Stereoselective Photochemistry for the Synthesis of Bioactive Molecules

立体选择性光化学合成生物活性分子

• 批准号: 10297483
• 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
• 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
• 来源: https://reporter.nih.gov/project-details/10297483
• 关键词: Acids; Alkylating Agents; Alkylation; Amines; Benign; Biological; Catalysis; Chemicals; Complement; Complex; Coupling; Development; Disease; Electrons; Energy-Generating Resources; Event; Generations; Goals; Health; Human; Hydrocarbons; Imines; Laboratories; Medicine; Methods; Molecular Conformation; Natural Products; Nitrogen; Periodicity; Pharmaceutical Preparations; Pharmacologic Substance; Photochemistry; Reaction; Reagent; Research; Salts; Structure; Visible Radiation; base; biological systems; carbonyl compound; charge transfer complex; chemical reaction; chiral molecule; enolate; functional group; innovation; interest; novel; novel strategies; programs; small molecule; tool

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提供了获得化学物质的途径，从而改变了人类的医学 研究生物系统的工具和治疗疾病的药物。尽管有几种方法可用于 合成具有生物价值的手性分子，在概念上有很大的发现潜力 催化立体选择性合成已知不容易获得的分子的新策略 方法：研究方法。我们对开发催化立体选择性光化学反应特别感兴趣 对于产生具有生物价值的手性产品是有用的，但传统上被认为是 不受不对称催化的影响。这些创新策略将补充目前已知的方法 在不对称光化学中。我们建议开发一个通用的平台，用于对映体选择性α-烷基化。 含吡啶盐的羰基化合物和亚胺的不对称C-H烷基化反应的新方法。 我们对这一研究计划的长期目标包括发现通用的和强大的战略 简单原料催化转化为结构复杂、生物活性小分子 分子。我们还预计，这些方法将挑战关于化学反应的既定观点 多年来，人们一直在讨论某些类别的光化学反应。通过利用可持续的资源 能源(如低能可见光)，立体选择光化学中的新策略 我们的实验室将提供一种环境友好的替代方法，以获得与药物相关的手性 用其他方法不易合成的富含对映体的分子。 在具体目标1中，我们建议开发一个通用的平台，用于催化不对称α-烷基化反应。 由容易获得的伯胺衍生的吡啶盐作为烷基化试剂的羰基化合物。 这个特定的目标是由一个假设指导的，即贫电子的吡啶盐可以形成基态电荷-- 与催化生成的富含电子的手性烯酸酯等效物的转移络合物。这些复合体可以 然后在低能量可见光存在的情况下进行立体选择性耦合。从长远来看，我们将 光化学催化对映选择性α-烷基化反应通用平台的建立 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烷基化反应。这一具体目标是由这样的假设指导的，即在 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胺。 通过加速亚胺底物与各种化合物之间的偶联事件来获得高立体选择性的产品 碳氢化合物烷基化试剂。从长远来看，我们将开发一种通用的光化学方法 亚胺与多种碳氢底物通过不同方式的不对称C-H烷基化反应 激活的结果。