PAd-dalPhos: a new ligand class for nickel-catalyzed cross-coupling

过渡金属催化剂已被证明在温和条件下能够有效地将简单分子转化为更复杂的增值产品。现代药物合成在很大程度上依赖于分子钯催化剂络合物的应用，以实现交叉偶联反应，所述交叉偶联反应用于构建在所寻求的药物分子内发现的C-C、C-N、C-O和其他键。这样的催化剂络合物由结合至供电子辅助配体分子（“配体”）的钯基片段组成。配体的明智选择是至关重要的，使一个给定的钯催化反应的利益的成功结果。在这方面，已经开发了许多专有配体类别并将其商业化用于制药工业以及学术研究。然而，钯既昂贵又相对低丰度，并且与钯一起使用的配体通常比钯本身更昂贵（每摩尔）。 这为开发全新类型的廉价配体提供了动力，这些配体能够使镍（约100）比钯便宜1000倍）来做钯的工作。所申请的资金旨在加速开发和优化我们的新型“PAd-DalPhos”辅助配体（图1，PhosphaADamantane-DALhousie PHOSPHINE）和衍生的镍前催化剂，用于与制药行业相关的抢手镍催化交叉偶联反应，特别是胺化反应。在获得临时专利保护后，为了加速这一有前途的技术的开发以促进商业化，本提案寻求开展关键的研发工作，使我们能够：（a）优化我们的铅配体原型，以扩大我们关于物质组成的专利要求;（B）评估PAd-DalPhos配体变体及其衍生的镍前催化剂在实现药学相关的镍催化反应中的效用，对于所述镍催化反应，通常使用昂贵的钯催化剂;和（c）在用户友好的工作台条件下评估优化的PAd-DalPhos配体变体及其衍生的镍前催化剂的保存期限。

Transition metal catalysts have proven to be effective in enabling the transformation of simple molecules into more complex, value-added products under mild conditions. Modern pharmaceutical synthesis relies heavily on the application of molecular palladium catalyst complexes to enable cross-coupling reactions that are utilized in the construction of C-C, C-N, C-O and other bonds found within sought-after drug molecules. Such catalyst complexes are comprised of a palladium-based fragment that is bound to an electron-donating ancillary ligand molecule ("ligand"). The judicious choice of ligand is crucial in terms of enabling the successful outcome of a given palladium-catalyzed reaction of interest. In this regard, a number of proprietary ligand classes have been developed and commercialized for use in the pharmaceutical industry, as well as in academic research. However, palladium is both expensive and relatively low in abundance, and ligands used with palladium are often more expensive (per-mole) than palladium itself. This provides motivation for the development entirely new classes of inexpensive ligands that enable nickel (ca. 1000X cheaper than palladium) to do the work of palladium. The requested funds are sought to accelerate the development and optimization of our novel "PAd-DalPhos" ancillary ligands (Fig. 1, PhosphaADamantane-DALhousie PHOSphine), and derived nickel pre-catalysts, for use in sought-after nickel-catalyzed cross-coupling reactions that are of relevance to the pharmaceutical industry, in particular amination. Having secured provisional patent protection, and in an effort to accelerate the development of this promising technology in order to promote commercialization, this proposal seeks to carry out key R&D work that will allow us to: (a) optimize our lead ligand prototype, so as to broaden our patent claims regarding composition of matter; (b) assess the utility of PAd-DalPhos ligand variants and their derived nickel pre-catalysts in enabling pharmaceutically relevant nickel-catalyzed reactions for which expensive palladium catalysts are normally employed; and (c) evaluate the shelf-life of optimized PAd-DalPhos ligand variants and their derived nickel pre-catalysts under user-friendly benchtop conditions.