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.

描述（由申请人提供）：烯烃的催化不对称功能化在有机化学领域提供了许多具有里程碑意义的反应。这些反应包括不对称环氧化、二羟基化、氢化和叠氮化，仅举几例。然而，多年来，不对称亲电卤化反应的成功程度要低得多。将不对称烯烃卤化反应与一些研究更深入、应用更广泛的不对称烯烃功能化反应相媲美，是我们小组不断追求的目标。为此，我们将采用多方面的方法来确定和解决与这一转型相关的众多挑战。我们将首先提出直接的理论方法，通过定义卤化亲和（HalA）作为一个前所未有的参数来预测烯烃卤化反应的容易程度。对烯烃卤化的化学和区域选择性的预测将在实验中得到验证，然后进一步应用于发现非直觉（但强大）的转化，从而排除了试错方法的需要。我们建议通过不对称烯烃卤化反应开发有价值的手性杂环，如环硫酸盐、咪唑类、氢嘧啶类、哌啶类和恶嗪类杂环的对映选择性路线；利用各种C-、O-和n -亲核试剂（芳基环、醇类、磺胺类、胍类、叔胺类和乙酰胺类等）的烯烃卤化反应将被研究。开发新的不对称分子间变体的卤代烃功能化与各种亲核试剂将继续进行。最后，我们将介绍一些例子，在这些例子中，烯烃卤化反应将被开发出来，以便能够最有效地获取天然产物中发现的某些支架。在这方面，我们将从理论预测（HalA值）和机械指导的反应优化中寻求obtusin， napyradomycin A1及其相关类似物和Calophyline a的全合成。这将挑战我们开发必要的卤化反应以产生有效的合成。总体目标是发展不对称烯烃卤化化学，作为一种工具，以实现目前用其他方法难以或不切实际地构建的战略键形成反应。