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的机会改变了人类医学研究生物系统和药物治疗疾病的工具。尽管存在几种方法生物有价值的手性分子的合成，从概念上发现很大的潜力催化中的新策略，用于不容易被已知分子的立体选择性合成方法。我们对开发催化立体选择光化学反应特别感兴趣对于生物有价值的手性产品的生成很有用，但传统上被认为是与不对称催化无关。这些创新的策略将完成当前的已知方法在非对称光化学中。我们建议开发一个通用平台，用于对映选择性A烷基化带有吡啶盐的羰基化合物和一种新方法，用于鉴定亚胺的C – H烷基化。我们对该研究计划的长期目标包括发现一般和强大的策略将简单的起始材料催化转化为结构复杂和生物活性的小分子。我们还预计，这些方法将挑战既定的化学反应性观点多年来，已经对某些类别的光化学反应进行了持有。通过使用可持续来源能量（例如低能可见光），立体选择光化学中的新策略由我们的实验室将提供一种环境良性的替代方案，以获取与药物相关的手性其他方法不容易合成的对映体分子。在特定目标1中，我们建议开发一个通用平台，以催化对映射的A烷基化含吡啶盐的羰基化合物源自烷基化试剂，衍生自原代胺作为烷基化试剂。这一特定目的是通过以下假设来指导的，即电子较差的吡啶盐可以形成地面电荷 - 用催化产生的富电子手性腐蚀等效物转移复合物。这些复合物可以然后在低能可见光存在下进行立体选择耦合。从长远来看，我们将开发一个通用平台，用于羰基化合物的光化学催化对映选择性A烷基化基于多种不对称催化模式的吡啶盐盐。在特定的目标2中，我们建议开发一个依赖对映射胺的一般平台通过无环亚胺的光化学C – H烷基化。在存在可见光的存在，亚化学计量量的手性刘易斯酸可以提供映射的胺通过加速亚胺基板和各种耦合事件，具有高立体选择性的产品烃烷基化剂。从长远来看，我们将为光化学开发一种一般方法通过不同模式，具有广泛碳氢化合物底物的亚胺的对映选择性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

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

DOI：
10.1021/ol4025937
发表时间：
2013-09
期刊：
Organic letters
影响因子：
5.2
作者：
A. Soheili;U. Tambar
通讯作者：
A. Soheili;U. Tambar

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