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.

伯烷基胺是所有脂族化学结构单元中最普遍存在的，甚至超过了烷基羧酸（例如，> 27，000的伯烷基胺，相对于> 25，000的烷基羧酸）。药物化学中前20个反应中有7个使用或产生伯胺，超过80%的市售药物具有烷基胺基序。伯烷基胺的原型化学反应性涉及在氮上的亲电攻击，形成碳-氮键，并且仅该过程就支撑了许多药物发现（例如，酰胺形成，SNAr）。从伯胺原料形成碳-碳键的新的和非常规的催化方法的开发将是变革性的，使得能够高度简化用于制药和农业化学科学的复杂胺的断开和无保护基合成。在这种情况下，我们最近报道了第一个使用可见光催化剂将未保护的伯胺与苯乙烯催化α-C-H烷基化的例子，并在有史以来最短的一种名为Fingolimod的畅销MS药物的合成中展示了这种策略。该项目将利用这一世界领先的突破，开发未保护的伯烷基胺的新催化转化，大大扩展了这一关键官能团的多功能性。具体而言，我们将发明使用伯胺作为原料合成γ-硼基胺、氮杂环丁烷、环状亚砜亚胺、杂苄基胺和α-氨基酮的模块化和可扩展策略。重点将在于方便地进入三维，“铅样”化学空间，目前由于缺乏合成化学的支持，未充分探索的领域。阿斯利康将把外消旋胺产品拆分成单一对映体，Enamine Ltd将把这些过程扩大到数百克，这样就可以立即向全球社区提供用于药物发现的新型对映体纯构建模块。