Harnessing the Power of Diels-Alderases in Sustainable Chemoenzymatic Synthesis

每种化学元素都是特别的，但有些元素比其他元素更特别！碳是元素周期表中的第六种元素，它的多功能性和对我们生活的影响是独一无二的。碳是所有有机分子的基本元素，包括材料、药品和燃料。没有其他元素比碳更能塑造我们周围的世界。因此，开发以理想结构将碳原子连接在一起的创新方法是非常重要的，也是有机化学领域的首要目标。可用于将碳原子连接在一起的反应的一个重要例子是Diels-Alder反应，自发现以来，该反应已被用于构建许多重要分子的复杂碳骨架，包括药品、维生素、激素、农用化学品和一系列香料化合物。从历史上看，Diels-Alder反应要么使用化学催化剂，要么使用高温高压。不幸的是，这些方法可能会产生混合的产品，并存在有害的可持续性问题(使用能源和金属催化剂)。然而，用于该反应的生物催化剂，即所谓的‘Diels-Alderase’，提供了一种有吸引力的替代方案，绕过了许多与化学催化相关的复杂性，从而使Diels-Alder反应能够在环境条件下进行，具有精确的区域和立体化学控制，并以一种固有的更环保的方式进行。在这个学术-工业项目中，建立在申请者在天然Diels-Alderase研究中的跨学科合作研究的坚实基础上，研究人员将：i)开发使用固定化酶来催化克尺度的Diels-Alder反应的流动系统；ii)研究天然Diels-Alderase和合理设计的变体催化分子内(在同一分子内具有两个活性基团)和分子间(在不同分子中具有活性基团)环加成反应的能力；iii)研究迄今尚未表征的天然Diels-Alderase及其来自隐蔽生物合成基因簇的相关天然产物；Iv)部署我们的天然和工程Diels-Alderase产品组合，结合辅助酶，进行高价值目标化合物的化学酶全合成。

Every chemical element is special, but some elements are more special than others! Carbon, the sixth element of the periodic table, is unique with respect to its versatility and impact on our lives. Carbon is the foundational element of all organic molecules including for example, materials, pharmaceuticals and fuels. No other element has shaped the world around us more than carbon. For this reason, the development of innovative methods to link carbon atoms together in desirable structures is of tremendous importance and is an overarching ambition in the field of organic chemistry. An important example of a reaction that can be used to link carbon atoms together is the Diels-Alder reaction, which since its discovery has been used to construct the complex carbon skeletons of numerous important molecules including pharmaceuticals, vitamins, hormones, agrochemicals and a raft of fragrance and flavour compounds. Historically, the Diels-Alder reaction has been performed using either chemical catalysts or high temperatures and pressures. Unfortunately, these approaches can give a mixture of products and have detrimental sustainability issues (use of energy and metal catalysts). However, biological catalysts for this reaction, so called 'Diels-Alderases', offer an attractive alternative, circumventing many of the complexities associated with chemical catalysis, and thus enabling Diels-Alder reactions to be performed under ambient conditions, with exquisite regio- and stereochemical control, and in an inherently 'greener' way. In this academic-industrial project, which builds on a strong foundation of interdisciplinary collaborative research by the applicants in the study of natural Diels-Alderases, the researchers will: i) Develop flow systems using immobilised enzymes to catalyse Diels-Alder reactions on gram scales; ii) investigate the ability of natural Diels-Alderases and rationally-engineered variants to catalyse both intramolecular (with both reactive groups within the same molecule) and intermolecular (with reactive groups in different molecules) cycloaddition reactions; iii) study hitherto uncharacterised natural Diels-Alderases and their associated natural products from cryptic biosynthetic gene clusters; iv) Deploy our portfolio of natural and engineered Diels-Alderases, in combination with auxiliary enzymes, to undertake chemoenzymatic total syntheses of high-value target compounds.