Cyclobutadiene Reloaded: A Generally Applicable Approach to Functionalised Four-Membered Heterocycles

虽然传统医学在很大程度上依赖于偶然发现的生物活性分子，但当代药物化学通常涉及设计可能不存在的新分子，这是基于对拟议药物分子与其生物靶点的相互作用的深刻理解。这一过程通常由计算机辅助，计算机可以根据对药物如何运作的理解，设计具有所需生物活性特征的药物分子。因此，现代药物发现在很大程度上依赖于制备新药物分子的有效方法的可用性，以及药物分子本身的前体。四元杂环是一类刚性分子，包含至少一个杂原子（碳原子以外的原子，例如氧、氮或硫）排列在一个由四个原子组成的环上。这些分子对药物发现很感兴趣，因为它们的刚性导致特定的拓扑结构，通常比更“松软”的分子更好地与生物靶标相互作用。特别是，这些分子的螺旋环版本（两个原子环连接在一起，共用一个原子）特别有希望成为药物分子的前体。然而，这些分子很难制备，而且现有的制备方法通常针对某些取代（高度取代的例子很难获得），导致这些药物前体的可用范围有限。本项目旨在通过开发适用于所有杂环类（即不考虑环内所含杂原子）的新方法，简化这些螺环四元杂环的制备。因此，一个简单的螺旋环药物前体库将被生成，然后可以使用现有的化学物质进一步“修饰”，以生产用于特定应用的定制药物分子。新方法将使用一种名为环丁二烯的试剂，这种试剂用途非常广泛，但以前使用有限。环丁二烯具有极强的反应性，因此它不能储存，必须在使用时立即制备，而且在此之前，没有方便的前体可用于生成它。该项目将开发新的环丁二烯前体，允许在温和条件下生成环丁二烯，并为不同的应用开发基本上相同的前体的几种不同变体。因此，一种普遍适用的四元杂环的模块化制备将成为可能，使这些分子可作为新药的前体。为了确保我们的方法被广泛采用，我们的产品将由我们的项目合作伙伴Key Organics（一家具有国际影响力的精细化学品公司）及时销售。这将最大化我们方法的影响，并确保我们的产品不仅可用于药物发现研究人员，还可用于各种其他领域。从长远来看，我们渴望开发分子支架的进一步应用，不一定局限于药物发现，但也在其他需要刚性的小分子基序的领域。

Whilst traditional medicine largely depended on the serendipitous discovery of biologically active molecules, contemporary medicinal chemistry often involves the design of new molecules that may not exist already, based on a deep understanding of the interaction of the proposed drug molecule with its biological target. This process is frequently aided by computers, which can design drug molecules with the required characteristics for the desired biological activity based on an understanding of how the drug will operate. Thus, modern drug discovery relies heavily on the availability of efficient methods to prepare new drug molecules, as well as the precursors to the drug molecules themselves.Four-membered heterocycles are a class of rigid molecules that contain at least one heteroatom (an atom other than carbon - for example, oxygen, nitrogen or sulfur) arranged in a ring of four atoms. These molecules are of interest in drug discovery because their rigidity results in specific topologies that often interact better with biological targets than more "floppy" molecules. In particular, spirocyclic versions of these molecules (in which two rings of atoms are joined, sharing one atom in common) are especially promising as precursors to drug molecules. However, these molecules are very difficult to prepare, and the methods that do exist for their preparation are often specific to certain substitution (highly substituted examples are difficult to access), resulting in a limited range of these drug precursors being available.This project aims to streamline the preparation of these spirocyclic four-membered heterocycles, by developing new methodology that will be applicable across all of the classes of heterocycle (i.e. irrespective of the heteroatom(s) contained within the ring). Thus, a library of simple spirocyclic drug precursors will be generated, which can then be further "decorated" using existing chemistries to produce bespoke drug molecules for specific applications. The new methodology will make use of a reagent named cyclobutadiene, which is extremely versatile but has seen limited use previously. Cyclobutadiene is extremely reactive, so it cannot be stored and must be prepared immediately as it is to be used, and previously, no convenient precursors were available for its generation. This project will develop new precursors to cyclobutadiene that allow the generation of cyclobutadiene under mild conditions, with several different variants of essentially the same precursor being developed for different applications. As a result, a generally applicable, modular preparation of four-membered heterocycles will be enabled, making these molecules available as precursors to new drugs.To ensure that our methodology is broadly adopted, our products will be marketed in a timely fashion by our project partner Key Organics - a fine chemicals company with international reach. This will maximise the impact of our methodology, and ensure that our products are available not only to drug discovery researchers, but also to a wide variety of other sectors. Longer term, we aspire to develop further applications of our molecular scaffolds, not necessarily limited to drug discovery, but also in other areas requiring rigid, small-molecule motifs.