Cu-Catalysed Amination of Alkylboronic Esters

铜催化烷基硼酯的胺化

基本信息

批准号：
EP/T009292/1
负责人：
Benjamin Partridge
金额：
$ 39.82万
依托单位：
University of Sheffield
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2020
资助国家：
英国
起止时间：
2020 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=EP%2FT009292%2F1
关键词：
Cu Catalysed Amination Alkylboronic Esters

项目摘要

The more planar a drug candidate is, the more likely it is to show unwanted side effects and be rejected in clinical trials. It is therefore desirable to build more "3-dimensional" molecules where there are fewer aromatic rings and more alkyl groups. This concept is challenging as there are few general chemical coupling methods to build complex "3D" molecules in a predictable and reliable manner. An opportunity to achieve this is through the formation of amines, one of the most common functional groups found in medicinal drugs and agrochemicals. Traditional methods to make (chiral) alkyl amines, such as nucleophilic substitution and reductive amination, are often non-trivial. They suffer from poor control (e.g. over alkylation), require protecting groups to overcome issues of chemoselectivity, and are challenging reactions to control stereoselectively.We aim to solve these difficulties by developing a Cu-catalysed amination of alkyl boronic esters, enabling access to complex "3D" amines. These organoboron reagents have several favourable properties which benefit this approach. They are air- and moisture-stable chemicals which tolerate a broad range of functional groups. They also show orthogonal reactivity to other common functionality, reducing the need for protecting groups. They can also be prepared stereoselectively, and typically do not racemise under conditions required for catalysis. These properties mean that formation of the key amine motif can be carried out at a late-stage in a synthetic sequence. This will enable the efficient preparation of diverse libraries of complex molecules from common boronic ester building blocks. Such technology will enable scientists in medicinal chemistry and agrochemical discovery to explore new chemical space, expediting the discovery of new medicines and crop protections.In addition, we will apply our Cu-catalysed amination method to the intramolecular coupling of amine-containing diboronic esters. In this reaction, one boronic ester will react to form a saturated N-heterocycle, with the second boronic ester remaining as a handle for further functionalisation. This will allow access to complex saturated heterocyclic boronic ester building blocks, which currently have limited availability. These heterocyclic boronic esters are attractive scaffolds for medicinal chemistry and agrochemical discovery. By working with our industrial partner, Redbrick Molecular Ltd., these boron reagents will be made commercially available, providing direct impact for this grant.

候选药物的平面越多，在临床试验中表现出不需要的副作用并被拒绝的可能性越大。因此，希望建造更多的“三维”分子，其中芳香环和更多的烷基群。这个概念具有挑战性，因为很少有一般的化学耦合方法可以以可预测且可靠的方式构建复杂的“ 3D”分子。实现这一目标的机会是通过胺的形成，胺是药物和农业化学物质中最常见的官能团之一。传统的制作（手性）烷基胺的方法，例如亲核取代和还原性胺化，通常是非平凡的。他们的控制不力（例如烷基化），需要保护组克服化学选择性问题，并且在立体选择性控制方面具有挑战性的反应。我们的目的是通过开发CU催化的烷基硼醇酯的胺化来解决这些困难，从而使复杂的“ 3D胺”访问复杂的“ 3D”胺。这些有机体试剂具有几种有利的特性，这些特性有益于这种方法。它们是空气和水分稳定的化学物质，可容忍广泛的官能团。它们还显示出对其他共同功能的正交反应性，从而减少了保护组的需求。它们也可以立体选择，并且通常在催化条件下不进行种族化。这些特性意味着可以在综合序列的后期进行关键胺基序的形成。这将使从普通的硼酯构建块中有效制备复杂分子的各种文库。这样的技术将使药物化学和农业化学发现能够探索新的化学空间，加快发现新药物和作物保护措施。此外，我们还将应用我们的CU催化胺化方法将含胺的二氨基酯的分子偶联。在此反应中，一个硼酯将反应形成饱和的N-近环体，而第二个硼酯则是用于进一步功能化的手柄。这将允许访问复杂的饱和杂环硼酸酯酯构建块，该酯目前的可用性有限。这些杂环硼酯是用于药物化学和农化学发现的吸引人的脚手架。通过与我们的工业合作伙伴Redbrick Molecular Ltd.合作，这些硼试剂将在商业上可用，从而为这笔赠款提供直接影响。