Cascade Catalysis: From Alkynes to Polycycles

高效、快速地制备环(环)有机分子是有机化学家面临的最重要的挑战之一。将这些分子构建为单一对映体--即左右手相互关联的两种镜像形式之一--对于有机化学的现代应用来说是同样重要的考虑因素。在这项建议中，我们的目标是发展化学，通过短的合成路线制备多个环系，并作为单一的对映体(即不对称)。我们将通过使用钯催化剂来控制连接到炔烃(碳-碳三键)的环系的形成来实现这一目标。在这一领域，我们的团队通过最近一篇备受瞩目的出版物确立了自己作为国际领先团队的地位，在这个项目中，我们打算扩大我们对这一反应原理的理解和使用，以制备复杂但基本有用的包含氧和氮原子的环体系-杂环-这构成了许多药物和农用化学品的核心。在我们计划的化学中，炔不仅通过与钯催化剂的相互作用来调节环的形成，而且本身也是一个有价值的官能团，在环形成步骤之后可以进行广泛的有用的化学。我们打算利用炔烃的独特性质来探索额外环系的形成。虽然我们预计这些过程将会成功，但更大的雄心和冒险是使用“级联”反应在一步中制备多个环，这一过程本质上导致了比前面描述的单独反应序列更高的反应效率和产率-这一原理从根本上与EPSRC Dial-A分子大挑战有关。在这一背景下，我们建议研究的反应也形成了它们各自的产物作为单一立体异构体(即存在多种可能性的单一三维结构)。这一点很重要，因为在新药物设计中的应用将依赖于这种选择性。该项目还旨在突破顺序催化和双重催化的界限--其中多个催化反应直接连续发生，要么在单独的反应中进行(顺序)，要么在同一反应瓶中更雄心勃勃和吸引人的(双重催化)。这导致了更大的分子复杂性，但不会增加制备原料所需步骤的额外成本，这是催化研究的前沿领域。总而言之，我们的目标是使用新的和当代的催化过程来以灵活和新颖的方式构建分子。我们打算在这些过程中探索的各种官能团将导致广泛的产品类型，这将增强在药物化学、农用化学品、化学生物学和材料化学中应用的可能性。

The efficient and rapid preparation of cyclic (ring-containing) organic molecules is one of the most important challenges for organic chemists. The construction of these molecules as single enantiomers - that is, one of two mirror image forms which are related as are left and right hands - is an equally vital consideration for modern applications of organic chemistry. In this proposal, we aim to develop chemistry which prepares multiple ring systems by short synthetic routes, and as single enantiomers (i.e asymmetrically).We will achieve this aim through the use of palladium catalysts to control the formation of ring systems which are connected to alkynes (carbon-carbon triple bonds). In this arena, our group has established itself as an internationally leading team through a recent high profile publication, and in this project we intend to expand our understanding and use of this reaction principle to prepare complex but fundamentally useful ring systems containing oxygen and nitrogen atoms - heterocycles - which form the core of many pharmaceuticals and agrochemicals.In our planned chemistry, the alkyne serves not only to mediate ring formation through its interaction with the palladium catalyst, but is also a valuable functional group in its own right which can undergo a wide range of useful chemistry after the ring-forming step. We intend to use the unique properties of the alkyne to explore the formation of additional ring systems.While we expect these processes to be successful, of greater ambition and adventure is the preparation of multiple rings in a single step using "cascade" reactions, processes which intrinsically lead to higher reaction efficiency and yields than the previously described separate reaction sequences - a principle which fundamentally links to the EPSRC Dial-A-Molecule Grand Challenge. The reactions we propose to study in this context also form their respective products as single stereoisomers (i.e. single three-dimensional structures where several possibilities exist). This is important, as applications in the design of new pharmaceuticals will rely on this selectivity.The project also aims to push boundaries in sequenced and dual catalysis - where multiple catalytic reactions take place in direct succession, either in separate reactions (sequenced) or more ambitiously and appealingly in the same reaction flask (dual catalysis). This leads to even greater molecular complexity but with no extra cost to the number of steps needed to prepare starting materials, and is an area at the forefront of catalysis research. In summary, we aim to employ new and contemporary catalytic processes to build molecules in a flexible and novel fashion. The variety of functional groups we intend to explore in these processes will lead to a broad expanse of product types, which will enhance possibilities for applications in medicinal chemistry, agrochemicals, chemical biology, and materials chemistry.