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、农用化学品和制药工业中发挥着重要作用。 含有多个紧密接近的立体中心的分子的合成是合成化学中的主要挑战之一，并且许多类别的具有生物学重要意义的天然产物都含有立体中心。 快速访问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包含 1,4-σ 重排 (1,4-SR) 的不对称串联反应。 我们最近发现了一种合成策略，使用串联光环化/1,4-SR 反应过程来获取重要的生物活性萜烯天然产物框架。 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产率和副产物的形成起着重要作用。 该研究计划旨在通过确定使用底物控制和催化方法控制 1,4-SR 区域选择性和立体选择性的新策略来提高该过程的实用性，从而减少总步骤数和合成成本。 该提案还旨在通过完成对与反应相容的环大小、杂原子和取代基的系统评估来扩大串联环化/1,4-SR过程的底物范围。 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强大的工具。 尽管 1,4-SR 在文献中是已知的，但由于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。 拟议的研究计划通过开发控制产物选择性、提高产量和扩大串联 1,4-SR 反应的底物范围的新方法来改进文献中的现有方法。 凭借如何控制串联 1,4-SR 选择性的知识，Derksen 团队证明了一种常见的中间体可用于合成三类倍半萜天然产物的框架：荠菜烷、螺菌烷，以及最重要的愈创木烷倍半萜烯。 由于这些天然产物具有多种生物活性，包括抗癌、抗真菌和抗炎剂，本提案中描述的工作不仅会影响合成化学界，而且还将为渴望了解这些天然产物如何发挥作用的生物学家提供宝贵的材料。化合物与其天然受体相互作用。 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，让他们能够轻松应对复杂的跨学科研究挑战。