Predicted Reaction Discovery and Application of Catalytic Asymmetric Alkene Halog

催化不对称烯烃卤化物的预测反应发现及应用

• 批准号: 9018048
• 负责人: BABAK BORHAN
• 金额: $ 23.2万
• 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 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9018048
• 关键词: Address; Adopted; Affinity; Alcohols; Alkenes; Amides; Architecture; Area; Back; Carbon; Carbonates; Chemistry; Complex; Development; Elements; Ensure; Family; Goals; Growth; Guanidines; Halog; Halogens; Health; Hydrogenation; Imidazolines; Indoles; Inorganic Sulfates; Intuition; Investigation; Kinetics; Knowledge; Lead; Measurable; Methodology; Names; Natural Products; Organic Chemistry; Outcome; Oxidation-Reduction; Phenols; Protons; Reaction; 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.

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。这些包括不对称环氧化、二羟基化、氢化和氮丙啶化等。尽管如此，近年来不对称亲电卤化反应的成功率要低得多。这是一个正在进行的追求，在我们的小组，使不对称烯烃卤化反应与一些更好地研究和广泛使用的不对称烯烃官能化反应。为此，我们将通过采取多方面的方法来确定和解决与这一转型相关的众多挑战。我们将开始，提出直接的理论手段来预测烯烃卤化反应的难易程度，通过定义卤素亲和力（HalA）作为一个前所未有的参数。由此产生的预测烯烃卤化的化学和区域选择性将实验验证，然后进一步应用于发现非直观的（但强大的）转换排除了试错法的需要。我们建议开发有价值的手性杂环，如环状硫酸酯，咪唑啉，氢嘧啶，哌啶和恶嗪杂环通过不对称烯烃卤化反应的对映选择性路线;将研究利用各种C-，O-和N-亲核试剂（芳环，醇，磺酰胺，胍，叔酰胺和乙酰胺等）的烯烃的卤环化反应。开发新的不对称分子间变体的烯烃与各种亲核试剂的卤代官能化将被追求。最后，我们将介绍一些例子，其中烯烃卤化反应将被开发，以使最有效的手段尚未获得某些支架中发现的天然产物。在这方面，我们将从理论预测（HalA值）以及机械引导的反应优化，追求obtusin，Napyradiomycin A1和相关类似物，和Calophyline A的全合成。这些将挑战我们开发必要的卤环化反应，以产生有效的合成。总体目标是开发不对称烯烃卤化化学作为一种工具，以实现目前难以或不切实际的使用其他手段构建的战略键形成反应。