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

为了支持药物发现的生物学探索和调节，有相当大的需求扩大可访问的化学和知识产权空间的传统限制。这对于探测难以找到命中化合物的挑战性目标尤其重要。一个重要的方法是检查较少的平面，更多的sp3丰富，拓扑多样性和手性体系，这些体系沿着定义的向量呈现取代基。有了这个目标，我们有兴趣产生新的合成方法，以基于取代杂环衍生物的新型筛选集合，具有明确的相对和绝对立体化学，并具有不同类型的功能，可以产生有价值的结合接触，或用于进一步制作支架。本研究的目的是开发一种DOS工艺，通过催化X-H插入和环化，结合现成的构建块矩阵，制备具有多种取代的手性饱和杂环。该策略将为杂环合成提供一种高度模块化的方法，并生成一个富含对映体的4,5,6和7元杂环文库。对映体富集的构建块以及新的对映体选择性环化将被检查。在每个杂环系列中，将根据物理化学性质和形状参数选择化合物子集进行合成。此外，硼基取代的杂环将被制备为交叉偶联的构建块试剂。杂环产品将适合直接筛选，并将具有进一步阐述的功能。

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.