Integrating Enzymes with Chemocatalysts to Create New Reactions Pathways

化学对可持续社会的发展起着关键作用。开发“更绿色”和对环境无害的工艺是非常有必要的。化学和生物学交界处的跨学科研究可以通过为合成有价值的产品提供新的和可持续的反应途径来应对这一全球挑战，如制药、农用化学品和其他精细化学品。很高比例的药物含有酰胺键，而酰胺的合成是药物化学中最常用的反应之一。尽管酰胺键的形成范围很广，但它面临着尚未解决的问题。酰胺的合成需要使用化学计量的偶联剂，这些偶联剂价格昂贵，在反应纯化中造成严重问题，并导致大量废物。此外，用于合成酰胺的许多试剂和溶剂都是有毒的。由于迫切需要替代的、更清洁的和更有效的催化方法来生成酰胺，通过将化学催化和生物催化相结合，已经开发出一种前所未有的形成酰胺键的方法。生物催化的重要性与日俱增，因为酶对反应活性的高度控制和环境友好的反应条件都是由生物催化实现的。然而，并不是所有的化学转化都可以通过使用生物催化剂来实现。相反，过渡金属催化的偶联反应并不自然地存在于生物系统中。因此，两种催化剂体系的结合为全新的化学转化打开了机会，而这不是仅靠生物催化或化学催化就能实现的。在这里，我报告了一种将酶腈水合酶(NHase)与过渡金属催化的Ullmann型芳基化反应相结合的综合反应方法，用于从容易获得的有机腈合成酰胺。所提出的集成化学和生物催化的工作已经被实现为一种在温和和环境友好的反应条件下合成含酰胺键分子的高效和史无前例的方法。生物催化剂可以很容易地大量制备。对化学催化步骤进行了广泛的优化，以实现廉价和丰富的第一排过渡金属催化剂的使用。宽广的范围显示了集成反应的适用性。此外，成功地实现了合成高价值手性酰胺构筑块的概念验证。因此，NHase和过渡金属催化的结合为酰胺的可持续合成提供了一条全新而有效的途径，克服了现有方法的局限性和缺陷。

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.