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Stereoselective Photochemistry for the Synthesis of Bioactive Molecules

立体选择性光化学合成生物活性分子

基本信息

批准号：
10624356
负责人：
UTTAM Krishan TAMBAR
金额：
$ 33.86万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
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：
2012-09-01 至 2025-05-31
项目状态：
未结题

项目摘要

Stereoselective chemical reactions have transformed human medicine by providing access to chemical tools to study biological systems and pharmaceutical drugs to treat disease. Although several methods exist for the synthesis of biologically valuable chiral molecules, there is great potential for discovering conceptually novel strategies in catalysis for the stereoselective synthesis of molecules not easily accessed by known methods. We are particularly interested in developing catalytic stereoselective photochemical reactions that are useful for the generation of biologically valuable chiral products but have been traditionally thought to be unamenable to asymmetric catalysis. These innovative strategies will complement the current known methods in asymmetric photochemistry. We propose to develop a general platform for enantioselective a-alkylations of carbonyl compounds with pyridinium salts and a new approach to enantioselective C–H alkylations of imines. Our long-term goals for this research program include the discovery of general and robust strategies for the catalytic conversion of simple starting materials into structurally complex and biologically active small molecules. We also anticipate that these methods will challenge established opinions of chemical reactivity that have been held about certain classes of photochemical reactions for years. By utilizing sustainable sources of energy (such as low energy visible light), the new strategies in stereoselective photochemistry discovered by our laboratory will provide an environmentally benign alternative to access medicinally relevant chiral enantioenriched molecules that are not easily synthesized by other methods. In Specific Aim 1, we propose to develop a general platform for the catalytic enantioselective a-alkylation of carbonyl compounds with pyridinium salts derived from readily available primary amines as alkylating reagents. This specific aim is guided by the hypothesis that electron poor pyridinium salts can form ground-state charge- transfer complexes with catalytically generated electron rich chiral enolate equivalents. These complexes can then undergo stereoselective couplings in the presence of low energy visible light. In the long-term, we will develop a general platform for the photochemical catalytic enantioselective a-alkylation of carbonyl compounds with pyridinium salts based on several modes of asymmetric catalysis. In Specific Aim 2, we propose to develop a general platform for the synthesis of enantioenriched amines via the photochemical C–H alkylation of acyclic imines. This specific aim is guided by the hypothesis that in the presence of visible light, a sub-stoichiometric amount of chiral Lewis acid can furnish enantioenriched amine products with high stereoselectivity by accelerating the coupling event between an imine substrate and various hydrocarbon alkylating agents. In the long-term, we will develop a general approach for the photochemical enantioselective C–H alkylation of imines with a broad range of hydrocarbon substrates through distinct modes of activation.

立体选择性化学反应通过提供化学物质的途径改变了人类医学研究生物系统和治疗疾病的药物的工具。尽管存在多种方法具有生物价值的手性分子的合成，在概念上具有巨大的发现潜力催化立体选择性合成已知分子不易获得的分子的新策略方法。我们对开发催化立体选择性光化学反应特别感兴趣可用于产生具有生物价值的手性产物，但传统上被认为是不适合不对称催化。这些创新策略将补充当前已知的方法在不对称光化学中。我们建议开发一个用于对映选择性α-烷基化的通用平台吡啶鎓盐的羰基化合物以及亚胺对映选择性 C-H 烷基化的新方法。我们这项研究计划的长期目标包括发现通用且稳健的策略将简单的起始原料催化转化为结构复杂且具有生物活性的小分子物质分子。我们还预计这些方法将挑战化学反应性的既定观点多年来，人们对某些类型的光化学反应进行了研究。通过利用可持续资源能量（如低能可见光），立体选择性光化学的新策略我们的实验室将提供一种环境友好的替代品来获取医学相关的手性化合物不易通过其他方法合成的对映体富集分子。在具体目标 1 中，我们建议开发一个用于催化对映选择性α-烷基化的通用平台羰基化合物与吡啶鎓盐衍生自易于获得的伯胺作为烷基化试剂。这一具体目标是以贫电子吡啶鎓盐可以形成基态电荷这一假设为指导的。与催化产生的富电子手性烯醇化物当量的转移络合物。这些复合物可以然后在低能量可见光存在下进行立体选择性耦合。从长远来看，我们将开发羰基化合物光化学催化对映选择性α-烷基化的通用平台基于几种不对称催化模式的吡啶鎓盐。在具体目标 2 中，我们建议开发一个用于合成对映体富集胺的通用平台通过无环亚胺的光化学C-H烷基化。这一具体目标是以这样的假设为指导的：在可见光存在下，亚化学计量的手性路易斯酸可以提供对映体富集的胺通过加速亚胺底物与各种物质之间的偶联事件，获得具有高立体选择性的产品烃类烷基化剂。从长远来看，我们将开发光化学的通用方法通过不同的模式用多种烃底物对亚胺进行对映选择性 C-H 烷基化的激活。

项目成果

期刊论文数量（32）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Catalytic allylic oxidation of internal alkenes to a multifunctional chiral building block.

DOI：
10.1038/nature22805
发表时间：
2017-07-13
期刊：
Nature
影响因子：
64.8
作者：
Bayeh L;Le PQ;Tambar UK
通讯作者：
Tambar UK

N-Heterocyclic carbene based catalytic platform for Hauser-Kraus annulations.

DOI：
10.1039/d0sc03116j
发表时间：
2020-06-30
期刊：
Chemical science
影响因子：
8.4
作者：
Sharique M;Tambar UK
通讯作者：
Tambar UK

Total Synthesis of (+)-Rubellin C.

DOI：
10.1021/acs.orglett.0c02127
发表时间：
2020-12-04
期刊：
Organic letters
影响因子：
5.2
作者：
Gartman JA;Tambar UK
通讯作者：
Tambar UK

Copper-Catalyzed Regiodivergent Internal Allylic Alkylations.

铜催化区域发散的内部烯丙基烷基化。

DOI：
10.1002/anie.202304848
发表时间：
2023
期刊：
Angewandte Chemie (International ed. in English)
影响因子：
0
作者：
Manna,MadhuSudan;Yoo,SeokYeol;Sharique,Mohammed;Choi,Hyoju;Pudasaini,Bimal;Baik,Mu-Hyun;Tambar,UttamK
通讯作者：
Tambar,UttamK

Synthesis of (±)-amathaspiramide F and discovery of an unusual stereocontrolling element for the [2,3]-Stevens rearrangement.