More sustainable biocatalytic imine reductions to chiral amines with hydrogen-driven NADPH recycling operated in batch and continuous flow

通过批量和连续流操作的氢驱动 NADPH 回收，更可持续地生物催化亚胺还原为手性胺

• 批准号: 2889869
• 金额: --
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Studentship
• 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=studentship-2889869
• 关键词: More; sustainable; biocatalytic; imine; reductions

This project is in the area of industrial biotechnology for cleaner chemical manufacturing, and is relevant to the pharmaceutical and fine chemicals sectors. Biocatalytic imine reductions are a valuable component in the synthetic tool-box for synthesis of chiral amines for pharmaceuticals or other fine chemicals. Imine reductase enzymes depend on nicotinamide cofactors, usually NADPH, for hydride transfer to an enzyme-bound imine substrate, and conventional approaches for regenerating NADPH during these reactions usually rely upon super-stoichiometric glucose as the reductant. Use of the six-carbon sugar, glucose, for a single hydride-transfer makes the overall process atom-inefficient in contrast to metal-catalysed hydrogenations where hydrogen gas (H2) is added across the C=N double bond of an imine, giving an amine product with no by-products. This project exploits approaches that fall neatly between these alternatives, offering the chiral and functional-group selectivity of isolated-enzyme biocatalysis, alongside the atom-efficiency of H2-driven hydrogenation reactions under mild temperature and pressure. We achieve this by exploiting an innovative strategy for NADPH recycling which uses biocatalysed H2 activation to drive the biocatalytic reduction of NADP+ to NADPH, as well as handling the enzymes on a heterogeneous support. The H2-driven cofactor recycling has the added advantage of simplifying purification of the chemical product. As well as replacing glucose by H2 as atom-efficient reductant, our approach also avoids a pH change associated with the cofactor recycling step, thereby simplifying the process chemistry. The project is conjunction with industrial partner, AstraZeneca. Overall, the project aims to deliver a robust platform for more sustainable, H2-driven NADPH recycling to support application of imine reductases for generation of chiral amines. This may be implemented in batch or continuous flow. We aim to demonstrate this for a series of imine reductions relevant to the synthesis of pharmaceuticals and other fine chemicals, which can be implemented readily within standard industrially-used hydrogenation reactors. The approach would be suitable for late-stage functionalisation, as well as synthesis of chiral building blocks. Results will be presented at conferences spanning organic synthesis, biotechnology and chemical manufacturing topics. This project falls within the EPSRC 'Manufacturing the Future' research area, and is also relevant to 'Energy and Decarbonisation' since it decarbonises industrial biotechnology for chemical manufacturing. As such, it is relevant to the EPSRC strategic priority area of 'Engineering Net Zero'.

该项目属于清洁化学品制造的工业生物技术领域，与制药和精细化学品行业相关。生物催化亚胺还原是用于合成药物或其他精细化学品的手性胺的合成工具箱中的重要组成部分。亚胺还原酶依靠烟酰胺辅因子（通常是 NADPH）将氢化物转移到酶结合的亚胺底物上，而在这些反应过程中再生 NADPH 的传统方法通常依赖于超化学计量的葡萄糖作为还原剂。与金属催化氢化相比，使用六碳糖、葡萄糖进行单次氢化物转移使得整个过程原子效率低下，在金属催化氢化中，氢气 (H2) 添加到亚胺的 C=N 双键上，从而得到一种没有副产物的胺产品。该项目利用了介于这些替代方案之间的方法，提供了分离酶生物催化的手性和官能团选择性，以及在温和温度和压力下 H2 驱动的氢化反应的原子效率。我们通过利用创新的 NADPH 回收策略来实现这一目标，该策略使用生物催化的 H2 活化来驱动 NADP+ 生物催化还原为 NADPH，以及在异质载体上处理酶。氢气驱动的辅因子回收具有简化化学产品纯化的额外优势。除了用 H2 代替葡萄糖作为原子效率还原剂外，我们的方法还避免了与辅因子回收步骤相关的 pH 变化，从而简化了化学过程。该项目是与工业合作伙伴阿斯利康合作的。总体而言，该项目旨在提供一个强大的平台，实现更可持续、H2 驱动的 NADPH 回收，以支持应用亚胺还原酶生成手性胺。这可以以分批或连续流的方式实施。我们的目标是通过与药物和其他精细化学品合成相关的一系列亚胺还原来证明这一点，这些还原可以在标准工业用氢化反应器中轻松实现。该方法适用于后期功能化以及手性结构单元的合成。结果将在涵盖有机合成、生物技术和化学制造主题的会议上公布。该项目属于 EPSRC“制造未来”研究领域，也与“能源和脱碳”相关，因为它使化学制造的工业生物技术脱碳。因此，它与 EPSRC 的“工程净零”战略优先领域相关。