Harnessing the Power of Diels-Alderases in Sustainable Chemoenzymatic Synthesis

利用 Diels-Alderases 进行可持续化学酶合成

• 批准号: BB/Y000846/1
• 负责人: Chris Willis
• 金额: $ 109.96万
• 依托单位: University of Bristol
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FY000846%2F1
• 关键词: Harnessing; Power; Diels; Alderases; Sustainable

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.

每一种化学元素都是特殊的，但有些元素比其他元素更特殊。碳是元素周期表中的第六种元素，其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，包括例如材料，药物和燃料。没有其他元素比碳更能塑造我们周围的世界。因此，开发将碳原子以理想结构连接在一起的创新方法具有巨大的重要性，并且是有机化学领域的总体目标。可以用来将碳原子连接在一起的反应的一个重要例子是狄尔斯-阿尔德反应，自从它被发现以来，它已经被用来构建许多重要分子的复杂碳骨架，包括药物，维生素，激素，农用化学品和大量的香料和风味化合物。历史上，狄尔斯-阿尔德反应已经使用化学催化剂或高温和高压进行。不幸的是，这些方法可能会产生产品的混合物，并具有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，所谓的“狄尔斯-阿尔德拉斯”，提供了一种有吸引力的替代方案，规避了与化学催化相关的许多复杂性，从而使狄尔斯-阿尔德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，并且以固有的“绿色”方式进行。在这个学术-工业项目中，申请人在天然Diels-Alderases研究中建立了强大的跨学科合作研究基础，研究人员将：i）开发使用固定化酶的流动系统，以催化克级的Diels-Alder反应; ii）研究天然狄尔斯-阿尔德酶和合理工程化的变体催化分子内降解和降解的能力;（在同一分子内具有两个反应性基团）和分子间（在不同分子中具有反应性基团）环加成反应; iii）研究迄今未表征的天然狄尔斯-阿尔德酶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-Alderases产品组合，结合辅助酶，进行高价值目标化合物的化学酶促全合成。