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

尽管饱和N-稠合双环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，但在药物发现中很少利用饱和N-稠合双环。这可能归因于它们的低商业可用性以及获得官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反应来制备，使得它们不易获得。该项目旨在利用胺α-C-H键功能化的现有知识，以简化和自动化的方式获得饱和的N-稠合自行车。这将使药物化学家能够进入具有潜在未开发潜力的结构空间。一旦实现这一目标，这些结构将用于展示新的后期C-H官能化过程。新方法必须适用于发现（毫克）和大规模（公斤）。该项目的第一个目标将着眼于通过催化环融合自动合成饱和N-稠合双环。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化伯胺成环化学相结合。第二个目标将转移到自动化合成的α-（杂）芳基化，饱和的N-稠合的自行车。最近发明的，使用新型γ-氨基亚砜作为试剂从芳香醛原料可规模化合成α-（杂）芳基N-杂环将扩展到使用新型γ-氨基亚砜作为关键试剂自动化合成α-（杂）芳基化吡咯烷。该化学反应将在布里斯托大学的ChemSpeed平台上在96个板中自动进行。第三，该项目旨在开发N-稠合双环结构上几个不同位置的后期C-H官能化，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放大的新C-H官能化反应，用于药物发现的新型N-稠合双环支架，用于α-（杂）芳基N-杂环的无金属合成的新方法，叔胺的新后期C-H官能化和1，2-二取代芳族化合物的新生物电子等排体概念。

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.