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

精确控制三维分子结构可用于改善、改变或调节潜在药物分子的一系列物理化学和药物动力学性质。影响药物功效和毒性的关键性质——亲脂性、水溶性、酸碱度和抗代谢降解的稳定性——都受到化学空间中官能团的三维排列的影响。尽管研究具有复杂三维结构的小分子候选药物有这些明确的动机，但许多用于筛选的小分子文库的特征是平面二维结构，这是基于碳骨架中广泛的sp2杂化。因此，开发能够快速、模块化地获取新型三维分子结构的方法具有巨大的价值。四元环，包括环丁烷、氮杂丁烷、氧烷和硫烷，由于其有限的灵活性，具有独特的三维结构。特别是，四元环的出口向量（取代基）在其空间配置上是明确的，从而允许关键官能团沿着预先选择的向量取向。作为正在进行的努力的一部分，开发有效的合成方法，以生成大型，多样化的生物相关小分子文库，本研究计划概述了三种相互关联的策略，用于合成密集功能化和结构多样化的四元环分子结构。提出的研究是基于双环[1.1.0]丁烷基序的显著的菌株释放特性，这是一个迷人的分子结构，由环丁烷部分和环两侧的两个碳原子之间的sigma键组成。这个sigma键表现出两亲性行为，这意味着它同时具有亲电性和亲核性。拟议的研究计划旨在利用这种独特的反应性来开发新的方法，从而能够快速生成各种环丁烷基分子文库。具体来说，第一种策略将研究双环[1.1.0]丁基锌酸盐配合物的生成，该配合物将经历非对映选择性1,2-迁移-开环-亲电捕获过程，以生成环丁烷取代的烷基锌配合物。然后，这些可以通过丰富的过渡金属催化的交叉耦合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点，允许沿着环丁烷核心周围的特定空间向量引入各种官能团。在第二种策略中，关键的构建单元双环[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、氮嘧啶和硫烷，从而产生新的、多样化功能化的杂环。这两种研究策略也将与azabicyclo[1.1.0]丁烷基序一起探索，这将导致基于azetidine的结构的不同文库。利用对映体富集的氮杂环[1.1.0]丁基亚砜作为构建块，还将开发一种亚砜定向锂化-亲电诱捕策略，以获得对映体纯密集功能化的氮杂啶基小分子文库。这些方法都基于利用嵌入在（aza）双环[1.1.0]丁烷基序中的强大反应性，将为基于四元单环和螺环结构的不同小分子文库的生成提供广泛的策略。这些文库在获取化学空间中未被充分探索的区域和推动成功的药物发现计划方面将是无价的。

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.