While metal insertion into, and subsequent functionalization of, sp3 C?H bonds has the potential to afford transformative tools in synthesis, the impact of this approach on asymmetric catalysis has been moderate due to a number of unanswered challenges encountered in the development of asymmetric version of these reactions. This proposal centers on the development of two approaches for enantioselective C?H activation reactions of broadly useful substrates: (A) the design of bisdentate chiral ligands and (B) catalytic chiral directing groups. We will develop enantioselective C?H activation reactions of ?-methyl C?H bonds and methylene C?H bonds of carboxylic acids and carboxylate derived substrates, as well as ?-C?H bonds of amines and amine derived substrates. These reactions will provide novel and versatile methodologies for constructing ?-, ?-, and ?-chiral centers in asymmetric synthesis. The use of abundant and common substrates, as well as the diversity of the transformations will render palladium-catalyzed enantioselective C?H functionalization broadly useful for the synthesis of bioactive chiral molecules. Specifically, desymmetrization of isobutyric and pivalic acids via enantioselective C?H activation will be applied to the generation of a library of novel serine hydrolase inhibitors that can be evaluated by activity-based protein profiling to identify new drug leads for diabetes, cognitive dementia and bacterial infection.
This proposal centers on development of enantioselective sp3 C?H activation reactions of readily available carboxylic acids, ketones and amines. These reactions provide new disconnections for constructing ?-, ?- and ?-chiral centers that are broadly useful in asymmetric syntheses of chiral bioactive compounds and drug molecules. In a collaborative effort, these new chiral technologies are applied to the discovery of promising new drug candidates for the treatment of human diseases.
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| Saint-Denis, Tyler G; Zhu, Ru-Yi; Chen, Gang et al. (2018) Enantioselective C(sp3)?H bond activation by chiral transition metal catalysts. Science 359: |
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| Zhu, Ru-Yi; Li, Zi-Qi; Park, Han Seul et al. (2018) Ligand-Enabled ?-C(sp3)-H Activation of Ketones. J Am Chem Soc 140:3564-3568 |
| Wu, Qing-Feng; Wang, Xiao-Bing; Shen, Peng-Xiang et al. (2018) Enantioselective C-H Arylation and Vinylation of Cyclobutyl Carboxylic Amides. ACS Catal 8:2577-2584 |
| Park, Hojoon; Verma, Pritha; Hong, Kai et al. (2018) Controlling Pd(IV) reductive elimination pathways enables Pd(II)-catalysed enantioselective C(sp3)-H fluorination. Nat Chem : |
| Shao, Qian; Wu, Qing-Feng; He, Jian et al. (2018) Enantioselective ?-C(sp3)-H Activation of Alkyl Amines via Pd(II)/Pd(0) Catalysis. J Am Chem Soc 140:5322-5325 |
| Zhu, Ru-Yi; Liu, Luo-Yan; Park, Han Seul et al. (2017) Versatile Alkylation of (Hetero)Aryl Iodides with Ketones via ?-C(sp3)-H Activation. J Am Chem Soc 139:16080-16083 |
| Fu, Haiyan; Shen, Peng-Xiang; He, Jian et al. (2017) Ligand-Enabled Alkynylation of C(sp3 )-H Bonds with Palladium(II) Catalysts. Angew Chem Int Ed Engl 56:1873-1876 |
| Pei, Qing-Lan; Che, Guan-Da; Zhu, Ru-Yi et al. (2017) An Epoxide-Mediated Deprotection Method for Acidic Amide Auxiliary. Org Lett 19:5860-5863 |
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