N-Heterocycles are essential components of bioactive structures including pharmaceutical entities. Development of novel and efficient synthesis elaborate N-heterocycles will substantially facilitate drug research and development and academic research. Au catalysis has attracted tremendous attention lately due to the exceptional capacities of Au salts/complexes in activating alkynes/allenes/alkenes. Pt catalysts, mostly PtCl2, have shown similar reactivities. Various highly efficient synthetic methods have been developed, especially in the synthesis of carbocycles of various ring sizes and with an array of structural features. However, Au/Pt-catalyzed preparations of N-heterocycles have been rather lagged behind and are mostly limited to simple N-heterocycles (e.g., pyridines, pyrroles, oxazoles, pyrroline and indoles). The goals of this proposal are to develop efficient synthetic methods for elaborate N- heterocycles and to apply them in synthesis of alkaloids and their analogs. Specifically, there are two aims: A. Development of Au/Pt-catalyzed synthesis of N-heterocycles of complexity. Via initial activation of alkynes/allenes with Au/Pt catalysts, more challenging and valuable elaborate N- heterocycles could be formed via two general strategies: a) from relatively simple substrates reactive intermediates can be generated and can undergo further reactions with/without further Au/Pt catalyst participation and lead to enhanced structural complexity;these intermediates include azomethine ylides, nitrones, azomethine imines, all-carbon metal-containing 1,3-dipoles and 1,4-dipoles;b) using relatively complex but readily available substrates, e.g., enynyl lactam/sultam and N-(2-alkynylphenyl)sultam. A range of unimolecular, bimolecular and three-component reactions will be designed and thus allow efficient synthesis of various N-heterocycles, including pyrrolo[2,1-a]isoindoles, indolizines, pyrrolizines, 1,2-heterocycle/carbocycle-fused indoles, pyrrolidinones, tetracyclic indolines, and benzoazepinones/benzoazocinones. Moreover, enantioselective synthesis of these complex N- heterocycles using chiral Au/Pt complexes will also be studied. B. Synthesis of 7-methoxyaziridinomitosene and its analogs A highly efficient, enantioselective synthesis of 7-methoxylaziridinomitosene is proposed via a modular approach. A previously developed Au/Pt-catalyzed efficient formation of 1,2-cyclopentanone-fused indoles will be used as a key transformation for constructing the mitosene skeleton. Using this approach, various aziridinomitosene analogs will be prepared for biological studies.

Public Health Relevance

This project would develop efficient and versatile synthetic methods to facilitate R&D in drug discovery and lower down manufacturing costs of pharmaceutics. The proposed syntheses of aziridinomitosene analogs will provide new lead structures for cancer treatment.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Synthetic and Biological Chemistry A Study Section (SBCA)
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Lees, Robert G
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University of California Santa Barbara
Schools of Arts and Sciences
Santa Barbara
United States
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Ji, Kegong; Zheng, Zhitong; Wang, Zhixun et al. (2015) Enantioselective oxidative gold catalysis enabled by a designed chiral P,N-bidentate ligand. Angew Chem Int Ed Engl 54:1245-9
Zheng, Zhitong; Tu, Huangfei; Zhang, Liming (2014) One-pot synthesis of fused pyrroles through a key gold-catalysis-triggered cascade. Chemistry 20:2445-8
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Li, Jiabin; Ji, Kegong; Zheng, Renhua et al. (2014) Expanding the horizon of intermolecular trapping of in situ generated ?-oxo gold carbenes: efficient oxidative union of allylic sulfides and terminal alkynes via C-C bond formation. Chem Commun (Camb) 50:4130-3
Zhang, Liming (2014) A non-diazo approach to ?-oxo gold carbenes via gold-catalyzed alkyne oxidation. Acc Chem Res 47:877-88
Ji, Kegong; Zhang, Liming (2014) A Non-Diazo Strategy to Cyclopropanation via Oxidatively Generated Gold Carbene: the Benefit of A Conformationally Rigid P,N-Bidentate Ligand. Org Chem Front 1:34-38
Ji, Kegong; D'Souza, Brendan; Nelson, Jon et al. (2014) Gold-Catalyzed Oxidation of Propargylic Ethers with Internal C-C Triple Bonds: Impressive Regioselectivity Enabled by Inductive Effect. J Organomet Chem 770:142-145
Zheng, Zhitong; Touve, Mollie; Barnes, Josue et al. (2014) Synthesis-enabled probing of mitosene structural space leads to improved IC?? over mitomycin C. Angew Chem Int Ed Engl 53:9302-5
Ji, Kegong; Zhao, Yulong; Zhang, Liming (2013) Optimizing P,N-bidentate ligands for oxidative gold catalysis: efficient intermolecular trapping of ?-oxo gold carbenes by carboxylic acids. Angew Chem Int Ed Engl 52:6508-12

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