Integrated Electro-Biocatalysis for Arylation

芳基化的集成电生物催化

• 批准号: 2279460
• 金额: --
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2279460
• 关键词: Integrated; Electro; Biocatalysis; Arylation

Despite a venerable history in synthetic chemistry, electrosynthesis has historically been regarded as the preserve of specialists and only rarely been used to discover new reactions and shape conceptual developments in molecule making. A number of developments have coincided to suggest this landscape is changing, and that electrosynthesis will be heavily influential in the immediate future of synthesis: 1) Sustainable chemistry - the availability of cheap energy sources to power new processes under very mild conditions has critical significance for the green chemistry agenda. 2) Technology - Synthetic chemists are now far more receptive to technological advances in the laboratory, with the success of flow chemistry exemplifying how process innovation can create reaction discovery. 3) Mechanism - Single electron transfer chemistry has undergone a major renaissance in the literature, with photoredox catalysis being one of the principal drivers of new synthesis over the past ten years. The conceptual overlap with electrochemistry is clear, whereby precise control of electron transfer enables new reaction pathways to be discovered in synthesis.We will explore 'electro-bio' processes to exploit the strengths of electrosynthesis (versatile C-C bond formations and / or global redox change) and those of biocatalysis (exquisite control of absolute stereochemistry), showcasing the exceptionally mild conditions that are axiomatic to both techniques. We have established some preliminary results in the laboratory in collaboration with the Turner (biocatalysis) and Dryfe (electrochemistry) groups, on an electro-oxidation system integrated with biocatalytic reductive amination (1->2). This has established expertise and equipment in the group and surmounted parts of the steep learning curve necessary to effectively use electrochemical methods to make molecules. We will apply these techniques to the discovery of new arylation methods that can exploit electricity to create sustainable routes to enantio-enriched heteroarenes. For example, the Oxidative Nucleophilic Substitution of Hydrogen (ONSH) developed by the Makosza group is an extremely powerful transformation in concept for the alkylation of electron poor arenes and azines, but is plagued by very harsh oxidants that restrict application. We will develop an aqueous electrochemical oxidation system that will oxidize the sigma-complex 5 formed from nucleophilic addition of enolate equivalents. The resultant protected amino acid 6 can then directly undergo biocatalytic deracemization to produce valuable enantioenriched building blocks for pharma and the wider fine chemical industry.Contrastingly, we will study electroreduction of pyridiniums (8) to enable the fundamental transformation of flat sp2 carbon residues into higher value sp3 moieties. The reduction of pyridines to piperidines is a powerful exemplification of this idea that has seen extensive research in the hydrogenation field using precious metal catalysis. We will develop a sustainable, metal-free electrochemical approach, beginning with activated substrates such as the nicotinidinium 8, that can access substituted piperidines 9 for further biocatalytic manipulation. The HDNO / IRED technology developed in the Turner group is extremely effective for de-racemizing secondary amines such as 9, and will deliver biologically-enriched piperidines 10.The electro/bio integration presents exciting possibilities for technology development to discover new transformations. Our preliminary work was established in batch and has been extended to a prototype flow system that puts an electrochemical cell in line with an immobilized enzyme compartment. Development of these concepts will be strengthened by iCAT interactions with flow engineering to develop new collaborative approaches to integrated systems that are discovered in the course of the programme.

尽管在合成化学中有着悠久的历史，但电合成在历史上一直被认为是专家的保留，很少用于发现新的反应和塑造分子制造的概念发展。许多发展同时表明这种情况正在发生变化，并且电合成将在不久的将来对合成产生重大影响：1）可持续化学-在非常温和的条件下为新工艺提供动力的廉价能源的可用性对绿色化学议程具有至关重要的意义。2)技术-合成化学家现在更容易接受实验室中的技术进步，流动化学的成功例证了工艺创新如何创造反应发现。3)单电子转移化学在文献中经历了一次重大的复兴，光氧化还原催化是过去十年来新合成的主要驱动力之一。与电化学的概念重叠是明确的，从而精确控制电子转移，使新的反应途径被发现在合成。我们将探讨'电生物'过程，利用电合成的优势（通用的C-C键形成和/或整体氧化还原变化）和生物催化的那些（绝对立体化学的精致控制），展示了两种技术都不言自明的异常温和的条件。我们与Turner（生物催化）和Dryfe（电化学）小组合作，在实验室中建立了一些初步结果，涉及与生物催化还原胺化（1->2）相结合的电氧化系统。这在小组中建立了专业知识和设备，并克服了有效使用电化学方法制造分子所需的陡峭学习曲线的一部分。我们将应用这些技术发现新的芳基化方法，可以利用电力创造可持续的路线，对映体丰富的杂芳烃。例如，由Makosza小组开发的氢的氧化亲核取代（ONSH）是用于贫电子芳烃和吖嗪的烷基化的概念上的极其强大的转变，但是受到限制应用的非常苛刻的氧化剂的困扰。我们将开发一种水性电化学氧化系统，该系统将氧化由烯醇化物等价物的亲核加成形成的σ-络合物5。然后，得到的保护的氨基酸6可以直接进行生物催化去外消旋化，以产生有价值的对映体富集的结构单元，用于制药和更广泛的精细化学工业。相比之下，我们将研究吡啶鎓（8）的电还原，以使平坦的sp2碳残基基本转化为更高价值的sp3部分。将吡啶还原为哌啶是这一想法的有力例证，在使用贵金属催化的氢化领域中已经看到了广泛的研究。我们将开发一种可持续的，无金属的电化学方法，从活化的底物开始，如nicotinidinium 8，可以访问取代的哌啶9进行进一步的生物催化操作。Turner集团开发的HDNO / IRED技术对于仲胺（如9）的去外消旋非常有效，并将提供生物富集的哌啶10。电/生物集成为技术开发提供了令人兴奋的可能性，以发现新的转化。我们的初步工作是建立在批处理，并已扩展到一个原型的流动系统，使一个电化学电池线与固定化酶隔室。这些概念的发展将通过iCAT与流量工程的互动来加强，以开发新的协作方法来实现在该计划过程中发现的集成系统。