Extension of the enantioselective, Cu-catalyzed Henry reaction to a broadly applicable synthetic tool

将对映选择性铜催化亨利反应扩展到广泛适用的合成工具

• 批准号: 407493296
• 负责人: Professor Dr. Matthias Breuning
• 金额: --
• 依托单位: Arbeitsgruppe Organische Chemie I/2
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/407493296?language=en
• 关键词: Extension; enantioselective; Cu; catalyzed; Henry

Enantioselective Henry reactions ( = nitroaldol reaction) are praised in many publications as valuable C,C-bond forming reactions since the resulting ß-nitro alcohols can be easily converted into chiral, multifunctional synthetic building blocks. And indeed, the preconditions for that are excellent, because nowadays highly enantioselective Cu-catalysts exist (including our catalyst) and the possibilities for transforming nitro compounds are manifold. However, the latter reactions have not yet been carried out on chiral Henry products or have only been done on singular examples (exception: reductions to ß-amino alcohols). The huge potential is therefore still unexploited. And this is exactly where our project comes into play:It aims to methodologically expand the enantioselective Henry reaction and, by combination with diverse follow-up reactions of the nitro group, to advance the enantioselective Henry reaction into a powerful, broadly applicable synthetic tool.The following three subgoals are pursued: (1) Extension of the enantioselective Henry reactions to storage-stable alcohols ('oxidative' Henry reactions): This simplifies the experimental efforts and, at the same time, it is the first example of a Cu-catalyzed tandem reaction of the type oxidation–asymmetric C,C-coupling.(2) Combination of the Henry reaction with [3+2]-cycloaddition: The primarily resulting isoxazol(id)ines can be converted into versatile, highly functionalized synthetic building blocks with up to four continuous, in part freely adjustable stereocenters. (3) Combination of the Henry reaction with denitration: This permits access to enantiopure, secondary alcohols with identical inner spheres, which are otherwise difficult to prepare.Preliminary studies have been carried out that prove the fundamental feasibility of all subprojects. On this basis, it is planned to develop robust, broadly useable protocols (methodological part) and to proof their practicability and efficacy through the enantioselective synthesis of several selected natural products and drugs (application-oriented part). These applications cover simpler examples, the syntheses of which permits a direct comparison with other approaches, as well as structurally more complex systems.

对映选择性亨利反应（=硝基醛醇反应）在许多出版物中被称赞为有价值的C，C-键形成反应，因为所得的β-硝基醇可以容易地转化为手性多官能合成结构单元。事实上，这方面的先决条件非常好，因为现在存在高度对映选择性的Cu催化剂（包括我们的催化剂），并且转化硝基化合物的可能性是多种多样的。然而，后面的反应尚未在手性亨利产物上进行，或者仅在单个实例上进行（例外：还原成α-氨基醇）。因此，巨大的潜力尚未开发。本研究的主要目的是在方法学上拓展对映选择性亨利反应，并结合硝基的后续反应，将对映选择性亨利反应发展成为一种功能强大、应用广泛的合成工具，主要研究内容包括：（1）将对映选择性亨利反应扩展到储存稳定的醇类化合物（“氧化”亨利反应）：这简化了实验工作，同时，它是氧化-不对称C，C-偶联类型的Cu催化串联反应的第一个例子。(2)亨利反应与[3+2]-环加成的组合：主要得到的异恶唑（i d）类可以转化为多用途的、高度官能化的合成结构单元，其具有多达四个连续的、部分可自由调节的立体中心。(3)将亨利反应与酯化反应相结合：这使得能够获得具有相同内球的对映体纯仲醇，否则难以制备。已经进行了初步研究，证明了所有子项目的基本可行性。在此基础上，计划制定稳健的、广泛可用的方案（方法部分），并通过对几种选定的天然产物和药物的对映选择性合成来证明其实用性和有效性（面向应用的部分）。这些应用涵盖了简单的例子，其合成允许与其他方法直接比较，以及结构上更复杂的系统。