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

使用高应变前体构建结构多样的四元（螺）环的模块化方法

基本信息

批准号：
EP/S017801/1
负责人：
Varinder Aggarwal
金额：
$ 74.11万
依托单位：
University of Bristol
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2019
资助国家：
英国
起止时间：
2019 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=EP%2FS017801%2F1
关键词：
Modular approach structurally diverse four

项目摘要

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.

三维分子结构的精确控制可用于改善、改变或调节潜在药物分子的一系列理化和药物动力学性质。影响药物功效和毒性的关键性质-亲脂性、水溶性、酸碱性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。尽管有这些明确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在于基于碳骨架中广泛的sp2-杂交的平坦二维结构。因此，开发快速、模块化地构建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、氮杂环丁烷、氧杂环丁烷和硫杂环丁烷，由于其有限的灵活性而具有独特的三维结构。特别地，四元环的出口矢量（取代基）在它们的空间布置中是明确限定的，并且因此允许关键官能团沿着预先选择的矢量取向。作为一个正在进行的努力，以开发有效的合成方法的一部分，产生大的，不同的图书馆的生物相关的小分子，这项研究计划概述了三个相互联系的战略，合成密集功能化和结构多样的四元环分子架构。拟议的研究是建立在显着的应变释放性能的双环[1.1.0]丁烷基序，其是一种迷人的分子结构，包括环丁烷部分，在环的相对侧上的两个碳原子之间具有σ键。这种σ键表现出两亲性行为，这意味着它参与亲电和亲核反应。该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基于环丁烷的分子库。具体地说，第一种策略将研究双环[1.1.0]丁基锌酸盐络合物的生成，该络合物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络合物。然后，这些可以通过大量的过渡金属催化的交叉偶联过程进行进一步的转化。在第二种策略中，关键的结构单元双环[1.1.0]丁基锂将与一系列对映体富集的取代的三元环（例如环氧化物、氮丙啶和硫杂环丙烷）反应，导致新的、这两种研究策略也将用氮杂双环[1.1.0]丁烷基序进行探索，这将导致基于氮杂环丁烷的结构的多样化库。使用对映体富集的氮杂双环[1.1.0]丁基亚砜作为结构单元，还将开发亚砜导向的锂化亲电捕获策略，以获得对映体纯的密集官能化的基于氮杂环丁烷的小分子库。将提供一个广泛的策略，为不同的小分子库的产生，基于四元单和螺环架构。这些图书馆在进入化学空间探索不足的区域和推动成功的药物发现计划方面将是非常宝贵的。