4-SR process by completing systematic evaluations of ring sizes, heteroatoms, and substituents that are compatible with the reaction. A clear understanding of the factors that dictate reaction selectivity will provide a powerful tool for use of this methodology in complex molecule synthesis. Although the 1,4-SR is known in the literature, it has been underutilized due to challenges in controlling regio- and stereoselectivity. The proposed research program improves on existing methods in the literature by developing new ways to control product selectivity, improve yields, and to expand the substrate scope of tandem 1,4-SR reactions. With the knowledge of how to control the tandem 1,4-SR selectivity, the Derksen group has demonstrated that a common intermediate can be used to synthesize the framework of three classes sesquiterpene natural products - the cubebane, sprioaxane, and most importantly, the guaiane sesquiterpenes. With the diverse array of bioactivity reported for these natural products, including anticancer, antifungal, and as antiinflammatory agents, the work described in this proposal will not only impact the synthetic chemistry community, but will also provide valuable materials for biologists eager to understand how these compounds interact with their natural receptors. The skills developed by students within this research program will provide highly-trained chemists for the Canadian workforce who are comfortable engaging in complex, interdisciplinary research challenges.

有机合成在精细化工、农化和制药工业中发挥着重要作用。合成含有多个近距离立体中心的分子是合成化学的主要挑战之一，许多具有重要生物学意义的天然产物都含有立体中心。快速获取这些复杂框架的一种策略是通过“一锅”串联反应——其中一个反应的产物是下一个转化的底物。Derksen小组的研究重点是开发不对称串联反应，包括1,4-异位重排（1,4- sr）。我们最近发现了一种利用串联光环化/1,4- sr反应过程获得重要生物活性萜烯天然产物框架的合成策略。这项工作表明，溶剂效应甚至用于引发反应的光的波长对目标萜烯框架的总体产率和副产物的形成起着重要的作用。本研究计划旨在通过使用底物控制和催化方法来确定控制1,4- sr的区域和立体选择性的新策略，从而减少合成步骤的总数和合成成本，从而提高该过程的实用性。本提案还旨在通过完成与反应相容的环尺寸、杂原子和取代基的系统评估，扩大串联环化/1,4- sr工艺的底物范围。清楚地了解决定反应选择性的因素将为在复杂分子合成中使用该方法提供有力的工具。虽然1,4- sr在文献中是已知的，但由于在控制区域选择性和立体选择性方面的挑战，它尚未得到充分利用。该研究计划通过开发新的方法来控制产物选择性，提高产率，并扩大串联1,4- sr反应的底物范围，从而改进文献中现有的方法。随着如何控制串联1,4- sr选择性的知识，Derksen小组已经证明了一个共同的中间体可以用来合成三类倍半萜天然产物的框架-立方体本，spriaxane，最重要的是，愈创烷倍半萜。随着这些天然产物的多种生物活性的报道，包括抗癌，抗真菌和抗炎剂，本提案中描述的工作不仅将影响合成化学界，而且还将为渴望了解这些化合物如何与其天然受体相互作用的生物学家提供有价值的材料。学生在该研究项目中培养的技能将为加拿大劳动力提供训练有素的化学家，他们可以轻松从事复杂的跨学科研究挑战。