Integrating Enzymes with Chemocatalysts to Create New Reactions Pathways

将酶与化学催化剂相结合以创建新的反应途径

• 批准号: 426555714
• 负责人: Dr. Luis Bering
• 金额: --
• 依托单位: Manchester Institute of Biotechnology
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/426555714?language=en
• 关键词: Integrating; Enzymes; Chemocatalysts; Create; New

Chemistry plays a key role for the development of a sustainable society. There is a tremendous need for the development of ‘greener’ and environmentally benign processes. Interdisciplinary research at the interface of chemistry and biology can address this global challenge by enabling new and sustainable reaction pathways for the synthesis of valuable products, such as pharmaceutical, agrochemicals and other fine chemicals. A high proportion of pharmaceuticals contain amide bonds and the synthesis of amides is one of the most frequently used reactions in medicinal chemistry. Despite the wide spread of amide bond formation, it faces unsolved problems. The synthesis of amides requires the use of stoichiometric quantities of coupling reagents, which are costly, create significant problems in reaction purification, and lead to large quantities of waste. Furthermore, many reagents and solvents for the synthesis of amides are toxic. Given the urgent need for alternative, cleaner, and more efficient catalytic methods to generate amides, an unprecedented approach for amide bond formation has been developed, by combining chemocatalysis with biocatalysis. Biocatalysis is of increasing importance, due to enzymes’ high control of reactivity and environmentally benign reaction conditions, which are enabled by biocatalysis. However, not every chemical transformation can be achieved by using biocatalysts. In contrast, transition-metal catalysed coupling reactions do not exist naturally in biological systems. Therefore, the combination of both catalyst regimes opens the opportunity for completely new chemical transformations, which cannot be achieved by solely using biocatalysis or chemocatalysis alone. Herein, I report the development of an integrated reaction approach combining the enzyme nitrile hydratase (NHase) with transition-metal catalysed Ullmann-type arylation for the synthesis of amides from readily available organic nitriles. The proposed work for integrated chemo- and biocatalysis has been realised as a highly efficient and unprecedented method for the synthesis of amide bond containing molecules under mild and environmentally benign reaction conditions. The biocatalysts can be readily prepared in large quantities. The chemocatalytic step has been extensively optimised to enable the utilisation of an inexpensive and abundant first-row transition-metal catalyst. The broad scope demonstrates the applicability of the integrated reaction. Further, proof of concept for the synthesis of highly valuable chiral amide building blocks has been successfully realised. Thus, the integration of NHase and transition-metal catalysis represents a completely new and powerful approach for the sustainable synthesis of amides, overcoming the present limitation and drawbacks of established methodologies.

化学对于发展可持续社会的发展起着关键作用。在“更绿”和环境良性过程中的发展非常需要。化学和生物学界面上的跨学科研究可以通过为合成有价值的产品（例如药物，农业化学物质和其他精细化学物质）促进新的和可持续的反应途径来解决这一全球挑战。一定比例的药物包含酰胺键，酰胺的合成是药物化学中最常用的反应之一。尽管酰胺键形成广泛，但仍面临未解决的问题。酰胺的合成需要使用化学计量量的耦合试剂，这是昂贵的，在反应净化方面造成了重大问题，并导致大量废物。此外，许多用于合成酰胺的试剂和溶液是有毒的。鉴于迫切需要替代，清洁剂和更有效的催化方法来产生酰胺，因此通过将化学分析与生物催化分析相结合，已经开发出一种前所未有的酰胺键形成方法。由于酶对反应性和环境良性反应条件的高度控制，生物催化的重要性越来越重要，这是通过生物催化来实现的。但是，并非使用生物催化剂可以实现每种化学转化。相反，生物系统中不存在过渡金属催化的耦合反应。因此，两种催化剂机制的组合为全新的化学转化打开了机会，这不能仅仅通过单独使用生物催化或化学分析来实现。在此，我报告了一种综合反应方法的发展，该方法将氮化酶（NHASE）与过渡金属催化的ullmann型芳基合成从易于使用的有机氮气中合成酰胺，从而结合了氮素型Ullmann型芳基化。提出的用于综合化学和生物催化的工作已被实现为在轻度和环境良性反应条件下合成含有分子的酰胺键合成的一种高效且前所未有的方法。可以大量制备生物催化剂。化学催化步骤已被广泛优化，以实现廉价且丰富的第一行转变金属催化剂的利用。广泛的范围证明了综合反应的适用性。此外，已经成功实现了合成高度有价值的手性酰胺构件的概念证明。这是NHASE和过渡金属催化剂的整合代表了一种全新的强大和强大的方法，用于酰胺的可持续综合，克服了既定方法的表现限制和缺点。