Pd(II)/Pd(IV) Catalytic Cycles involving Pseudohalides in Cross-Coupling Processes: Mechanistic Studies and Synthetic Applications

过渡金属可以作为催化剂，影响许多类型的底物的反应，以提供具有非凡复杂性和结构多样性的重要产品。这种增强反应通常进行得快，产率高，副产物比相关的非催化反应少。事实上，在许多情况下，在没有催化剂的情况下，反应根本不会发生，这就是过渡金属催化反应的重要之处。金属中心本质上是催化的活性位点，它的活性可以使用配体来调节，这些配体能够根据金属的大小和电子性质不同程度地结合金属。人们可以设想改变催化性质，就像改变无线电接收器上的可调拨号盘一样。所需的精确性质，无论是高活性、选择性还是催化剂寿命，都可以通过改变这些配体来调整，以适应每个感兴趣的特定反应。对合成化学家来说，最通用的过渡金属之一是钯。它在制备有价值的合成靶标（如具有独特药用和生物学特性（抗癌等）的天然产物和治疗剂）和先进材料的许多反应中引起了极大的兴趣。在这个提议中，我们希望研究一个重要的钯催化反应Stille交叉偶联的机制，使用催化剂（PPh3）2Pd(n - suc)Br，最近由我们的研究小组开发。许多钯催化剂已经被发现用于该反应，尽管大多数研究人员都集中在制备更活跃的催化剂上，这是通过改变钯的供体中性配体的类型来实现的。然而，阴离子配体（如卤化物和假卤化物）的改变是一个相对被忽视的领域，这令人惊讶，因为这些配体可能比中性供体配体更可能涉及全局催化剂反应性。我们发现了一种不寻常的假卤化物，琥珀酰亚胺和相关的假卤化物，在Stille偶联中（对烯丙基和苯基底物）具有有趣的底物选择性效应；这对于其他已知的钯催化剂来说是前所未有的。一般来说，产品选择性是在这一领域中被忽视的东西，特别是当两个反应中心可能产生两种结果时。能够指导一个结果是一个重要的目标，因为第二个反应中心可以用于其他合成转化，使整个合成路线更有效。选择性的起源可能来自一个不寻常的机制途径。我们希望通过使用经典和最先进的工具来帮助阐明（PPh3）2Pd(N-Succ)Br的精确机制，以收集见解和理解。明确的反应途径的识别使我们能够利用这些知识来合理设计更高效、更有选择性和更环保的催化剂，并利用已经建立的新的机制暗示。后一点很重要，因为这通常有助于开发新的综合转换。使用我们的催化剂和相关衍生物，底物范围和反应类型将显著扩大。我们计划使用提议的技术识别和开发新的综合转换。概述了一种利用（PPh3）2Pd(N-Succ)Br在Stille交叉偶联及相关交叉偶联过程中合成令人兴奋的靶点-吡咯酮A的有效途径。总的目的是证明这和相关催化剂的多功能性的目标化合物含有一个迷人的安排功能作为一个大环的一部分。

Transition metals can act as catalysts, effecting the reactions of many types of substrates to provide important products that display extraordinary complexity and structural diversity. Such enhanced reactions often proceed rapidly, are higher yielding and give fewer by-products than the related non-catalysed reaction. Indeed, there are many cases where reactions do not occur at all in the absence of a catalyst and it is this what makes transition metal-catalysed reactions important. The metal centre is essentially the active site for catalysis, the activity of which can be modulated using ligands that are capable of binding metals to varying degrees, depending on their size and electronic properties. One can envisage changing the catalytic properties just like a tunable dial on a radio receiver. The precise property required, whether that is high activity, selectivity or catalyst lifetime, can be tuned by alteration of these ligands, to each specific reaction of interest. One of the most versatile transition metals available to synthetic chemists is palladium. It has attracted significant interest for use in many reactions applied to the preparation of valuable synthetic targets such as natural products and therapeutic agents, that possess unique medicinal and biological properties (anti-cancer etc.), and advanced materials.In this proposal, we wish to study the mechanism of an important palladium-catalysed reaction known as Stille cross-coupling, employing the catalyst (PPh3)2Pd(N-Succ)Br, recently developed by our research groups. Many palladium catalysts have been found for this reaction, although the majority of researchers have focussed on preparing catalysts that are more active, something accomplished through alteration of the type of donor neutral ligand for palladium. However, alteration of anionic ligands e.g. halides and pseudohalides, is an area that has been relatively neglected, which is surprising given that these ligands are likely to involve the global catalyst reactivity arguably more so than neutral donor ligands. We have found that an unusual pseudohalide, succinimide and related pseudohalides, exerts intriguing substrate selectivity effects in Stille coupling (for allylic and benzylic substrates); effects that are unprecedented for any other known palladium catalyst. Generally, product selectivity is something which has been overlooked in this field, particularly when two outcomes are possible (from two reactive centres). Being able to direct one outcome is an important goal, as the second reactive centre can be used for other synthetic transformations, making overall synthetic routes more efficient. The selectivity origin is likely to derive from an unusual mechanistic pathway. We wish to gather insights and understanding into the precise mechanism by which (PPh3)2Pd(N-Succ)Br operates by using classical and state-of-the-art tools to assist mechanism elucidation. The identification of clear reaction pathways allows us to exploit this knowledge in the rational design of more efficient, selective and environmentally friendly catalysts, as well as taking advantage of novel mechanistic implications that have been established. The latter point is important, as this often facilitates the development of new synthetic transformations. The substrate scope and reaction types, using our catalyst and related derivatives, will be significantly expanded.We plan to identify and develop new synthetic transformations using the proposed technology. An efficient synthetic route to an exciting target, phacelocarpus-pyrone A, using (PPh3)2Pd(N-Succ)Br in Stille cross-coupling and related cross-coupling processes, is outlined. The overall aim is to demonstrate the versatility of this and related catalysts in a target compound containing a fascinating arrangement of functionality as part of a macrocyclic ring.