New Catalytic Systems for Stereoselective C-H Amination

描述（由申请人提供）：一般和有效的化学反应的发展为设计和合成生物学和药学上重要的分子提供了必要的工具。由于对映异构体常常表现出不同的生物活性，因此越来越重视发展合成对映异构体纯化合物的实用方法。与外消旋混合物相比，除其他临床益处外，使用对映体纯化合物可改善所需的活性并降低毒性。因此，食品和药物管理局要求在提交批准之前对新的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各种方法中，过渡金属基不对称催化为开发成本效益高、环境友好的方法提供了希望。在当今的制药工业中，单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催化工艺的需求日益增长。通过插入亚硝基的催化碳氢胺化反应是一类最重要的化学转化。这种类型的催化硝基转移过程为丰富的碳氢化合物中通过立体选择性碳氮键形成的碳氢键功能化提供了一种直接和通用的方法。它为设计和合成具有重要生物学和药学意义的手性胺分子提供了有价值的工具。本研究项目旨在为立体选择性C-H胺化反应开发新的催化体系。对于这个特殊的提议，我们将重点利用钴（II）手性卟啉配合物[Co(II)(Por*)]作为一类新的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二胺和氨基醇。这些新的催化方法将应用于生物和药学上有趣的含氮分子的立体选择性合成，包括光学活性氨基酸，二氨基酸和含氟氨基酸的抗生素或肿瘤显像剂化合物。我们希望这些研究最终能够开发出实用的Co（II）基催化体系，用于一般的C-H胺化反应，并成功地应用于具有重要生物学意义的天然产物和具有药学意义的小分子的立体选择性合成。

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.