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构件中最普遍的一种，甚至超过了烷基羧酸的可获得性(例如，&gt；27,000个伯烷基胺可从Enamine Ltd商业上获得，而&gt；25,000个烷基羧酸)。在药物化学中排名前20位的反应中，有7个要么使用或产生伯胺，超过80%的上市药物具有烷基胺基元。伯烷基胺的典型化学反应涉及对氮的亲电攻击，形成碳-氮键，这一过程本身就支撑了许多药物发现(例如，酰胺形成，SNAR)。开发从伯胺原料形成碳-碳键的新的和非传统的催化工艺将是变革性的，能够极大地简化断开并保护用于制药和农用化学科学的复合胺的无基团合成。在这方面，我们最近报道了第一个利用可见光催化无保护伯胺与苯乙烯的α-C-H烷基化反应的例子，并在有史以来最短的合成多发性硬化症重磅炸弹药物Fingolimod中展示了这一策略。该项目将利用这一世界领先的突破，开发无保护伯烷基胺的新催化转化，极大地扩展这一关键官能团的多功能性。具体地说，我们将发明模块化和可扩展的策略来合成以伯胺为原料的伽马-硼基胺、氮杂环亚磺胺、杂苯胺和α-氨基酮。重点将放在方便地进入三维、类似铅的化学空间领域，由于缺乏合成化学支持，目前该领域尚未得到充分开发。外消旋胺产品将由阿斯利康公司分解成单一的对映体，这些过程将由Enamine有限公司扩大到数百克，这样全球社会就可以立即获得用于药物发现的新型对映体构建块。