Reductive Coupling Reactions: Trading Organometallic Reagents for Organic Halides

描述(申请人提供)：催化C-C键形成反应使学术界和工业界小分子的发现和合成发生了革命性的变化，但过渡金属催化的全部潜力现在经常受到预制有机金属试剂的需求的限制。很少有这样的试剂可以商业化，因为它们的合成不是微不足道的，而且许多试剂的稳定性有限。这些限制对药物发现和生物化学产生了影响，因为许多潜在的重要分子在被认为过于耗时而无法访问时并未被制造出来。这个问题的一个潜在解决方案是用亲电体取代亲核金属有机试剂，如有机卤化物，它们是稳定的和充足的。该计划的长期目标是开发新的催化反应，将两个或两个以上的亲电体偶联，并阐明控制这些还原偶联反应的选择性和反应性的因素。在建议的拨款中，将为两种最重要的C-C键形成反应：交叉偶联和共轭加成开发还原替代方案。这项工作的指导机制假设是，第一排过渡金属的单电子化学将允许在一个金属中心发生多个氧化加成，从而使两个亲电体能够耦合。尽管几乎可以肯定涉及到自由基中间体，但这些过渡金属催化的反应可以通过选择金属和配体来调节。因此，所开发的反应将为更好地研究其他金属的两电子过程提供补充的反应性。根据强有力的初步数据，该建议的具体目标是：(1)从简单的有机卤化物或假卤化物开发形成Csp3-Csp2键的直接还原交叉偶联反应，并更好地了解转化机理；(2)创建形成Csp3-Csp3键的直接还原偶联方法；以及(3)扩展还原偶联的概念，以包括有机卤化物与一氧化碳、烯烃和炔烃的偶联。在每个目标下，在申请人的实验室中都发现了一个有希望的催化剂系统，该系统将成为开发几种通用方法的基础。这种方法是创新的，因为它专注于开发完全避免中间有机金属试剂的新反应。已经确定了克服交叉选择性和反应性挑战的战略，这些战略以前阻碍了进展。通过研究不同机制的反应，这项拟议的研究为关键的C-C成键反应以及新的键结构提供了显著改进的机会，这是以前不可能的。这项拟议的研究意义重大，因为它有望扩大可以从商业上获得的材料中快速制造出的分子的数量。从长远来看，这种易于获取的分子多样性的扩大将使分子生物学和药理学的发现成为可能，这些发现将直接影响人类健康。 与公共健康相关：本申请中提出的新的偶联反应不需要专门的技术或排除空气，使健康科学中的那些人，即使是那些化学经验有限的人，也能够自己合成所需的分子。这项拟议的研究与公共卫生和NIH的使命相关，因为正是从这个扩大的、多样化的池中，明天的药物和分子探测器将被发现。

DESCRIPTION (provided by applicant): Catalytic C-C bond forming reactions have revolutionized the discovery and synthesis of small molecules in academia and industry, but the full potential of transition-metal catalysis is now frequently limited by the need for pre-formed organometallic reagents. Few such reagents are commercially available because their synthesis is not trivial and many of the reagents have limited stability. These limitations have consequences for drug discovery and biochemistry because many potentially important molecules are not made when they are deemed too time consuming to access. One potential solution to this problem is the replacement of nucleophilic organometallic reagents with electrophiles, such as organic halides, which are bench stable and plentiful. This program's long-term goals are the development of new catalytic reactions that couple two or more electrophiles as well as the illumination of the factors which control selectivity and reactivity in these reductive coupling reactions. In the proposed grant, reductive alternatives will be developed for two of the most important types of C-C bond forming reactions: cross-coupling and conjugate addition. The guiding mechanistic hypothesis for this work is that the single-electron chemistry of first-row transition metals will enable the coupling of two electrophiles by allowing multiple oxidative additions to occur at a single metal center. Although radical intermediates are almost certainly involved, these transition-metal catalyzed reactions can be tuned through choice of metal and ligand. Thus, the reactions developed will provide a complementary reactivity to the better studied two-electron processes of other metals. Following up on strong preliminary data, the specific aims of the proposal are to: (1) develop direct reductive cross-coupling reactions that form Csp3- Csp2 bonds from simple organic halides or pseudohalides and better understand the mechanism of the transformation; (2) create direct reductive coupling methods that form Csp3-Csp3 bonds; and, (3) extend the concept of reductive coupling to include the coupling of organic halides with carbon monoxide, alkenes, and alkynes. Under each aim a promising catalyst system has been discovered in the applicant's laboratory that will become the basis for the development of several general methods. The approach is innovative because it focuses on the development of new reactions that completely avoid intermediate organometallic reagents. Strategies to overcome the challenges of cross-selectivity and reactivity have been identified that have previously prevented progress. By investigating reactions with different mechanisms, the proposed research presents the opportunity for dramatic improvements in critical C-C bond-forming reactions as well as new bond constructions that were not previously possible. The proposed research is significant because it is expected to expand the number of molecules that can be rapidly made from commercially available materials. In the long run, this expansion of readily accessible molecular diversity will enable discoveries in molecular biology and pharmacology that will directly impact human health. PUBLIC HEALTH RELEVANCE: The new coupling reactions proposed in this application do not require specialized techniques or the exclusion of air, empowering those in the health sciences, even those with limited chemistry experience, to synthesize needed molecules themselves. The proposed research is relevant to public health and the mission of the NIH because it is from this expanded, diversified pool that tomorrow's drugs and molecular probes will be discovered.