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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）：快速有效地获得不同类别的生物活性先导化合物是药物发现的重要组成部分。不同环尺寸和不同取代模式的杂环构成了寻找生物活性的极其重要的结构类别（例如生物碱）。有机合成中的当代挑战是以原子经济的方式通过串联或级联反应绘制新的化学空间。我们的策略，以获得这些生物学上重要的杂环依赖于环化引发的串联除了炔催化的容易获得的亲炔金属如铜，通过亲电活化的烯胺中间体。我们的串联化学将使我们能够产生生物学上重要的N-杂环，如环状氨基酸，其设施是以前的方法无法比拟的。在我们的前期工作中，我们通过胺化/炔基化序列和串联胺化/氰化以接近定量的产率合成了各种氮杂环，所有这些都是在一锅中进行的。我们的研究计划将大大扩大这一战略的范围。该提案的主要部分侧重于探索这些多功能串联变换的化学空间，通过改变变换的组成部分，并将其应用于生物学上重要的杂环的合成。我们计划1）探索串联序列中的亲核试剂; 2）开发不对称版本; 3）寻找瞬时环状烯胺的替代作用。所提出的工作是重要的，原因如下：首先，在N-杂环上具有官能化基团将使得能够进一步转化，从而产生更复杂的环系统（方案1）。第二，这个提议的原则之一--将烯胺转化为良好的亲电试剂--将阐明烯胺作为亲电试剂的相对模糊的作用。第三，除了带来有效的方法来产生各种环大小（5-7）和不同的碳连接（稠合，桥接，螺环）的N-杂环，这项工作将产生数十种新的化合物，这些化合物将由礼来公司在其阿尔茨海默病，癌症和糖尿病的药物发现计划中筛选。公共卫生相关性：不同环尺寸和不同取代模式的氮环系统构成了寻找候选药物的极其重要的结构线索。在这方面，生物碱是代表性的例子。我们已经发现了一个强大的战略，以获得许多重要的N-杂环，通过环化触发的串联协议，依赖于过渡金属催化的亲电激活的烯胺中间体。这项工作将提供单-，稠-桥-或螺-杂环系统，包括生物学上重要的非天然环状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.