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

尽管在生物活性生物碱中很常见，并且母体化合物具有广泛的商业可用性，但饱和n -融合环很少用于药物发现。这可能归因于它们的低商业可用性以及获得功能化衍生物所需的高成本和高合成努力。它们目前需要长时间的多步骤反应来准备，使它们不易获得。该项目旨在利用现有的胺- c - h键功能化知识，以简化和自动化的方式获得饱和n -熔融自行车。这将允许药物化学家进入具有潜在未开发潜力的结构空间。一旦实现了这一点，这些结构将用于展示新的晚期C-H功能化过程。至关重要的是，新方法适用于发现（毫克）和大（公斤）规模。该项目的第一个目标将着眼于通过催化环聚变实现饱和n -熔融自行车的自动化合成。这将涉及将仲胺的自动化“催化环融合”方法与最近开发的全自动伯胺环化化学相结合。第二个目标将转移到a-（杂）芳基化，饱和n -熔融自行车的自动合成。以新型y-氨基亚砜为主要试剂，以芳香醛为原料合成A -（杂）芳基n -杂环的新发明，将扩展到以新型y-氨基亚砜为关键试剂自动合成A -（杂）芳基吡咯里嗪。使用布里斯托尔大学的ChemSpeed平台，化学反应将在96个板上自动进行。第三，本项目将致力于在n -熔融自行车结构的几个不同位置上发展后期碳氢功能化，立体选择性由双环系统控制。总之，该项目旨在提供适用于发现和扩大规模的新的C-H功能化反应，用于药物发现的新型n -融合双环支架，无金属合成-（杂）芳基n -杂环的新方法，叔胺的新晚期C-H功能化以及1,2-二取代芳烃的新生物同位体概念。

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.