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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Schwab, John M
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University of California Santa Barbara
Schools of Arts and Sciences
Santa Barbara
United States
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