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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改变了人类医学研究生物系统的工具和治疗疾病的药物。尽管存在几种方法，合成具有生物学价值的手性分子，在概念上发现有很大潜力用于立体选择性合成分子的催化中的新策略不容易被已知的方法获得，方法.我们特别感兴趣的是开发催化立体选择性光化学反应，可用于产生生物学上有价值的手性产物，但传统上认为不适合不对称催化。这些创新的策略将补充目前已知的方法不对称光化学。我们建议开发一个通用的平台，用于对映选择性的α-烷基化反应，羰基化合物与吡啶盐的反应以及亚胺的不对称C-H烷基化反应的新方法。我们这项研究计划的长期目标包括发现一般和强大的战略，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。我们还预计，这些方法将挑战化学反应性的既定观点，关于某些类别的光化学反应的争论已经持续多年。通过利用可持续的能量（如低能量可见光），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方案，不容易通过其它方法合成的对映体富集的分子。在具体目标1中，我们提出开发一个通用的平台，用于催化对映选择性的α-烷基化，羰基化合物与衍生自容易获得的伯胺的吡啶鎓盐作为烷基化试剂。这个特定的目标是由贫电子吡啶鎓盐可以形成基态电荷的假设指导的，具有催化生成的富电子手性烯醇化物等价物的转移络合物。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偶联。从长远来看，我们开发了羰基化合物光催化对映选择性α-烷基化反应的通用平台与基于几种不对称催化模式的吡啶盐反应。在具体目标2中，我们建议开发一个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。这一具体目标的指导假设是，在在可见光存在下，亚化学计量量的手性刘易斯酸可提供对映体富集的胺通过加速亚胺底物和各种化合物之间的偶联事件，烃烷基化剂。从长远来看，我们将开发一种光化学的通用方法，通过不同的模式用广泛的烃底物进行亚胺的对映选择性C-H烷基化激活。

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.