Aliphatic Effects in Transition Metal Catalysis

项目摘要。过渡金属催化方法的多样性令人难以置信， 是围绕着一小部分基本有机金属反应而发展起来的。总体 我们的研究计划的目标是扩大这一工具箱，包括新的有机金属 这些机制可以反过来整合到许多新的催化转化中， 产生新的有机结构。这一建议的一个核心假设是， 催化剂结构中的持久配位不饱和性可以使独特的 有机金属机制，例如在所有碳- 碳和碳-杂原子交叉偶联反应-一些最常用的 反应在各个层次的药物研究。我们的方法受到潜在的启发 对于大的脂肪族基团中的大量有吸引力的货车范德华力，我们能够 使用大的有机磷配体将其引入到金属催化剂结构中。主 这项工作的重点将是了解机制，并利用，一个不寻常的 一系列的金属转移反应，我们已经观察到与低坐标的混合物， 钯络合物和质子亲核试剂，如有机硼酸。这些反应 即使在没有强碱的情况下，也可以在非常温和的条件下发生， 在许多交叉偶联反应中历史上是必要的，但也损害了 与敏感化合物的相容性金刚石的独特影响，如在 三（1-金刚烷基）膦，在促进这种化学反应可能反映了大的极化 和分散力表现在大的脂肪族分子中。为了推广这些 脂肪族的影响，我们将同时追求新的，模块化的方法来构建拥挤的 C（sp3）−P键，这是两种催化结构中的常见基序，也是许多 生物活性化合物。此外，我们将这些脂肪族效应扩展到 促进铁中具有历史挑战性的金属转移和氧化加成反应， 铜催化，分别，这是阻碍努力的一般问题， 阻碍开发使用大量贱金属的更可持续的交叉偶联方法 该提案的催化和有机磷合成努力将产生 通过新的碳元素键形成的新的生物活性分子结构 反应.

Project Summary. An incredible diversity of transition metal-catalyzed methods has been developed around a small subset of elementary organometallic reactions. The overarching goal of our research program is to expand this tool box to include new organometallic mechanisms that can in turn be integrated into many new catalytic transformations to generate new organic structures. A central hypothesis of this proposal is that enforcing persistent coordinative-unsaturation in catalyst structures can enable unique organometallic mechanisms, such as in the transmetalation step common to all carbon- carbon and carbon-heteroatom cross-coupling reactions – some of the most practiced reactions at all levels of pharmaceutical research. Our approach is inspired by the potential for substantial attractive van der Waals forces in large aliphatic groups, which we are able to incorporate into metal catalysts structures using large organophosphorus ligands. A primary focus of this work will be to understand the mechanisms of, and to leverage, an unusual series of transmetalation reactions we have observed with mixtures of low-coordinate palladium complexes and protic nucleophiles, such as organoboronic acids. These reactions can occur under very mild conditions even in the absence of strong base, which has been historically necessary in many cross-coupling reactions yet also compromises the compatibility with sensitive compounds. The unique influence of diamondoids, such as in tri(1-adamantyl)phosphine, in promoting this chemistry may reflect the large polarizability and dispersion forces manifested in large aliphatic molecules. In order to generalizing these aliphatic effects, we will concurrently pursue new, modular methods to construct congested C(sp3)−P bonds, which are common motifs in both catalytic structures and also many biologically active compounds. Furthermore, we will expand these aliphatic effects to promote historically challenging transmetalation and oxidative addition reactions in iron and copper catalysis, respectively, which are general problems that have hindered efforts hindered to develop more sustainable cross-coupling methods using abundant base metals Together the catalytic and organophosphorus synthetic efforts of this proposal will generate new biologically active molecular structures through novel carbon-element bond forming reactions.