Shape Shifting Phosphines in Transition Metal Catalysis

描述(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前沿，并且通常是试图构建过多的C-C、C-N和C-O键类型时的选择方法。钯通常是各种此类反应的金属选择，这些反应的规模通常从毫克到吨不等。虽然已知大量的催化剂/配体系统，但通常情况下，它们只对某些反应类别的某些底物起作用。这就是说，还没有发现真正通用的交叉偶联催化剂。一个可能的原因是，很难想象有一种催化剂对催化循环的每一步(氧化加成、转移、还原消除)都是最佳的，因为这些基本的有机金属反应中的每一个在金属中心的电子和配体的空间需求方面都有不同的偏好。一种非传统的配基设计方法是，配基的性质(电子供体能力和空间需求)可以在整个催化过程中改变，从而以不同的方式促进个别步骤。能够进行单分子周环反应的碳环基团将被连接到膦基团上，作为实现这些目标的手段。介绍了三类具有独特化学性质的新型配体及其在交叉偶联反应和芳基氟化反应中的应用。尽管铃木偶联是一个常规的合成过程，但在尝试使用某些底物类别时仍会遇到重大挑战。涉及缺电子的硼化合物，特别是2-吡啶基硼酸的偶联就是一个例子。将研究独特设计的变形配体促进此类反应的能力。金属催化的Pd(0)/Pd(11)催化合成芳基氟化物迄今已被证明是困难的。通过改变配体的大小来促进芳基氟化物从Pd(11)中的还原消除(这是目前比较麻烦的步骤)，将会被研究。这项研究与公共卫生的关系很简单：含氟化合物出现在许多药物中，它们的合成目前很困难，而且往往是危险的。衡量氟化在医学中重要性的一个标准是，在2007年销售的20种最畅销的品牌药物中，有9种含有氟，5种含有芳基氟化物。此外，交叉偶联反应使制药工业发生了革命性的变化，特别是铃木偶联反应已经成为药物化学中的主要成分。因此，整个提案寻求在配基设计中使用新的见解来解决对公共卫生和治疗学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.