Transition metal catalyzed construction of ring systems

过渡金属催化构建环系

基本信息

批准号：
8290765
负责人：
GERALD B HAMMOND
金额：
$ 33.51万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-06-01 至 2016-11-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Quick and efficient access to diverse classes of biologically active lead compounds is an essential part of drug discovery. Heterocycles of different ring sizes and with different substitution patterns constitute extremely important structure classes (e.g. alkaloids) in the search for bioactivity. A contemporary challenge in organic synthesis is the mapping of new chemical spaces through tandem or cascade reactions in an atom economical fashion. Our strategy to access these biologically important heterocycles relies on a cyclization-triggered tandem addition to alkynes catalyzed by readily available alkynophilic coinage metals like copper, through an electrophilic activation of the enamine intermediate. Our tandem chemistry will enable us to generate biologically important N-heterocycles like cyclic aminoacids with a facility unmatched by previous methods. During our preliminary work, we synthesized various nitrogen heterocycles through an amination/alkynylation sequence and a tandem amination/cyanation in near quantitative yields, all in one pot. Our research plan will expand the scope of this strategy substantially. The major part of this proposal focuses on exploring the chemical space of these versatile tandem transformations by changing the components of the transformation and applying them to the synthesis of biologically important heterocycles. We plan to 1) explore nucleophiles in tandem sequences; 2) develop an asymmetrical version; 3) seek alternative roles for transient cyclic enamines. The proposed work is significant for the following reasons: first, having a functionalized group on the N-heterocycle will enable further transformations, resulting in more complex ring systems (Scheme 1). Second, one of the tenets of this proposal--transforming an enamine into a good electrophile--will shed light on the relatively obscure role of enamines as electrophiles. Third, beyond bringing about efficient ways to generate N-heterocycles of various ring sizes (5-7) and diverse carbon connectivities (fused, bridged, spiro), this work will produce scores of new compounds that will be screened by Eli Lilly in their drug discovery program for Alzheimer's disease, cancer, and diabetes. PUBLIC HEALTH RELEVANCE: Nitrogen ring system of different ring sizes and with various substitution patterns constitute extremely important structure leads in the search for drug candidates. In this regard, alkaloids are representative examples. We have discovered a powerful strategy to access many important N-heterocycles, through a cyclization triggered tandem protocol that relies on a transition metal-catalyzed electrophilic activation of the enamine intermediate. The proposed work will furnish single-, fused- bridged- or spiro-heterocyclic systems, including biologically important unnatural cyclic aminoacids and fluorinated ring systems.

描述（由申请人提供）：快速有效地访问不同类别的生物活性铅化合物是药物发现的重要组成部分。在寻找生物活性时，不同环尺寸和不同替代模式的杂环构成了极为重要的结构类别（例如生物碱）。有机合成中的当代挑战是以原子经济方式通过串联或级联反应映射新的化学空间。我们进入这些生物学上重要的杂环的策略依赖于环化触发的串联串联串联添加到炔烃（如铜等随时可用的藻类金属）所催化的，这些金属（如铜金属）通过烯胺中间体的亲电激活。我们的串联化学将使我们能够生成具有生物学上重要的N型核体，例如循环氨基酸氨基酸，具有先前方法无与伦比的设施。在我们的初步工作中，我们通过胺化/藻类序列和几乎定量产量的串联胺化/cyanation合成了各种氮杂环。我们的研究计划将大大扩大该策略的范围。该提案的主要部分着重于通过改变转化的组成部分并将其应用于生物学上重要的杂环的合成来探索这些多功能串联转化的化学空间。我们计划1）以串联序列探索亲核试剂； 2）开发不对称版本； 3）寻求瞬态循环膜源的替代作用。由于以下原因，提出的工作很重要：首先，在N-杂环上具有官能化的组将实现进一步的转换，从而导致更复杂的环系统（方案1）。其次，该提案的宗旨之一 - 将搪瓷转化为良好的电力机脚 - 将阐明磁胺作为电力的相对晦涩的作用。第三，除了提出有效的方法来产生各种环尺寸（5-7）和多样的碳连接性（融合，桥接，螺旋罗）的N杂环外，这项工作还将产生许多新化合物，这些新化合物将由Eli Lilly在其阿尔茨海默氏病，癌症和糖尿病的药物发现计划中筛查，这些新化合物将在其药物发现计划中进行筛查。公共卫生相关性：不同环尺寸和各种替代模式的氮气环系统构成了非常重要的结构，在寻找候选药物时。在这方面，生物碱是代表性的例子。我们通过触发的串联协议发现了一种强大的策略，可以访问许多重要的N-杂环，该协议依赖于磁胺中间体的过渡金属催化的亲电激活。拟议的工作将提供单个融合的桥接或螺旋 - 型型系统系统，包括生物学上重要的不自然循环氨基酸和氟化环系统。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Synthesis of Cyclic α-Aminophosphonates through Copper Catalyzed Enamine Activation.

DOI：
10.1055/s-0032-1317984
发表时间：
2013-02-01
期刊：
Synthesis
影响因子：
0
作者：
Han J;Paton RS;Xu B;Hammond GB
通讯作者：
Hammond GB

Synthesis of Pyrrolidines and Pyrroles via Tandem Amination/Cyanation/Alkylation and Amination/Oxidation Sequences.

DOI：
10.1002/ejoc.201402748
发表时间：
2014-09-01
期刊：
EUROPEAN JOURNAL OF ORGANIC CHEMISTRY
影响因子：
2.8
作者：
Han, Junbin;Lu, Zhichao;Hammond, Gerald B.;Xu, Bo
通讯作者：
Xu, Bo

Achieving regio- and stereo-control in the fluorination of aziridines under acidic conditions.

DOI：
10.1039/c6cc07855a
发表时间：
2016-11-08
期刊：
Chemical communications (Cambridge, England)
影响因子：
0
作者：
Okoromoba OE;Li Z;Robertson N;Mashuta MS;Couto UR;Tormena CF;Xu B;Hammond GB
通讯作者：
Hammond GB

Designer HF-based fluorination reagent: highly regioselective synthesis of fluoroalkenes and gem-difluoromethylene compounds from alkynes.