A Unified Route to Bicyclic Heterocycles: Synthesis and Applications

双环杂环化合物的统一路线：合成与应用

• 批准号: EP/H025839/1
• 负责人: Edward Anderson
• 金额: $ 40.74万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2010
• 资助国家: 英国
• 起止时间: 2010 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FH025839%2F1
• 关键词: Unified; Route; Bicyclic; Heterocycles; Synthesis

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.

双环杂环-含有至少一个氮，氧或硫原子的两个环的分子-形成药物化学的支柱，并且是新药开发的绝对基础，正如前50名销售的药物中的21种含有这种类型的分子核心所证明的那样。不出所料，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单一类型的双环，例如吲哚或喹诺酮合成。在这个建议中，我们描述了一个令人兴奋的级联反应（其中几个步骤是在一个合成操作中实现），可以应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方法双环杂环。这是我们以前在全碳领域开发的方法学的一个具有挑战性的扩展。（无N/O/S）系统，这将为药物开发带来新的机会。杂环的两个环在一个步骤中形成，使用一种在此类系统中几乎完全未开发的反应类型，并且基底的高度可调性质意味着我们可以潜在地访问许多不同的自行车-而不仅仅是一个例子。此外，我们可以选择在杂双环的全碳环上引入各种基团，这通常是传统合成后期最难官能化的环。我们建议通过一些重要的药物和天然产物目标的合成来证明这一工作。我们还打算利用级联反应产物在其他类型的复杂性诱导反应，包括在不对称合成中的应用。这将包括导致许多新的稠环（两个环通过一个共同的键连接）和螺环（两个环通过一个原子连接）核心的过程，包含多达五个相邻的立构中心，所有这些都只需要两个或三个步骤，从简单的起始材料。现代合成的主要挑战之一是在短步骤中引入分子复杂性，因为这通常伴随着高反应效率（产率）和低成本。总之，我们的目标是开发第一个真正通用的双环杂环方法，这对人类健康至关重要。我们解决这个问题使用新的和有趣的方法，将发现许多其他化学家的应用。我们建议使用我们最初制备的双环产品在广泛的冒险的复杂性诱导转换，导致过多的不寻常的，具有挑战性的，并可能非常有用的含杂原子的分子。

项目成果

Palladium- and ruthenium-catalyzed cycloisomerization of enynamides and enynhydrazides: a rapid approach to diverse azacyclic frameworks.

• DOI: 10.1002/anie.201304186
• 发表时间: 2013-08
• 期刊: Angewandte Chemie
• 作者: P. Walker;C. D. Campbell;A. Suleman;G. Carr;E. Anderson

Computational ligand design in enantio- and diastereoselective ynamide [5+2] cycloisomerization.

• DOI: 10.1038/ncomms10109
• 发表时间: 2016-01-05
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Straker RN;Peng Q;Mekareeya A;Paton RS;Anderson EA
• 通讯作者: Anderson EA

Synthesis of cyclic alkenylsiloxanes by semihydrogenation: a stereospecific route to (Z)-alkenyl polyenes.

• DOI: 10.1002/chem.201403255
• 发表时间: 2014-07-07
• 期刊: Chemistry (Weinheim an der Bergstrasse, Germany)
• 作者: Elbert BL;Lim DS;Gudmundsson HG;O'Hanlon JA;Anderson EA
• 通讯作者: Anderson EA

Ynamide carbopalladation: a flexible route to mono-, bi- and tricyclic azacycles.

• DOI: 10.1002/chem.201501710
• 发表时间: 2015-09-01
• 期刊: Chemistry (Weinheim an der Bergstrasse, Germany)
• 作者: Campbell CD;Greenaway RL;Holton OT;Walker PR;Chapman HA;Russell CA;Carr G;Thomson AL;Anderson EA
• 通讯作者: Anderson EA

Selectivity in Transition Metal-catalyzed Cyclizations: Insights from Experiment and Theory.

过渡金属催化环化的选择性：实验和理论的见解。

• DOI: 10.2533/chimia.2018.614
• 发表时间: 2018
• 期刊: Chimia
• 影响因子: 1.2
• 作者: Anderson EA