Diversity Oriented Synthesis of Chiral Saturated Heterocycles: A New Approach to a Screening Collection of Fragment and Lead-like Compounds

为了支持对药物发现的生物学探索和调整，有相当大的需求扩大可访问的化学空间和IP空间的传统范围。这与探测具有挑战性的目标尤其相关，因为在这些目标中，很难找到命中化合物。一种重要的方法是研究平面较少、富含SP3、拓扑多样化的手性体系，这些体系沿着定义的载体呈现取代基。出于这一目标，我们有兴趣开发新的合成方法，以取代杂环衍生物为基础，以定义的相对和绝对立体化学为基础，并具有不同类型的功能，这些功能可以进行有价值的结合接触，或用于进一步阐述支架。这项研究的目的是开发一种DOS过程，通过催化X-H插入和环化，将容易获得的构筑基团结合在一起，制备具有不同取代度的手性饱和杂环。这一策略将为杂环的合成提供一个高度模块化的方法，并生成一个对映体富含4，5，6和7元杂环的文库。我们将考察富含对映体的构筑块以及新的对映体选择性环化反应。在每个杂环系列中，将根据物理化学性质和形状参数选择用于合成的化合物的子集。此外，还将制备含硼基团取代的杂环作为交叉偶联的构筑块试剂。杂环产物将适合直接筛选，并将携带进一步精制的官能团。

To underpin the exploration and modulation of biology for drug discovery, there is considerable demand to expand the traditional confines of accessible chemical- and IP-space. This is particularly relevant to probe challenging targets where hit compounds have been difficult to find. An important approach has been to examine less planar, more sp3 rich, topologically diverse and chiral systems that present substituents along defined vectors. With this aim, we are interested in generating new synthetic approaches towards novel screening collections based around substituted heterocyclic derivatives, with defined relative and absolute stereochemistry, and bearing different types of functionality that can make valuable binding contacts, or be used to further elaborate a scaffold. The aims of this studentship are to develop a DOS process to prepare chiral saturated heterocycles with diverse substitution by combining a matrix of readily available building blocks through catalytic X-H insertion and cyclisation. This strategy will provide a highly modular approach to heterocycle synthesis, and generate a library of enantioenriched 4, 5, 6 and 7 membered heterocycles. Enantioenriched building blocks as well as novel enantioselective cyclisations will be examined. Within each heterocyclic series, subsets of compounds will be selected for synthesis based on physicochemical properties and shape parameters. In addition, heterocycles substituted with boron groups will be prepared as building-block reagents for cross-coupling. The heterocyclic products will be suitable for screening directly, and will carry functionality for further elaboration.