Taming N-Fused Saturated Bicycles for Discovery Chemistry and Scale-Up

驯服 N 熔合饱和自行车以实现化学发现和放大

• 批准号: 2891677
• 金额: --
• 依托单位: University of Bath
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2891677
• 关键词: Taming; Fused; Saturated; Bicycles; Discovery

Despite being common in bioactive alkaloids and having broad commercial availability of parent compounds, saturated N-fused bicycles are rarely exploited in drug discovery. This could be attributed to their low commercial availability as well as high cost and high synthetic effort required to access functionalised derivatives. They currently require long multi-step reactions to prepare making them not readily available. This project aims to use existing knowledge of amine alpha-C-H bond functionalisation to access saturated N-fused bicycles in a simplified and automated manner. This will allow medicinal chemists access to a space of structures with potentially untapped potential. Once this has been achieved, these structures will be used to demonstrate new late-stage C-H functionalisation processes. It is crucial that new methodologies are applicable on a discovery (mg) and large (kg) scale. The first aim of the project will look at automating the synthesis of saturated N-fused bicycles via catalytic ring fusion. This will involve combining automated 'catalytic ring fusion' methodology for secondary amines with recently developed, fully automated annulation chemistry with primary amines. The second aim will move on to the automated synthesis of a-(hetero)arylated, saturated N-fused bicycles. A recently invented, scalable synthesis of a-(hetero)aryl N-heterocycles from aromatic aldehyde feedstocks using novel y-amino sulfoxides as reagents will be expanded to the automated synthesis of a-(hetero)arylated pyrrolizidines, using novel y-amino sulfoxide as the key reagent. The chemistry will be automated in 96-plates using ChemSpeed platform at the University of Bristol.Thirdly, this project will aim to develop late-stage C-H functionalisation at several different positions on the N-fused bicycle structure, the stereoselectivity is controlled by the bicyclic system. In summary, this project aims to deliver new C-H functionalisation reactions applicable to both discovery and scale-up, novel N-fused bicyclic scaffolds for use in drug discovery, new methodology for metal-free synthesis of a-(hetero)aryl N-heterocycles, new late-stage C-H functionalisations for tertiary amines and a new bioisostere concept for 1,2-disubstituted aromatics.

尽管在生物活性生物碱中很常见，并且在药物发现中很少利用饱和的N融合自行车的饱和N融合自行车。这可能归因于其较低的商业可用性以及访问功能性衍生品所需的高成本和高合成工作。他们目前需要长的多步反应，以使其不容易获得。该项目旨在利用胺alpha-c-h键功能化的现有知识以简化和自动化的方式访问饱和的N融合自行车。这将使药物化学家进入具有潜在尚未开发的潜力的结构空间。一旦实现了这一目标，这些结构将用于展示新的后期C-H功能化过程。至关重要的是，新方法适用于发现（MG）和较大（kg）量表。该项目的第一个目的将考虑通过催化环融合自动化饱和的N融合自行车的合成。这将涉及将二级胺的自动化“催化环融合”方法与最近开发的，完全自动化的环状化学与原代胺相结合。第二个目标将转移到A-（杂种）芳基饱和的N型自行车的自动合成中。使用新型Y-氨基亚氧化物作为试剂的芳族醛原料中A-（异杂）芳基N-脱环的合成，将扩展到使用新型Y-氨基甲基甲基甲基氧化甲酰基甲基化的吡咯烷的自动合成。化学将使用布里斯托尔大学的Chemspeed平台在96个板中自动化。三分之二的项目将旨在在N融合的自行车结构上的几个不同位置开发晚期C-H功能化，立体选择性由Bicicclic System控制。 In summary, this project aims to deliver new C-H functionalisation reactions applicable to both discovery and scale-up, novel N-fused bicyclic scaffolds for use in drug discovery, new methodology for metal-free synthesis of a-(hetero)aryl N-heterocycles, new late-stage C-H functionalisations for tertiary amines and a new bioisostere concept for 1,2-disubstituted aromatics.