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

基本信息

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
项目类别：
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

项目摘要

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。这些包括不对称的环氧化，二羟基化，氢化和中氮化作用，仅举几例。尽管如此，多年来，不对称的亲电卤化反应的成功率较小。在我们小组中，这是一种持续的追求，它与一些研究良好和广泛利用的不对称烯烃官能化反应相当地带来了不对称的烯烃卤化反应。为此，我们将通过采用多方面的方法来定义和解决与这种转变相关的众多挑战。我们将首先提出直接的理论手段，以通过将Halenium亲和力（HALA）定义为前所未有的参数来预测烯烃卤素反应的易度性。将通过实验验证烯烃卤素化学和区域选择性的结果预测，然后进一步应用于发现非直觉（但功能强大的）转化，从而排除了对试验和错误方法的需求。我们建议通过不对称的烷烃卤素化反应来开发有价值的手性杂环，例如环状硫酸盐，咪唑啉，氢接胺，哌啶，哌啶，哌啶，哌啶，哌啶和阿恶嗪杂环；利用各种C-，O-和N-核噬菌体（芳基环，醇，磺酰胺，磺酰胺，鸟胺，第三纪酰胺和乙酰酰胺剂等）的烯烃反应将进行研究。将追求新型烯烃与各种亲核试剂的盐功能化的新型不对称间变体的发展。最后，我们将介绍将开发烯烃卤化反应的例子，以便能够提供最有效的手段，以访问天然产物中发现的某些脚手架。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中汲取灵感，以追求obtusin，Napyradiomycin A1和相关类似物的总合成，以及Calophyline A，以及Calophyline A。这些都会挑战我们以开发必要的卤代基准反应以产生有效的合成。总体目标是开发不对称的烯烃卤化化学，作为一种工具，以实现目前难以或不切实际地使用其他方式构建的战略粘结反应。