Spiroclip Technology: from Catalogue to Spirocycle in One Step

为了满足日益增长的全球医疗保健和食品安全需求，快速获得多样化的有机结构是制药和农用化工行业持续发展的关键。越来越多的人认识到，传统的合成方法在复杂3D结构的范围内受到限制，目前有许多基于对更多3D分子的调查的研究来解决这一不足。然而，这种非平面有机结构的合成方法通常是耗时和劳动密集型的。对于一类被称为螺旋环的分子的合成来说，较差的合成可及性问题尤其严重，该系统最近被确定为重要但未得到充分利用的支架。该提案的主要目的是设计和开发新的化学方法，通过一步或一锅程序，从目录起始材料开始，使用健壮且可扩展的协议，这些协议将很容易被工业合作伙伴采用，以生成构建块，生物探针，特别是用于药物发现的片段。扩展以提供“单手”（对映异构纯）变体，固体支持选项和进一步的多样化将被探索。还将尝试验证合成真实药物/生物活性材料的新方法。将咨询合作者，以确保所制造的分子适合现实生活中的工业应用；例如，它们具有良好的“类药物”特性，具有进一步细化的能力，并且在可能的情况下，它们占据了典型药物筛选文库中代表性不足的3d空间。潜在的医药和农化先导化合物，可用于生物筛选。这项建议得到了重要和有希望的初步研究的支持，我们预计这项研究也将导致我们在催化、机制和合成化学的基本原理方面的知识的进步。我们也期望这些序列将被工业和学术领域的合成化学家所采用。所描述的新化学和技术完全符合EPSRC Dial-a-Molecule大挑战领域，以及当前的几个优先领域（催化、新型高效化学合成、可持续化学和最终用于生物和医疗保健的新物理科学，以及创新生产工艺）。这门新科学也与EPSRC 2015年战略计划中强调的催化和培训领域相关，在2015年计划中也强调了制造业和医疗保健行业的巨大潜力。此外，新的化学反应应该有助于制备与2014年EPSRC抗微生物耐药性（AMR）计划相关的新结构。特别重要的是新方法在英国制药和农用化学工业的潜在应用。这一雄心勃勃的方案将由PDRA在三年期间内执行。

In order to meet burgeoning worldwide healthcare and food-security demands, rapid access to diverse organic structures is the key to continued progress in the pharmaceutical and agrochemical industries. There is a growing acknowledgment that traditional synthetic approaches have been limited in terms of the range of complex 3D-structures and there is much current research based on the investigation of more 3D molecules to address this shortfall. However, such synthetic approaches to non-planar organic architectures are often time-consuming and labour-intensive.The problems of poor synthetic accessibility are particularly acute for the synthesis of a class of molecules called spirocycles, systems that have been recently identified as important but under-exploited scaffolds. The main aim of this proposal is to design and develop novel chemistry to make a diverse range of spirocyclic structural types via one-step or one-pot procedures, from catalogue starting materials, using robust and scalable protocols which will be readily adopted by industrial partners to generate building blocks, biological probes and, particularly, fragments for drug discovery. Extensions to give 'single-handed' (enantiomerically pure) variants, solid-supported options, and further diversification will be explored. Validation of the new methods in the synthesis of real drugs/biologically active materials will also be attempted. Collaborators will be consulted to ensure that the molecules made are appropriate for real-life industrial applications; e.g. they possess good 'drug-like' properties, with capacity for further elaboration, and where possible, that they occupy 3D-space that is under-represented in typical drug screening libraries. Potential pharmaceutical and agrochemical lead compounds which will be made available for biological screening. The proposal is underpinned by significant and promising preliminary studies and we anticipate that the study will also lead to advances in our knowledge of fundamental principles in catalysis, mechanism and synthetic chemistry. We also expect that the sequences will be adopted by synthetic chemists in both industrial and academic arenas. The new chemistry and technology described fits full square in the EPSRC Dial-a-Molecule grand challenge area, and in several current Priority Areas (Catalysis, Novel and Efficient Chemical Synthesis, Sustainable Chemistry and eventually New Physical Sciences for Biology and Healthcare, and Innovative Production Processes). The new science is also relevant to the areas of catalysis and training highlighted in the EPSRC Strategic Plan 2015, with great potential in the manufacturing and healthcare sectors, also highlighted in the 2015 plan. In addition, the novel chemistry should be useful to prepare new structures relevant to the 2014 EPSRC initiative in anti-microbial resistance (AMR). Of particular importance are the potential applications of the new methodology in the UK pharmaceutical and agrochemical industries.This ambitious programme will be carried out by a PDRA over a 3 year period.