Predicted Reaction Discovery and Application of Catalytic Asymmetric Alkene Halogenations

催化不对称烯烃卤化反应的预测反应发现及应用

• 批准号: 8674424
• 负责人: BABAK BORHAN
• 金额: $ 32.36万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8674424
• 关键词: Address; Adopted; Affinity; Alcohols; Alkenes; Amides; Architecture; Area; Back; Biological Factors; Carbon; Carbonates; Chemistry; Complex; Development; Elements; Ensure; Family; Goals; Growth; Guanidines; Halogens; Health; Hydrogenation; Imidazolines; Indoles; Inorganic Sulfates; Intuition; Investigation; Kinetics; Knowledge; Lead; Measurable; Methodology; Names; Organic Chemistry; Outcome; Oxidation-Reduction; Phenols; Protons; Reaction; Relative (related person); Reporting; Research; Resolution; Route; Site; Source; Sulfonamides; System; Unspecified or Sulfate Ion Sulfates; Variant; analog; design; functional group; halogenation; novel; novel strategies; pi bond; piperidine; programs; propadiene; protocol development; scaffold; success; tool

DESCRIPTION (provided by applicant): Catalytic asymmetric functionalization of alkenes has provided numerous landmark reactions in the field of organic chemistry. These include asymmetric epoxidations, dihydroxylations, hydrogenations and aziridinations to name a few. Nonetheless, asymmetric electrophilic halogenation reactions have witnessed much less success over the years. It is an ongoing pursuit in our group to bring asymmetric alkene halogenation reactions at par with some the more well studied and widely utilized asymmetric alkene functionalization reactions. To this end, we will define and address the numerous challenges associated with this transformation by adopting a multi-faceted approach. We will begin by proposing straightforward theoretical means to predict the ease of alkene halogenation reactions by defining Halenium Affinity (HalA) as an unprecedented parameter. The resulting predictions of chemo- and regioselectivity in alkene halogenations will be verified experimentally and then further applied to the discovery of non-intuitive (yet powerful) transformations precluding the need for trial-and-error approaches. We propose to develop enantioselective routes to valuable chiral heterocycles such as cyclic sulfates, imidazolines, hydropyrimidines, piperidines and oxazine heterocycles via the asymmetric alkene halogenation reactions; halocyclization reactions of alkenes that utilize a variety of C-, O- and N-nucleophiles (aryl ring, alcohols, sulfonamides, guanidines, tertiary amides and acetamidates among many others) will be investigated. Development of novel asymmetric intermolecular variants of halofunctionalization of olefins with a variety of nucleophiles will be pursued. Finally, we will present examples where alkene halogenation reactions will be developed in order to enable the most efficient means yet to access certain scaffolds found in natural products. In this regard, we will draw from both theoretical predictions (HalA values) as well as mechanistically guided reaction optimizations to pursue the total syntheses of obtusin, Napyradiomycin A1 and related analogs, and Calophyline A. These will challenge us to develop the necessary halocyclization reactions to yield efficient syntheses. The overarching goal is to develop asymmetric alkene halogenation chemistry as a tool to enable strategic bond formation reactions that are currently difficult or impractical to construct using other means.

描述(申请人提供)：烯烃的催化不对称官能化在有机化学领域提供了许多里程碑式的反应。这些反应包括不对称环氧化、二羟基化、氢化和氮杂环化等。然而，多年来，不对称亲电卤化反应的成功要少得多。使不对称烯烃卤化反应与一些研究得更好、应用更广泛的不对称烯烃官能化反应相媲美，是我们团队不断追求的目标。为此，我们将通过采取多方面的方法来界定和解决与这一转变相关的众多挑战。我们将首先提出直接的理论方法，通过将卤素亲和力(HALA)定义为一个前所未有的参数来预测烯烃卤化反应的易度。由此得到的对烯烃卤化反应中化学选择性和区域选择性的预测将得到实验验证，然后进一步应用于发现非直观(但强大的)转化，从而排除了反复试验的必要性。我们建议通过不对称的烯烃卤化反应开发有价值的手性杂环的对映选择性路线，如环硫酸盐、咪唑啉、氢嘧啶、哌啶和恶嗪杂环；利用各种C-、O-和N-亲核剂(芳环、醇、磺胺、胍、叔胺和乙酰胺等)的烯烃的卤化反应将被研究。开发新型的不对称分子间卤代官能化的烯烃与各种亲核试剂的变体。最后，我们将提供一些例子，其中将开发烯烃卤化反应，以便使迄今最有效的方法能够访问在天然产品中发现的某些支架。在这方面，我们将从理论预测(HALA值)以及机械指导的反应优化两个方面进行研究，以实现牛油菌素、纳皮射线霉素A1及其相关类似物和茶碱A的全合成。这将挑战我们发展必要的卤代环化反应来产生有效的合成。首要目标是发展不对称烯烃卤化化学，作为一种工具，使目前难以或不切实际地用其他方法建立的战略性键形成反应成为可能。