General Cross-Metathesis with Vinyl Halides through Catalyst Design

描述（由申请人提供）：大量的生物活性化合物，包括天然产物和治疗剂，含有取代的烯烃。这些基序的化学合成可以通过亲核试剂和卤代乙烯亲电试剂之间的Pd（0）-、Ni（0）-或Cu（I）-介导的交叉偶联来完成。这种化学的缺点是取代的乙烯基卤化物不容易获得，并且通常必须使用具有固有差的原子经济性和/或使用有毒、危险材料的方法合成。一种有吸引力的替代方法是在末端烯烃和合适的卤代亚甲基供体之间进行交叉复分解。预期这种类型的铼催化的反应具有广泛的官能团耐受性，在温和的条件下操作，并提供通过催化剂控制影响E/Z选择性的潜力。 尽管烯烃复分解总体上取得了广泛的进展，但与卤乙烯的交叉复分解仍然是一个未解决的问题，并且少数报道的实施例存在催化效率低、缺乏E/Z选择性以及与合成有用的溴乙烯或碘乙烯基本上没有反应性的问题。这些实际问题通常都被认为是源于一个单一的基本问题，即假定的[Ru-卤代亚甲基]中间体的高热力学稳定性，这使得催化剂在动力学上不反应并且易于分解。 这项建议的目标是开发第一个综合有用的，通用的跨协议， 通过组合的计算、有机金属和过程优化方法，用乙烯基卤化物进行复分解。具体而言，计划中的研究旨在测试以下假设：通过使用配体结构，通过不利的偶极-偶极相互作用使[Ru-卤代亚甲基]基态不稳定，可以实现增强的反应性。为此，将在密度泛函理论（DFT）水平上进行计算分析，以计算生产CM与乙烯基卤化物的自由能分布，以及已知的分解途径。接下来，我们将制备一系列含氟联芳基NHC配体的新型钌配合物，并研究它们在溶液和固体状态下的化学行为。 这些新的催化剂和其他催化剂将在卤乙烯CM反应中进行测试，目标是开发温和和选择性的方案，以获得（E）和（Z）-立体异构体。如果成功，这种方法将通过简化有价值的卤乙烯中间体的合成并开辟一个新的可再生原料池作为起始材料，对制药和学术化学产生巨大的影响。

DESCRIPTION (provided by applicant): A large number of biologically active compounds, including natural products and therapeutics, contain substituted olefins. Chemical synthesis of these motifs can be accomplished by Pd(0)-, Ni(0)-, or Cu(I)- mediated cross-coupling between a nucleophile and a vinyl halide electrophile. A drawback of this chemistry is that substituted vinyl halides are not readily available and typically must be synthesized using methods that have inherently poor atom economy and/or utilize toxic, hazardous materials. An attractive alternative approach would be to perform cross-metathesis between a terminal olefin and a suitable halomethylidene donor. A ruthenium-catalyzed reaction of this type would be expected to have broad functional group tolerance, operate under mild conditions, and offer the potential to affect E/Z selectivity through catalyst control. Despite widespread progress in olefin metathesis in general, cross-metathesis with vinyl halides remains an unsolved problem, and the few reported examples suffer from low catalytic efficiency, a lack of E/Z selectivity, and essentially no reactivity with synthetically useful viny bromides or -iodides. These practical problems are all generally thought to stem from a single fundamental problem, the high thermodynamic stability of the putative [Ru-halomethylidene] intermediate, which renders the catalyst kinetically unreactive and susceptible to decomposition. The goal of this proposal is to develop the first synthetically useful, general protocol for cross- metathesis with vinyl halides through a combined computational, organometallic, and process optimization approach. Specifically, the planned research aims to test the hypothesis that enhanced reactivity can be achieved by using ligand structures that destabilize the [Ru-halomethylidene] ground state through unfavorable dipole-dipole interactions. To this end, computational analysis at the density functional theory (DFT) level will be performed to calculate the free energy profile of productive CM with vinyl halides, as well as that of known decomposition pathways. Next, a series of novel Ru complexes bearing fluorinated biaryl NHC ligands will be prepared, and their chemical behavior will be studied in solution- and solid state. These new catalysts and others will then be tested in vinyl halide CM reactions, with the goal of developing mild and selective protocols to access both (E)- and (Z)-stereoisomers. If successful, this method will have tremendous relevance to pharmaceutical and academic chemistry by streamlining the synthesis of valued vinyl halide intermediates and opening up a new pool of renewable feedstocks as starting materials.