A Multi-Component Strategy for the Synthesis of Complex Aliphatic Amines using Photo-redox Catalysis

利用光氧化还原催化合成复杂脂肪胺的多组分策略

基本信息

批准号：
EP/S020292/1
负责人：
Matthew Gaunt
金额：
$ 89.67万
依托单位：
University of Cambridge
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2019
资助国家：
英国
起止时间：
2019 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=EP%2FS020292%2F1
关键词：
Multi Component Strategy Synthesis Complex

项目摘要

Alkylamines are ubiquitous amongst pharmaceuticals, small-molecule biological probes, natural products and pre-clinical candidates1. Despite their importance, amine synthesis is still dominated by two methods: N-alkylation and carbonyl reductive amination2. The increasing demand for 'sp3-rich' molecules in drug-discovery3 continues to drive development of practical catalytic methods to synthesize complex saturated alkylamines4-6. In particular, processes that transform diverse, readily-available feedstocks into structurally diverse sp3-rich architectures provides a strategic advantage in complex alkylamine synthesis. Here, we propose a multicomponent reductive photocatalytic technology that combines readily-available dialkylamines, carbonyls and radical acceptor feedstocks to build architecturally complex and functionally diverse tertiary alkylamines in a single step. This process involves a visible-light-mediated reduction of in-situ generated iminium ions, selectively furnishing previously inaccessible alkyl-substituted alpha-amino radicals, which engage radical acceptors and lead to C(sp3)-C(sp3) bond formation. The potential of this operationally straightforward reaction suggests a broad functional group tolerance, could facilitate the synthesis of drug-like amines not readily accessible by other methods and would be amenable to late-stage functionalization applications, making it of interest in pharmaceutical research and other areas.

烷基胺在药物，小分子生物探针，天然产物和临床前候选物中无处不在1。尽管它们的重要性，但胺的合成仍然由两种方法主导：N-烷基化和羰基还原性胺化2。药物发现中对“ SP3富”分子的需求不断增长，继续推动实用催化方法的发展，以合成复杂的饱和烷基胺4-6。特别是，将各种，易于可用的原料转化为结构多样的SP3富含体系结构的过程为复杂的烷基胺合成提供了战略优势。在这里，我们提出了一种多组分的还原光催化技术，该技术结合了易于获取的二甲胺，羰基和自由基受体原料，以在一个步骤中构建建筑且功能多样的第三级烷基胺。该过程涉及可见光介导的原位产生的亚米离子的降低，有选择地提供了先前无法接近的烷基取代的α-氨基自由基，该烷基取代的α-氨基自由基会吸引自由基受体，并导致C（SP3）-C（SP3）-C（SP3）键形成。这种操作直接反应的潜力表明，功能群的耐受性广泛，可以促进类似药物的胺的合成，而其他方法不容易访问，并且可以适合后期的功能化应用，从而使其对药物研究和其他领域感兴趣。