Iron-Catalyzed Cross-Coupling

描述（由申请人提供）：催化交叉偶联反应解决了全合成、药物化学和精细化学品生产中的无数问题。虽然这些反应传统上是用铂族金属（PGMs）进行的，但最近一直在推动开发避免需要昂贵和有毒的贵金属催化剂的方法。越来越多的研究表明，铁可以是一种优良的催化剂，实现交叉偶联，如具有高活性和选择性的烷基卤化物和格氏试剂的偶联，这些偶联已被证明是铂族金属难以实现的。虽然铁催化的C-C交叉偶联化学为可持续的、低成本的方法提供了巨大的潜力，用于在可用的亲核试剂和亲电试剂的光谱中选择性地形成C-C键，但对这些系统的详细分子水平的理解仍然是难以捉摸的。事实上，目前仍然没有一个单一的铁催化的交叉偶联反应，其中一个广泛接受的机制已被确定，阻碍了合理的催化剂的发展。这种限制与钯化学形成鲜明对比，钯化学中对活性催化剂结构和机理的详细研究为继续设计和开发具有新颖和/或改进的催化性能的催化剂提供了基础。我们的长期目标是将铁催化的C-C交叉偶联发展到目前对钯的理解水平，从而使铁化学在所需C-C键形成反应的范围内得到合理的发展。在拟议的资助中，一种新的实验方法结合无机光谱，密度泛函理论和合成将被用来开发分子水平的洞察到活性催化剂的结构和th目前领先的铁催化C-C交叉偶联反应所涉及的机制，并利用这种洞察力开发新的催化剂和反应方法，提高催化性能。根据强有力的初步数据，该提案的具体目标是：（1）发展对铁-双膦催化的C-C交叉偶联中存在的活性铁催化剂和反应机理的分子水平理解，（2）发展对由简单铁盐催化的C-C交叉偶联中存在的活性铁催化剂和反应机理的分子水平理解，（3）在对活性催化剂结构和机理的基本认识的驱动下，发展新型铁基C-C交叉偶联方法。这项研究是创新的，因为它涉及一种新的物理-无机方法来研究铁交叉偶联催化，推进了我们对这种催化中所涉及的活性催化剂和机制的理解，并利用这种基本见解来设计和开发新的铁催化剂和交叉偶联反应方法。这项研究意义重大，因为它有望扩大使用低成本，可持续的铁交叉偶联方法可以制造的分子数量。从长远来看，这种合成方法的扩展将使分子生物学和药理学的发现对人类健康产生直接影响。

DESCRIPTION (provided by applicant): Catalytic cross-coupling reactions have solved countless problems in total synthesis, pharmaceutical chemistry, and the production of fine chemicals. While these reactions have traditionally been carried out with platinum group metals (PGMs), there has been a recent push to develop methods that circumvent the need for expensive and toxic precious metal catalysts. A growing body of research has demonstrated that iron can be an excellent catalyst, effecting cross-couplings that have proven difficult for PGMs such as the coupling of alkyl halides and Grignard reagents with both high activity and selectivity. While iron-catalyzed C-C cross-coupling chemistry offers tremendous potential for sustainable, low-cost methodologies for selective C-C bond formation across the spectrum of available nucleophiles and electrophiles, a detailed molecular level understanding of these systems has remained elusive. In fact, at present there remains no single iron-catalyzed cross-coupling reaction for which a broadly accepted mechanism has been determined, hindering rational catalyst development. This limitation is in stark contrast to palladium chemistry, where detailed studies of active catalyst structure and mechanism have provided the foundation for the continued design and development of catalysts with novel and/or improved catalytic performance. Our long-term goal is to develop iron-catalyzed C-C cross-coupling to the level of understanding currently present for palladium, thus permitting the rational development of iron chemistry across the spectrum of desired C-C bond forming reactions. In the proposed grant, a novel experimental approach combining inorganic spectroscopies, density functional theory and synthesis will be utilized to develop molecular-level insight into active catalyst structure and th mechanisms involved in current leading edge iron-catalyzed C-C cross-coupling reactions, and to utilize this insight to develop new catalysts and reaction methodologies with improved catalytic performance. Following up on strong preliminary data, the specific aims of the proposal are to: (1) develop molecular-level understanding of the active iron catalysts and reaction mechanisms present in iron-bisphosphine catalyzed C-C cross-coupling, (2) develop molecular-level understanding of the active iron catalysts and reaction mechanisms present in C-C cross-coupling catalyzed by simple ferric salts, and (3) develop novel iron-based C-C cross-coupling methods driven by fundamental insight into active catalyst structure and mechanism. The research is innovative because it involves a novel physical-inorganic approach to study iron cross-coupling catalysis, advances our understanding of the active catalysts and mechanisms involved in this catalysis and leverages this fundamental insight to the design and development of new iron catalysts and reaction methodologies for cross-coupling. The proposed research is significant because it is expected to expand the number of molecules that can be made using low-cost, sustainable iron cross-coupling methods. Long term, this expansion of synthetic methods will enable discoveries in molecular biology and pharmacology of direct impact to human health.