New Catalytic Systems for Stereoselective C-H Amination

用于立体选择性 C-H 胺化的新型催化系统

• 批准号: 8297064
• 负责人: X. Peter ZHANG
• 金额: $ 25.51万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8297064
• 关键词: Acids; Address; Amination; Amines; Amino Acids; Amino Alcohols; Antibiotics; Azides; Benign; Biological; Biological Factors; Catalysis; Chemicals; Clinical; Cobalt; Complex; Development; Diamines; Diamino Amino Acids; Drug Industry; Electrons; Evaluation; Exhibits; Fluorine; Gases; Goals; Hydrocarbons; Hydrogen Bonding; Image; Isomerism; Lead; Ligands; Marketing; Metals; Methodology; Methods; Nature; Nitrogen; Oxidants; Pharmaceutical Preparations; Porphyrins; Process; Reaction; Reagent; Research; Research Project Grants; Source; Stress; System; Toxic effect; Transition Elements; United States Food and Drug Administration; base; carboxylate; catalyst; chemical reaction; cost effective; design; direct application; enantiomer; improved; interest; nitrene; small molecule; tool; tumor

DESCRIPTION (provided by applicant): The development of general and efficient chemical reactions provides the necessary tools for the design and synthesis of biologically and pharmaceutically important molecules. There has been a growing emphasis on developing practical methodologies for the synthesis of enantiomerically pure compounds, since enantiomeric isomers often exhibit different biological activities. Compared to a racemic mixture, the use of an enantiomerically pure compound improves the desired activity and reduces toxicity in addition to other clinical benefits. Consequently, the Food and Drug Administration requires the evaluation of both enantiomers of new chiral drugs before they can be submitted for approval. Among different approaches for preparing chiral non-racemic molecules, transition metal-based asymmetric catalysis offers promise for the development of cost-effective and environmentally benign methods. In today's pharmaceutical industry, where the market share of single enantiomer chiral drugs continues to rise, there are growing demands for new powerful stereoselective catalytic processes. Catalytic C-H amination via nitrene insertion represents one of the most important classes of chemical transformations. This type of catalytic nitrene transfer process provides a direct and general approach for the functionalization of C-H bonds in abundant hydrocarbons through stereoselective C-N bond formation. It serves as a valuable tool for the design and synthesis of biologically and pharmaceutically important chiral amine molecules. This research project is directed toward the development of new catalytic systems for stereoselective C-H amination reactions. For this particular proposal, we will focus on the utilization of cobalt(II) chiral porphyrin complexes [Co(II)(Por*)] as a class of new chiral catalyts to advance the enantioselective C-H amination reactions for stereoselective synthesis of valuable diamines and amino alcohols. These new catalytic methods will be applied to the stereoselective synthesis of biologically and pharmaceutically interesting nitrogen-containing molecules, including optically active amino acid-, diamino acid-, and fluoridated amino acid-based compounds that are antibiotics or tumor imaging agents. We hope these studies will ultimately lead to the development of practical Co(II)-based catalytic systems for general C-H amination reactions that can be successfully applied toward the stereoselective synthesis of biologically important natural products and pharmaceutically interesting small molecules. PUBLIC HEALTH RELEVANCE: This proposed research is directed toward the development of general and efficient chemical reactions that will provide the necessary tools for the design and synthesis of biologically and pharmaceutically important molecules. There has been a growing emphasis to develop practical methodologies for the synthesis of enantiomerically pure compounds, since enantiomeric isomers often exhibit different biological activities. Compared to a racemic mixture, the use of an enantiomerically pure compound improves the desired activity and reduces toxicity, in addition to other clinical benefits. Consequently, the Food and Drug Administration requires the evaluation of both enantiomers of new chiral drugs before they can be submitted for approval.

描述（由申请人提供）：通用且有效的化学反应的发展为生物和药学重要分子的设计和合成提供了必要的工具。人们越来越重视开发合成对映体纯化合物的实用方法，因为对映体异构体通常表现出不同的生物活性。与外消旋混合物相比，使用对映体纯的化合物除了具有其他临床益处外，还可提高所需的活性并降低毒性。因此，美国食品和药物管理局要求在提交批准之前对新手性药物的两种对映体进行评估。在制备手性非外消旋分子的不同方法中，基于过渡金属的不对称催化为开发具有成本效益且环境友好的方法提供了希望。在当今的制药行业，单一对映体手性药物的市场份额不断上升，对新型强大的立体选择性催化过程的需求不断增长。通过氮宾插入进行的催化 C-H 胺化代表了最重要的化学转化类别之一。这种类型的催化氮宾转移过程为通过立体选择性 C-N 键形成来功能化丰富的碳氢化合物中的 C-H 键提供了直接且通用的方法。它是设计和合成生物学和药学上重要的手性胺分子的宝贵工具。该研究项目旨在开发用于立体选择性 C-H 胺化反应的新型催化系统。对于这个特别的提案，我们将重点关注利用钴(II)手性卟啉配合物[Co(II)(Por*)]作为一类新型手性催化剂来推进对映选择性C-H胺化反应，以立体选择性合成有价值的二胺和氨基醇。这些新的催化方法将应用于生物和药学上感兴趣的含氮分子的立体选择性合成，包括作为抗生素或肿瘤显像剂的光学活性氨基酸、二氨基酸和氟化氨基酸基化合物。我们希望这些研究最终能够开发出用于一般 C-H 胺化反应的实用 Co(II) 基催化系统，该系统可以成功应用于生物学上重要的天然产物和药学上有趣的小分子的立体选择性合成。 公共健康相关性：这项拟议的研究旨在开发通用且有效的化学反应，为生物和药学重要分子的设计和合成提供必要的工具。由于对映体异构体通常表现出不同的生物活性，因此人们越来越重视开发合成对映体纯化合物的实用方法。与外消旋混合物相比，使用对映体纯的化合物除了具有其他临床益处外，还可提高所需的活性并降低毒性。因此，美国食品和药物管理局要求在提交批准之前对新手性药物的两种对映体进行评估。