Integrated Electro-Biocatalysis for Arylation

尽管在合成化学方面有着悠久的历史，但电合成历来被认为是专家的专利，很少被用来发现新的反应和塑造分子制造中的概念发展。一些发展表明，这种情况正在改变，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获得廉价能源为新过程提供动力，对绿色化学议程具有关键意义。2)技术-合成化学家现在更容易接受实验室中的技术进步，流动化学的成功证明了过程创新如何创造反应发现。3)机理--在过去的十年中，单电子转移化学在文献中经历了一次重大的复兴，光氧化还原催化是新合成的主要驱动力之一。与电化学在概念上的重叠是显而易见的，因此对电子转移的精确控制使人们能够在合成中发现新的反应途径。我们将探索“电-生物”过程，以利用电合成(多功能C-C键的形成和/或全局氧化还原变化)和生物催化(绝对立体化学的精细控制)的优势，展示对这两种技术都适用的异常温和的条件。我们与Turner(生物催化)和Dryfe(电化学)小组合作，在实验室建立了一些初步结果，涉及电氧化系统和生物催化还原胺化(1-gt；2)。这在该团队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必需的陡峭学习曲线的一部分。我们将应用这些技术来发现新的芳基化方法，这些方法可以利用电力来创建可持续的路线，以获得富含对映体的杂芳烃。例如，Makosza集团开发的氧化亲核取代氢(ONSH)在概念上是一种非常强大的转化，用于贫电子芳烃和氮杂环的烷基化，但受到非常苛刻的氧化剂的困扰，限制了应用。我们将开发一种水溶液电化学氧化系统，该系统将氧化由烯酸酯类化合物的亲核加成形成的sigma络合物5。生成的受保护的氨基酸6可以直接进行生物催化去消旋反应，以产生制药和更广泛的精细化学工业中有价值的富对映体构筑块。相反，我们将研究吡啶(8)的电还原，使平坦的sp2碳残基从根本上转化为更高价值的sp3部分。将吡啶还原为哌啶是这一观点的有力例证，这一观点在使用贵金属催化的加氢领域得到了广泛的研究。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，例如尼古丁8，它可以获得取代的哌啶9以进行进一步的生物催化操作。特纳集团开发的HDNO/IRED技术对9等仲胺的去外消旋非常有效，并将产生生物丰富的哌啶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。我们的初步工作是批量建立的，并已扩展到原型流动系统，将电化学电池与固定化酶隔间排成一条线。ICAT与流量工程的互动将加强这些概念的发展，以便为方案过程中发现的综合系统开发新的协作方法。

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.