Pd-Catalyzed Olefin Functionalization Reactions for Organic Synthesis

说明(申请人提供)：烯烃是极具吸引力的合成官能团。新发现的和显著改进的烯烃官能化反应可以直接影响靶向合成的效率。因此，发展选择性的、实用的烯烃功能化反应是学术界和工业界化学家面临的持续挑战。在这个建议中，我们瞄准了一系列新的烯烃官能化反应，这些反应利用Pd(II)催化及其促进烯烃亲核加成反应和交叉耦合过程的能力，在整个烯烃框架上形成多个新的C-C、C-H或C-X键。这种反应方法的发展与仔细的机理研究相结合，旨在阐明支配反应结果的基本特征，以及刺激新的反应开发和催化剂设计。目前的建议是开发新的钯催化的烯烃官能化反应，使用氧化法和经典方法来生成钯-烷基中间体。这里描述的反应发展集中于两个重要的目标：A)通过使用创新的方法使最初来自烯烃的Pd-烷基中间体官能化(目标1和2)，使新的机械衍生的分子合成策略成为可能，以及B)利用我们最近开发的电子无偏置烯烃的Heck反应来获得重要的手性构建块，同时还探索了控制选择性Pd-氢化物插入和β-氢化物消除的因素(目标3)。 与公共健康相关：拟议研究的目标是开发新的钯催化的烯烃官能化反应，使其能够通过独特的键断开轻松合成与生物相关的目标和新的小分子。拟议方法的进步将直接影响生物医学使命，因为它提供了有效地获得生物活性核心结构的衍生品的途径。

DESCRIPTION (provided by applicant): Alkenes are exceptionally attractive functional groups for synthesis. Newly discovered and significantly improved alkene functionalization reactions can have a direct impact on the efficiency of targeted synthesis. Therefore, the development of selective, practical alkene functionalization reactions is a continuing challenge facing chemists in both academia and industry. In this proposal, we target a new collection of alkene functionalization reactions that exploit Pd(II)-catalysis and its ability to promote both alkene nucleophilic addition reactions and cross-coupling processes to form multiple new C-C, C-H, or C-X bonds across the alkene framework. This reaction method development is coupled to careful mechanistic studies, which are designed to elucidate the fundamental features governing reaction outcomes, as well as to stimulate new reaction development and catalyst design. The current proposal is directed toward the development of new Pd-catalyzed olefin functionalization reactions using both oxidative and classical methods to generate Pd-alkyl intermediates. The reaction development described herein is focused on two significant goals: A) enabling new mechanistically-derived tactics for molecule synthesis by using innovative approaches to functionalize Pd-alkyl intermediates originally derived from an alkene (Aims 1 & 2), and B) exploiting our recently developed Heck reactions of electronically non-biased olefins to access important chiral building blocks, while also probing the factors that govern selective Pd-hydride insertion and ?-hydride elimination (Aim 3). PUBLIC HEALTH RELEVANCE: The goal of the proposed research is to develop new palladium-catalyzed alkene functionalization reactions to enable the facile synthesis of biologically-relevant targets and novel small molecules through unique bond disconnections. Advances in the proposed methodology will directly impact the biomedical mission by providing efficient access to derivatives of biologically-active core structures.