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

基本信息

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

项目摘要

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——包含两个环且至少有一个氮、氧或硫原子的分子——构成了药物化学的支柱，对于新药的开发绝对是基础，最畅销的 50 种药物中有 21 种含有这种类型就证明了这一点的分子核心。毫不奇怪，已经设计了多种方法来合成这些重要分子，但是大多数方法特定于单一类型的自行车，例如吲哚或喹诺酮合成。在这个提案中，我们描述了一个令人兴奋的级联反应（其中在一个合成操作中实现了几个步骤），它可以应用于许多不同双环骨架的合成，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。杂环的两个环都是在一个步骤中形成的，使用一种类型在此类系统中几乎完全未探索过的反应，并且基板的高度可调性质意味着我们有可能获得许多不同的自行车 - 而不仅仅是一个例子。此外，我们可以选择在杂二环的全碳环上引入各种基团，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证明这项工作。拟议的研究不仅限于芳香自行车。我们还打算在其他类型的复杂性诱导反应中开发级联反应产物的反应性，包括在不对称合成中的应用。这将包括产生许多新型稠环（两个环通过一个共同键连接）和螺环（两个环通过一个原子连接）核心的过程，其中包含多达五个相邻的立构中心，所有这些都只需两到三个步骤从简单的起始材料开始。现代合成的主要挑战之一是在短时间内引入分子复杂性，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方法双环杂环，对人类健康至关重要。我们对这个问题的解决方案使用了新的、有趣的方法，该方法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物用于各种冒险的复杂性诱导转化中，从而产生大量不寻常的、具有挑战性的和潜在高度有用的含杂原子分子。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
影响因子：
0
作者：
P. Walker;C. D. Campbell;A. Suleman;G. Carr;E. Anderson
通讯作者：
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

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)
影响因子：
0
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

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