Shape Shifting Phosphines in Transition Metal Catalysis

描述（由申请人提供）：过渡金属催化反应已经上升到合成有机化学的前沿，并且通常是尝试构建过多的C-C， C-N和C-0键类型时的首选方法。钯通常是这些反应的金属选择，这些反应通常以毫克到吨的规模进行。虽然已知有大量的催化剂/配体体系，但通常情况下，它们只对某些反应类别中的某些底物起作用。也就是说，一种真正通用的交叉偶联催化剂尚未被发现。一个可能的原因是，很难设想一种催化剂对催化循环的每个步骤（氧化加成、透化、还原消除）都是最佳的，因为这些基本的有机金属反应在金属中心的电子和配体的空间要求方面都有不同的偏好。配体设计的一种非正统方法是配体的性质（电子供体能力和空间需求）可以在整个催化过程中改变，从而不同地促进各个步骤。能够进行单分子周环反应的碳环基团将与磷化氢基团结合，作为实现这些目标的手段。介绍了三种具有独特化学性质的新型配体，以及它们在交叉偶联反应和芳基氟化反应中目前具有挑战性的问题中的应用。尽管Suzuki耦合是一个常规的合成过程，但在尝试使用某些基板类时仍然会遇到重大挑战。偶联涉及缺电子硼化合物，特别是2-吡啶硼酸就是一个例子。独特设计的变形配体促进这种反应的能力将被研究。利用Pd(0)/Pd（ll）催化金属催化合成芳基氟化物迄今为止已被证明是困难的。将研究使用尺寸变化配体促进Pd（ll）中芳基氟的还原消除（这是目前比较麻烦的步骤）。这项研究与公共卫生的相关性很简单：含氟化合物出现在许多药物中，它们的合成目前很困难，而且往往很危险。氟化在医学中的重要性的一个衡量标准是，在2007年销售的20种最畅销的名牌药物中，有9种含有氟，5种含有芳基氟基。此外，交叉偶联反应已经彻底改变了制药工业，特别是铃木偶联已成为药物化学的主要成分。因此，整个提案寻求使用配体设计的新见解来解决对公共卫生和治疗具有真正意义的问题。

DESCRIPTION (provided by applicant): Transition metal-catalyzed reactions have risen to the forefront of synthetic organic chemistry and are often the method of choice when trying to construct a plethora of C-C, C-N, and C-0 bond types. Palladium is often the metal of choice for a variety of these reactions which are routinely carried out on scales ranging from milligrams to tons. Although a large number of catalyst/ligand systems are known, it is often the case that they work for only certain substrates in certain reaction classes. That is to say a truly general cross- coupling catalyst has yet to be discovered. One likely reason is that it is difficult to envision a catalyst that is optimal for each step of the catalytic cycle (oxidative addition, transmetilation, reductive elimination) since each of these fundamental organometallic reactions have different preferences in the electronics of the metal center and the steric demands of the ligands. An unorthodox approach to ligand design would be a ligand whose properties (electron donor ability and steric demands) could change throughout catalysis thus promoting individual steps differently. Carbocyclic groups, capable of undergoing unimolecular pericyclic reactions will be attached to phosphine groups as a means to achieve these goals. Three novel ligand classes, each of which possesses unique chemical properties, are introduced as well as their application to currently challenging problems in cross-coupling reactions as well as aryl fluorination. Although the Suzuki coupling is a routine synthetic procedure, significant challenges can still be encountered when trying to use certain substrate classes. Couplings involving electron deficient boron compounds, particularly 2-pyridyl boronic acids are an example. The ability of uniquely designed shape-shifting ligands to promote such reactions will be investigated. The metal-catalyzed synthesis of aryl fluorides using Pd(0)/Pd(ll) catalysis has proven difficult to date. The use of size changing ligands to promote aryl fluoride reductive elimination from Pd(ll) (which is currently the troublesome step) will be investigated. The relevance of this research to public health is simple: fluorine containing compound appear in numerous medicines and their syntheses are currently difficult and often dangerous. One measure of the importance of fluorination in medicine is the fact that of the 20 top selling brand-name drugs sold in 2007, nine contained fluorine and five possessed an aryl fluoride motif. In addition, cross coupling reactions have revolutionized the pharmaceutical industry, and in particular the Suzuki coupling has become a staple in medicinal chemistry. Thus the entire proposal seeks to use novel insight in ligand design to address problems that are of real significance to public health and therapeutics.