Shape Shifting Phosphines in Transition Metal Catalysis

描述（由申请人提供）：过渡金属催化的反应已经上升到合成有机化学的最前沿，并且在试图构建过多的C-C、C-N和C-O键类型时通常是选择的方法。钯通常是各种这些反应的金属选择，这些反应通常在从毫克到吨的规模上进行。尽管已知大量的催化剂/配体体系，但通常情况是它们仅对某些反应类别中的某些底物起作用。也就是说，真正通用的交叉偶联催化剂还有待发现.一个可能的原因是，很难设想一种催化剂，这是最佳的催化循环的每一步（氧化加成，transmetilation，还原消除），因为这些基本的有机金属反应中的每一个具有不同的偏好，在电子的金属中心和空间需求的配体。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发生变化，从而以不同的方式促进各个步骤。能够进行单分子周环反应的碳环基团将连接到膦基团作为实现这些目标的手段。三个新的配体类，其中每一个都具有独特的化学性质，以及它们的应用，目前具有挑战性的问题，在交叉偶联反应，以及芳基取代。虽然Suzuki偶联是常规合成程序，但当尝试使用某些底物类别时仍然会遇到重大挑战。涉及缺电子硼化合物，特别是2-吡啶基硼酸的偶联是一个实例。将研究独特设计的形状变化配体促进此类反应的能力。迄今为止，使用Pd（0）/Pd（II）催化剂的芳基氟化物的金属催化合成已被证明是困难的。将研究使用尺寸变化配体来促进芳基氟从Pd（II）的还原消除（这是目前麻烦的步骤）。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，目前合成它们很困难，而且往往很危险。在2007年销售的20种最畅销的品牌药物中，有9种含有氟，5种含有芳基氟基序，这一事实表明了氟在医学上的重要性。此外，交叉偶联反应已经彻底改变了制药工业，特别是Suzuki偶联已经成为药物化学中的主食。因此，整个提案旨在利用配体设计的新见解来解决对公共卫生和治疗学具有真实的重要意义的问题。

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.