Spirocycles, Carbocycles and Heterocycles: Unified Routes via Catalyst Selection

快速获得结构多样的有机化合物是制药和农用化学品行业领先生产的基石，对于满足全球迅速增长的医疗保健和营养需求至关重要。人们越来越认识到，传统的铅识别程序在处理3D结构方面受到限制，目前有许多研究是基于对分子的研究，这些分子覆盖了更广泛的化学空间区域。然而，这种生成复杂3D有机结构的合成方法通常是耗时且劳动密集型的，并且通常需要单独的路线来访问不同类型的结构。在该计划中，将设计一些简单的合成路线，将廉价、易得的起始材料转化为高能活性中间体，通过仔细选择催化剂，这些中间体将被选择性地转化为一系列不同的结构类型。将注意环境因素（催化剂装载量低、缩短的程序、扩大规模的潜力）。这部分的研究将揭示催化，机理和反应中间体化学的基本原理。这些序列将被设计为产生占据3D空间的产物，该3D空间在典型的筛选文库中代表性不足，并且具有良好的“铅样”性质;将使用称为主惯性矩（PMI）的过程通过计算评估3D形状。我们将探索不对称变体的扩展、固体支持的选择和进一步的多样化，以及验证靶向合成的新方法。我们将与工业合作伙伴合作，选择一些靶向化合物，以产生潜在的药物和农用化学品先导化合物，用于生物筛选。该提议得到了重要和有希望的初步研究的支持，我们预计该序列将被工业和学术领域的合成化学家采用。所描述的新化学和技术完全符合EPSRC Dial-a-Molecule重大挑战领域，以及当前的几个优先领域（催化，新颖高效的化学合成，可持续化学以及最终的生物学和医疗保健新物理科学，以及创新生产工艺）。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，在制造业和医疗保健领域具有巨大潜力，也在2015年计划中得到强调。此外，这种新的化学方法应该有助于制备与2014年EPSRC抗微生物耐药性（AMR）倡议相关的新结构。特别重要的是新方法在英国制药和农业化学工业中的潜在应用。这个雄心勃勃的计划将由PDRA在3年内实施。

Rapid access to structurally diverse organic compounds is the cornerstone of lead generation in the pharmaceutical and agrochemical industries, essential to meet the burgeoning worldwide healthcare and sustenance requirements. There is a growing realisation that traditional lead identification programmes have been limited in terms of their treatment of 3D structures and there is much current research based on the investigation of molecules which cover much wider regions of chemical space. However, such synthetic approaches to generate complex 3D organic architectures are often time-consuming and labour-intensive - and separate routes are normally required to access different types of structure. In this programme, a number of simple synthetic routes will be designed to convert cheap, readily available starting materials into high energy reactive intermediates which will be selectively converted into a range of diverse structural types by careful choice of catalysts. Attention will be given to environmental factors (low catalyst loading, telescoped procedures, scale-up potential). This part of the study will uncover fundamental principles in catalysis, mechanism and reactive intermediate chemistry. The sequences will be designed to produce products which occupy 3D space that is under-represented in typical screening libraries and which possess good 'lead-like' properties; 3D shape will be evaluated computationally using a process called principal moments of inertia (PMI). Extensions to give asymmetric variants, solid-supported options, and further diversification will be explored as will validation the novel methodology in target synthesis.In collaboration with our industrial partners, some targets will be chosen with the aim of generating 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 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.