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.

伯烷基胺是所有脂肪族化学结构单元中最普遍的一种，甚至超过了烷基羧酸的可用性（例如，从 Enamine Ltd 可以买到 >27,000 种伯烷基胺，而 >25,000 种烷基羧酸）。药物化学中排名前 20 的反应中有 7 个使用或生成伯胺，超过 80% 的上市药物都具有烷基胺基序。伯烷基胺的典型化学反应性涉及对氮的亲电攻击，形成碳-氮键，并且这一过程本身就支撑了许多药物发现（例如酰胺形成，SNAr）。开发由伯胺原料形成碳-碳键的新型非常规催化工艺将是变革性的，能够高度简化制药和农业化学科学中使用的复杂胺的断开和保护无基团合成。本着这一精神，我们最近报道了第一个利用可见光光催化将未受保护的伯胺与苯乙烯进行 α-C-H 烷基化的例子，并在有史以来最短的合成重磅 MS 药物芬戈莫德 (Fingolimod) 中展示了这一策略。该项目将利用这一世界领先的突破，开发未受保护的伯烷基胺的新催化转化，从而极大地扩展这一关键官能团的多功能性。具体来说，我们将发明模块化和可扩展的策略，用于合成使用伯胺作为原料的γ-硼基胺、氮杂环丁烷、环亚砜亚胺、杂苄胺和α-氨基酮。重点将在于方便地进入三维“类铅”化学空间区域，由于缺乏合成化学支持，目前该区域尚未得到充分探索。外消旋胺产品将由阿斯利康（AstraZeneca）解析成单一对映异构体，而这些工艺将由 Enamine Ltd 扩大到数百克，这样用于药物发现的新型、对映异构体纯的构建模块就可以立即提供给全球社区。