Stable Carbenes: Emerging Ligands for Catalysis

描述（由申请人提供）：有机分子的高效和选择性制备对于治疗药物的合成至关重要。许多最熟练的已知工艺取决于催化剂的可用性。有机金属催化的优点之一是能够通过修饰金属中心周围的配体来调节活性和选择性。近年来，由于使用了体积庞大、富电子的磷化氢和环二氨基碳（NHCs），催化，特别是pd交叉偶联反应取得了重大进展。该研究计划基于我们在稳定卡宾合成方面的长期经验，其目标是合成环卡宾，以提高表征膦和NHC配体的电子和/或立体参数尺度，特别关注配体家族，它将有可能精确调整立体电子参数。人们迫切需要技术来生产纯对映体形式的治疗药物。对于不对称配体，可以制备手性中心位于碳烯α位置的碳烯，以及手性为C2且有两个不同给体的双齿配体；这将导致高手性诱导效应。我们将重点关注钯催化的芳酰氯偶联反应（Suzuki-Miyaura和根岸工艺）以及醛/亚胺的α -芳化反应。由于这种几乎未知的反应，并且由于吲哚在生物系统中发挥的突出作用，我们将开发一种新的从亚胺和邻二卤芳烃中合成多种吲哚的一锅法。为了加速我们的配体的广泛应用，我们已经正式建立了两项合作，我们期待着进一步的伙伴关系。这项研究的最终目标是为催化界提供新的、容易获得的配体，这将允许开发实用的催化剂，这些催化剂将在工业和学术界中找到应用，用于选择性合成重要的生物化合物。

DESCRIPTION (provided by applicant): Efficient and selective preparation of organic molecules is critical for the synthesis of therapeutics. Many of the most proficient known processes depend on the availability of catalysts. One of the advantages of organometallic catalysis is the ability to tune the activity and selectivity through modification of the ligands around the metal center. Recently, major advances in catalysis, especially in Pd-cross-coupling reactions, have been reported thanks to the use of bulky, electron-rich phosphines and cyclic diaminocarbenes (NHCs). The proposed research program, built on our long standing experience in stable carbene synthesis, has as its objective the synthesis of cyclic carbenes that push upward the electronic and/or steric parameter scales characterizing both phosphine and NHC ligands, with special attention on families of ligands for which it will be possible to precisely tune the stereo-electronic parameters. There is a demanding need for technology to produce therapeutics in a pure enantiomeric form. For the asymmetric versions of the ligands, carbenes with a chirality center in a position alpha to the carbene, and bidentate ligands featuring C2 chirality and two very different donors will be prepared; this should result in high chiral induction effects. We will focus on palladium-catalyzed coupling reactions of aryl chlorides (Suzuki-Miyaura and Negishi processes) and on the alpha-arylation of aldehydes/imines. Thanks to this virtually unknown reaction, and because of the prominent role played by indoles in biological systems, we will develop a novel one-pot synthesis of a variety of indoles from imines and ortho-dihaloarenes. To accelerate the widespread implementation of our ligands, we have already formalized two collaborations and we are looking forward to further partnerships. The ultimate goal of this proposed research effort is to provide the catalytic community with new, readily available ligands, which will allow for the development of practical catalysts that will find applications in both industry and academia for the selective synthesis of biologically important compounds.