A Unified Route to Bicyclic Heterocycles: Synthesis and Applications

双环杂环-含有至少一个氮、氧或硫原子的两个环的分子-构成了药物化学的中流砥柱，对新药的开发绝对是至关重要的，含有这种分子核心的前50种畅销药物中的21种证明了这一点。不出所料，人们已经设计了多种方法来合成这些重要的分子，然而大多数方法都是针对一种类型的自行车的，例如吲哚或喹诺酮的合成。在这个方案中，我们描述了一种激动级联反应(在一次合成操作中实现了几个步骤)，它可以用于合成一些不同的双环骨架，因此确实代表了第一个真正统一的双环杂环方法。这是我们之前在全碳(无N/O/S)系统中开发的方法的一个具有挑战性的扩展，这将为药物开发带来新的机会。杂环的两个环是一步形成的，使用的是一种在此类系统中几乎完全未被探索的反应类型，底物的高度可调性质意味着我们可能获得许多不同的自行车--而不仅仅是一个例子。此外，我们还可以选择在杂二环的全碳环上引入广泛的基团，这通常是传统合成中后期最难官能化的环。我们建议通过合成一些重要的药物和天然产物目标来展示这项工作。拟议的研究并不局限于芳香自行车。我们还打算利用级联反应产物在其他类型的复杂诱导反应中的反应性，包括在不对称合成中的应用。这将包括一些新的稠环(通过公共键连接的两个环)和螺环(通过单个原子连接的两个环)核心的工艺，这些核心包含多达五个相邻的立体中心，所有这些都只需两到三个步骤就可以从简单的起始材料开始。现代合成的主要挑战之一是在很短的步骤中引入分子的复杂性，因为这通常伴随着高反应效率(产率)和低成本。综上所述，我们的目标是开发第一个真正通用的方法来合成对人类健康至关重要的双环杂环。我们对这个问题的解决方案使用了新的有趣的方法，这将被其他化学家广泛应用。我们建议将我们最初制备的双环产品用于广泛的冒险复杂性诱导转化，导致大量不寻常的、具有挑战性的和潜在的高度有用的含有杂原子的分子。

Bicyclic heterocycles - molecules containing two rings with at least one nitrogen, oxygen or sulfur atom - form the mainstay of medicinal chemistry and are absolutely fundamental to the development of new drugs, as evidenced by the 21 of the top 50 selling pharmaceuticals which contain this type of molecular core. Unsurprisingly, a multitude of methods have been devised to synthesise these important molecules, however most methods are specific to a single type of bicycle, such as an indole or quinolone synthesis. In this proposal, we describe an exciting cascade reaction (in which several steps are achieved in one synthetic operation) that can be applied to the synthesis of a number of different bicyclic skeletons, and thus indeed represents the first truly unified approach to bicyclic heterocycles. This is a challenging extension of methodology we have previously developed in all-carbon (no N/O/S) systems, which will lead to new opportunities for pharmaceutical development.Both rings of the heterocycle are formed in a single step, using a type of reaction that is almost entirely unexplored in such systems, and the highly tuneable nature of the substrate means we can potentially access many different bicycles - not just a single example. Furthermore, we have the option to introduce a wide range of groups on the all-carbon ring of the heterobicycle, which is usually the hardest ring to functionalise at a late stage in traditional syntheses. We propose to demonstrate this work through the synthesis of some important pharmaceutical and natural product targets.The proposed research is not limited to aromatic bicycles. We also intend to exploit the reactivity of the cascade reaction products in other types of complexity-inducing reactions, including applications in asymmetric synthesis. This will include processes which lead to a number of novel fused-ring (two rings joined through a common bond) and spirocyclic (two rings joined through a single atom) cores, containing up to five adjacent stereocentres, all in just two or three steps from simple starting materials. One of the main challenges for modern synthesis is this introduction of molecular complexity in a short number of steps, as this is often accompanied by high reaction efficiency (yield) and low cost.In summary, we aim to develop the first truly general approach to bicyclic heterocycles, which are of key importance in human health. Our solution to this problem uses new and interesting methodology which will find much application by other chemists. We propose to use our initially prepared bicyclic products in a wide range of adventurous complexity-inducing transformations, leading to a plethora of unusual, challenging, and potentially highly useful heteroatom-containing molecules.