New Photocatalytic C-C Bond-Forming Reactivity of Unprotected Primary Amines

未受保护伯胺的新光催化 C-C 键形成反应

• 批准号: EP/X026566/1
• 负责人: Alexander Cresswell
• 金额: $ 61.3万
• 依托单位: University of Bath
• 依托单位国家: 英国
• 项目类别: Research Grant
• 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=EP%2FX026566%2F1
• 关键词: New; Photocatalytic; Bond; Forming; Reactivity

Primary alkylamines are among the most ubiquitous of all aliphatic chemical building blocks, surpassing even the availability of alkyl carboxylic acids (e.g., >27,000 primary alkylamines commercially available from Enamine Ltd, versus >25,000 alkyl carboxylic acids). Seven of the top 20 reactions in medicinal chemistry either use or generate primary amines, and over 80% of marketed drugs feature alkylamine motifs. The archetypal chemical reactivity of primary alkylamines involves electrophilic attack at nitrogen, forming carbon-nitrogen bonds, and this process alone underpins much of drug discovery (e.g., amide formation, SNAr). Development of new and unconventional catalytic processes that form carbon-carbon bonds from primary amine feedstocks would be transformative, enabling highly simplifying disconnections and protecting group-free synthesis of complex amines used in pharmaceutical and agrochemical science. In this vein, we recently reported the first example of a catalytic alpha-C-H alkylation of unprotected primary amines with styrenes, using visible-light photocatalysis, and showcased this strategy in the shortest ever synthesis of a blockbuster MS drug called Fingolimod. This project will capitalise on this world-leading breakthrough, developing new catalytic transformations of unprotected primary alkylamines that greatly expand the versatility of this critical functional group. Specifically, we will invent modular and scalable strategies for the synthesis of gamma-boryl amines, azetidines, cyclic sulfoximines, heterobenzylic amines, and alpha-amino ketones that use primary amines as feedstocks. Emphasis will lie on expedient access to areas of 3-dimensional, 'lead-like' chemical space that is currently underexplored due to a lack of synthetic chemistry enablement. The racemic amine products will be resolved into single enantiomers by AstraZeneca, and these processes will be scaled up to hundreds of grams by Enamine Ltd, such that novel, enantiopure building blocks for drug discovery can be made immediately available to the global community.

原代烷基胺是所有脂肪族化学块中最普遍的烷基之一，甚至超过了烷基羧酸的可用性（例如，> 27,000个从Enamine Ltd商业上获得的原代烷基胺，与> 25,000烷基羧酸相比）。在药物化学的前20个反应中，有7种使用或产生催化胺，超过80％的销售药物具有烷基胺基序。原代烷基胺的原型化学反应性涉及氮的亲电攻击，形成碳氮键，并且仅此过程为大部分药物发现（例如，酰胺形成，SNAR）。从原发性胺原料中形成碳碳键的新的和非常规的催化过程将具有变化，从而使高度简化的断开连接并保护对药物和硬化学科学中使用的复杂胺的无组合成。在这种情况下，我们最近报道了使用可见光光催化的催化α-C-H烷基化催化α-C-h烷基化对未受保护的原代胺的烷基化，并以有史以来最短的Blockbuster MS药物合成为Fandolimod，并以最短的合成来展示这种策略。该项目将利用这个世界领先的突破，开发出未受保护的原代烷基胺的新催化转化，这些烷基胺大大扩大了这个关键功能群的多功能性。具体而言，我们将发明模块化策略，用于合成γ-胺胺，偶氮替丁，环氧胺，杂苯胺和α-氨基酮，这些胺将原代胺用作原料。重点将取决于进入三维“铅样”化学空间区域，由于缺乏合成化学启示，目前未能驱动。外消毒胺产品将通过阿斯利康（Astrazeneca）解决单个对映异构体，这些过程将通过Enamine Ltd缩放多达数百克，因此可以立即使全球社区可用新颖的，对照的药物构建块。