Modular approach to structurally diverse four-membered (spiro)cycles using highly strained precursors

对三维分子结构的精确控制可以用来改善、改变或调节潜在药物分子的一系列物理化学和药代动力学性质。影响药物有效性和毒性的关键性质-亲脂性、水溶解性、酸碱性和对代谢降解的稳定性-都受到化学空间中官能团的三维排列的影响。尽管有这些明显的动机来研究具有复杂三维结构的小分子候选药物，但许多用于筛选的小分子文库的特征是基于碳骨架中广泛的sp2杂化的平面二维结构。因此，开发能够快速、模块化地获得新的三维分子结构的方法具有巨大的价值。四元环，包括环丁烷、氮杂环丁烷、氧杂环烷和硫杂环烷，由于其有限的灵活性而具有独特的三维结构。特别是，四元环的出射向量(取代基)在其空间配置中被很好地定义，从而允许关键官能团沿着预先选择的向量定向。作为正在进行的开发有效的合成方法以产生与生物相关的大的、多样化的小分子文库的努力的一部分，这项研究计划概述了三种相互关联的合成密集官能化和结构多样化的四元环分子结构的策略。拟议的研究基于双环[1.1.0]丁烷基序显著的应变释放特性，这是一种迷人的分子结构，包括环丁烷基团，环两侧的两个碳原子之间具有sigma键。这种西格玛键表现出双亲行为，这意味着它同时具有亲电和亲核反应活性。拟议的研究计划旨在利用这种独特的反应能力来开发能够快速生成各种基于环丁烷的分子库的新方法。具体地说，第一个策略将研究双环[1.1.0]丁基锌配合物的生成，它将经历非对映选择性的1，2-迁移-开环-亲电捕获过程，以生成复杂的环丁烷取代的烷基锌配合物。然后，它们可以通过大量过渡金属催化的交叉偶联过程进行进一步的转化。通过这种方式，可以控制三个多样化的点，允许沿着环丁烷核心的特定空间矢量引入各种官能团。在第二个策略中，关键的构建块双环[1.1.0]丁基锂将与一系列富含对映体的取代三元环反应，如环氧化物、氮杂环和硫杂环，从而产生新的、多样化的官能化杂环。这两种研究策略也将被探索到氮杂双环[1.1.0]丁烷基元，这将导致不同的基于氮杂二环的结构文库。以富含对映体的氮杂双环[1.1.0]丁基亚砜为基块，亚硫醚导向的锂离子亲电捕获策略也将被开发出来，使人们能够获得基于氮杂环[1.1.0]丁烷模体中嵌入的强大反应性的手性稠密官能化氮杂二环小分子文库。这些方法将为基于四元单环和螺环结构的各种小分子文库的生成提供广泛的策略。这些图书馆将在访问探索不足的化学空间区域和推动成功的药物发现计划方面发挥无价的作用。

Precise control of three-dimensional molecular structure can be used to improve, alter or modulate a range of physiochemical and pharmo-kinetic properties in potential drug molecules. Key properties that will influence the efficacy and toxicity of a drug - lipophilicity, aqueous solubility, acidity/basicity and stability against metabolic degradation - are all influenced by the three-dimensional arrangement of functional groups in chemical space. Despite these clear incentives for investigating small-molecule drug candidates that possess complex three-dimensional architectures, many small-molecule libraries used for screening are characterised by flat two-dimensional structures, based on extensive sp2-hybridisation in the carbon skeleton. Thus, the development of methods that allow rapid, modular access to novel three-dimensional molecular architectures is of immense value.Four-membered rings, which include cyclobutanes, azetidines, oxetanes and thietanes, possess unique three-dimensional structures due to their limited flexibility. In particular, the exit vectors (substituents) of four-membered rings are well-defined in their spatial disposition and thus allow for the orientation of key functional groups along pre-selected vectors. As part of an ongoing effort to develop effective synthetic methods for the generation of large, diverse libraries of biologically-relevant small molecules, this research programme outlines three interconnected strategies for the synthesis of densely-functionalised and structurally diverse four-membered ring molecular architectures.The proposed research is founded on the remarkable strain-release properties of the bicyclo[1.1.0]butane motif, which is a fascinating molecular structure comprising a cyclobutane moiety with a sigma bond between two carbon atoms on opposite sides of the ring. This sigma bond exhibits ambiphilic behaviour, which means that it engages in both electrophilic and nucleophilic reactivity. The proposed research programme aims to exploit this unique reactivity to develop new methods that will enable the rapid generation of varied cyclobutane-based molecular libraries.Specifically, the first strategy will investigate the generation of bicyclo[1.1.0]butyl zincate complexes, which will undergo a diastereoselective 1,2-migration - ring opening - electrophile trapping process to generate complex cyclobutane-substituted alkylzinc complexes. These can then undergo further transformation through a wealth of transition metal-catalysed cross-coupling processes. In this way, three points of diversification can be controlled, allowing the introduction of a variety of functional groups along specific spatial vectors about the cyclobutane core.In a second strategy, key building block bicyclo[1.1.0]butyl lithium will be reacted with a range of enantioenriched substituted three-membered rings, such as epoxides, aziridines and thiiranes, leading to new, diversely functionalised heterospirocycles.Both these research strategies will also be explored with the azabicyclo[1.1.0]butane motif, which will lead to diverse libraries of azetidine-based structures. Using enantiomerically enriched azabicyclo[1.1.0]butyl sulfoxide as a building block, a sulfoxide-directed lithiation - electrophile trapping strategy will also be developed to enable access to enantiopure densely functionalised azetidine-based small molecule libraries.These methodologies, all based on exploiting the powerful reactivity embedded within the (aza)bicyclo[1.1.0]butane motif, will provide a broad strategy for the generation of diverse small molecule libraries, based on four-membered mono- and spiro-cyclic architectures. These libraries will be invaluable in accessing poorly explored regions of chemical space and driving forward successful drug discovery programmes.