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。在寻找生物活性时，不同环大小和不同取代模式的杂环构成极其重要的结构类别（例如生物碱）。有机合成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。我们获得这些生物学上重要的杂环的策略依赖于环化引发的串联加成，通过烯胺中间体的亲电子活化，由容易获得的亲炔造币金属（如铜）催化的炔烃。我们的串联化学将使我们能够以以前的方法无法比拟的设施生成生物学上重要的N-杂环，例如环状氨基酸。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/氰化以接近定量的收率合成了各种氮杂环，所有这些都在一锅中进行。我们的研究计划将大大扩展该战略的范围。该提案的主要部分侧重于通过改变转化的成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) 探索串联序列中的亲核试剂； 2）开发非对称版本； 3）寻找瞬态环状烯胺的替代作用。拟议的工作具有重要意义，原因如下：首先，N-杂环上有一个官能团将能够进行进一步的转化，从而产生更复杂的环系统（方案1）。其次，该提案的宗旨之一——将烯胺转化为良好的亲电子试剂——将揭示烯胺作为亲电子试剂相对模糊的作用。第三，除了提供产生各种环尺寸（5-7）和不同碳连接（稠合、桥连、螺环）的 N-杂环的有效方法之外，这项工作还将产生数十种新化合物，礼来公司将在其研究中对这些化合物进行筛选。针对阿尔茨海默病、癌症和糖尿病的药物发现计划。公共卫生相关性：不同环大小和不同取代模式的氮环系统构成了寻找候选药物中极其重要的结构线索。在这方面，生物碱是代表性的例子。我们发现了一种强大的策略来获取许多重要的N-杂环，通过环化触发的串联方案，该方案依赖于过渡金属催化的烯胺中间体的亲电子活化。拟议的工作将提供单环、稠合桥环或螺杂环系统，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.

通过铜催化烯胺活化合成环状α-氨基膦酸盐。

DOI：
发表时间：
2013-02-01
期刊：
影响因子：
0
作者：
Han, Junbin;Paton, Robert S;Xu, Bo;Hammond, Gerald B
通讯作者：
Hammond, Gerald B

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

在酸性条件下实现氮丙啶氟化的区域和立体控制。

DOI：
发表时间：
2016-11-08
期刊：
影响因子：
0
作者：
Okoromoba, Otome E;Li, Zhou;Robertson, Nicole;Mashuta, Mark S;Couto, Uenifer R;Tormena, Cláudio F;Xu, Bo;Hammond, Gerald B
通讯作者：
Hammond, Gerald B

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

设计基于 HF 的氟化试剂：从炔烃中高度区域选择性合成氟代烯烃和偕二氟亚甲基化合物。