Shape Shifting Phosphines in Transition Metal Catalysis

过渡金属催化中的变形膦

基本信息

批准号：
7744107
负责人：
Thomas John Maimone
金额：
$ 4.52万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2012-09-29
项目状态：
已结题

项目摘要

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.

描述（由申请人提供）：过渡金属催化反应已上升到合成有机化学的最前沿，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。钯通常是各种此类反应的首选金属，这些反应的规模通常从毫克到吨不等。尽管已知大量催化剂/配体系统，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尚未被发现。一个可能的原因是，很难设想一种对于催化循环的每个步骤（氧化加成、转金属、还原消除）来说都是最佳的催化剂，因为这些基本有机金属反应中的每一个在金属中心和电子的电子方面都有不同的偏好。配体的空间需求。配体设计的一种非正统方法是配体的特性（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上，作为实现这些目标的手段。介绍了三种新型配体类别，每种配体都具有独特的化学性质，以及它们在交叉偶联反应和芳基氟化中当前具有挑战性的问题上的应用。尽管铃木偶联是常规合成程序，但在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例子。将研究独特设计的变形配体促进此类反应的能力。迄今为止，使用 Pd(0)/Pd(II) 催化的金属催化合成芳基氟化物已被证明是困难的。将研究使用尺寸改变配体促进芳基氟从 Pd(II) 中还原消除（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，目前其合成很困难而且通常很危险。衡量氟化在医学中的重要性的一个标准是，2007 年销售的 20 种最畅销的品牌药物中，有 9 种含有氟，5 种具有芳基氟化物基序。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内容。因此，整个提案旨在利用配体设计的新颖见解来解决对公共卫生和治疗具有真正意义的问题。