Numerous pharmaceuticals contain at least one nitrogen atom and many of those nitrogen atoms are directly attached to stereogenic centers. Therefore, synthetic methods that incorporate selective nitrogen atom transfer to readily available hydrocarbons are important tools for the synthesis of these valuable molecules. While methods for selective olefin aziridination and direct C-H amination are well-established, methods for direct difunctionalization of olefins with a nitrogen atom and a range of heteroatom-based functional groups are less explored yet critically important to organic synthesis and its applications to the biomedical sciences. In particular, a general and selective nitrogen atom transfer approach that can achieve the aminohydroxylation, aminofluorination, and aminohalogenation of a wide variety of olefins has yet to be discovered. Our long-term goal is to develop selective and general nitrogen atom transfer methods that directly difunctionalize a wide variety of olefins with a nitrogen and a range of heteroatom-based functional groups. The objective of the proposed research is to develop a series of iron-catalyzed nitrogen atom transfer methods for direct olefin difunctionalization with an emphasis on aminohydroxylation, aminofluorination, and aminohalogenation. Based upon our preliminary discoveries, our underlying hypothesis is that a unique iron- nitrenoid can be modulated to mediate a range of olefin difunctionalization reactions rather than only precedent aziridination and C-H amination reactions. The proposed research will explore this hypothesis in the context of two Specific Aims. First, we plan to develop iron-catalyzed, selective aminohydroxylation methods that will incorporate a variety of olefin and heteroarene substrates for synthesis of amino alcohols and b-hydroxyl amino acids. Second, we will develop iron-catalyzed, selective aminofluorination and aminohalogenation methods for a range of olefins that will afford b-fluoro, chloro, and bromo amines as well as b-fluoro and chloro amino acids. The proposed approach is innovative because it explores the new reactivity of an iron-nitrenoid in a context that significantly departs from the established reactivity of metal-nitrenoids. The proposed research is significant because it will lay the foundation for the development of a wide range of methods for selective olefin difunctionalization from the same type of reactive intermediate generated from a first-row transition metal. Completion of the proposed research will provide an array of unique olefin difunctionalization methods that would become valuable tools for medicinal chemists. Furthermore, it will also produce a variety of valuable synthetic building blocks and biologically important molecules that will accelerate the basic biomedical and clinical research.

Public Health Relevance

Numerous pharmaceuticals and small-molecule biological probes are synthetic agents and many of them contain at least one nitrogen atom; therefore, the subject of this proposal-discovery of novel synthetic methods for efficient synthesis of these nitrogen- containing molecules will advance drug discoveries as well as the basic biomedical and clinical research.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Lees, Robert G
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Georgia State University
Schools of Arts and Sciences
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Zhu, Cheng-Liang; Wang, Cheng; Qin, Qi-Xue et al. (2018) Iron(II)-Catalyzed Azidotrifluoromethylation of Olefins and N-Heterocycles for Expedient Vicinal Trifluoromethyl Amine Synthesis. ACS Catal 8:5032-5037
Shen, Shou-Jie; Zhu, Cheng-Liang; Lu, Deng-Fu et al. (2018) Iron-Catalyzed Direct Olefin Diazidation via Peroxyester Activation Promoted by Nitrogen-Based Ligands. ACS Catal 8:4473-4482
Li, Hongze; Shen, Shou-Jie; Zhu, Cheng-Liang et al. (2018) Enantioselective Synthesis of Oseltamivir Phosphate (Tamiflu) via the Iron-Catalyzed Stereoselective Olefin Diazidation. J Am Chem Soc 140:10619-10626
Zhu, Hai-Tao; Arosio, Luca; Villa, Roberto et al. (2017) Process Safety Assessment of the Iron-Catalyzed Direct Olefin Diazidation for the Expedient Synthesis of Vicinal Primary Diamines. Org Process Res Dev 21:2068-2072
Lu, Deng-Fu; Zhu, Cheng-Liang; Sears, Jeffrey D et al. (2016) Iron(II)-Catalyzed Intermolecular Aminofluorination of Unfunctionalized Olefins Using Fluoride Ion. J Am Chem Soc 138:11360-7
Zhu, Cheng-Liang; Lu, Deng-Fu; Sears, Jeffrey D et al. (2016) Practical Synthetic Procedures for the Iron-Catalyzed Intermolecular Olefin Aminohydroxylation Using Functionalized Hydroxylamines. Synthesis (Stuttg) 48:3031-3041
Yuan, Yong-An; Lu, Deng-Fu; Chen, Yun-Rong et al. (2016) Iron-Catalyzed Direct Diazidation for a Broad Range of Olefins. Angew Chem Int Ed Engl 55:534-8
Tian, Jun-Shan; Zhu, Cheng-Liang; Chen, Yun-Rong et al. (2015) Iron-Catalyzed Diastereoselective Intramolecular Olefin Aminobromination with Bromide Ion. Synthesis (Stuttg) 47:1709-1715
Zhu, Cheng-Liang; Zhang, Yong-Qiang; Yuan, Yong-An et al. (2015) Copper-Catalyzed Aerobic C-H Trifluoromethylation of Phenanthrolines. Synlett 26:345-349
Zhu, Cheng-Liang; Tian, Jun-Shan; Gu, Zhen-Yuan et al. (2015) Iron(II)-catalyzed asymmetric intramolecular olefin aminochlorination using chloride ion. Chem Sci 6:3044-3050

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