Nitrogen heterocycles are ubiquitous components of pharmaceutical drugs essential for human health. A particularly attractive approach to nitrogen containing compounds is the modification of cheap and readily available amines via C?H bond functionalization. However, methods that efficiently accomplish this task typically require the use of expensive transition metal catalysts and/or oxidants. This proposal is focused on the design and development of efficient and practical methods for amine functionalization. The main goal is the alpha-functionalization of amines through conceptually new and underdeveloped methods of substrate activation. One tactic will achieve amine C?H bond functionalization in redox-neutral fashion by combining a reductive amine N- alkylation with an oxidative alpha-functionalization, utilizing azomethine ylides as reactive intermediates. Water is generated as the only byproduct and the only required promoters are cheap carboxylic acids. A second strategy facilitates the functionalization of cyclic amines via a novel method involving intermolecular hydride transfer. This approach does not require protecting groups and provides valuable secondary amine products. Reactions are highly enantiospecific and enable late-stage functionalization of drug candidates. A third goal is the direct transformation of simple cyclic amines to alpha,beta-difunctionalized amines. This will be accomplished via a novel strategy that involves azaallyl anions. In addition to targeting the rapid preparation of compounds related to structures with known biological activities, efforts will center on the development of particularly powerful reactions that rapidly produce new polycyclic amines. A priority is the generation of new structural frameworks that are absent from current drug discovery screening libraries.

Public Health Relevance

PUBLIC HEALTH RELEVANCE: As the majority of pharmaceutical drugs contain nitrogen, the ability to prepare these materials in the most rapid way possible is of the utmost importance. The broad availability of drugs is directly dependent on the existence of cost-efficient methods that can reliably build complex molecular structures. The main objective of this proposal is the development of powerful new methods and strategies for amine C?H bond functionalization that will facilitate rapid access to valuable building blocks for the synthesis of biologically active compounds and pharmaceuticals.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM101389-08
Application #
9689463
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Lees, Robert G
Project Start
2012-09-21
Project End
2022-02-28
Budget Start
2019-03-01
Budget End
2020-02-29
Support Year
8
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Florida
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Zhu, Zhengbo; Chandak, Hemant S; Seidel, Daniel (2018) Redox-Annulations of Cyclic Amines with 2-(2-Oxoethyl)malonates. Org Lett 20:4090-4093
Chen, Weijie; Ma, Longle; Paul, Anirudra et al. (2018) Direct ?-C-H bond functionalization of unprotected cyclic amines. Nat Chem 10:165-169
Paul, Anirudra; Thimmegowda, N R; Galani Cruz, Thiago et al. (2018) Decarboxylative Annulation of ?-Amino Acids with ?-Ketoaldehydes. Org Lett 20:602-604
Zhu, Zhengbo; Lv, Xin; Anesini, Jason E et al. (2017) Synthesis of Polycyclic Imidazolidinones via Amine Redox-Annulation. Org Lett 19:6424-6427
Zhu, Zhengbo; Seidel, Daniel (2017) Acetic Acid Promoted Redox Annulations with Dual C-H Functionalization. Org Lett 19:2841-2844
Ma, Longle; Paul, Anirudra; Breugst, Martin et al. (2016) Redox-Neutral Aromatization of Cyclic Amines: Mechanistic Insights and Harnessing of Reactive Intermediates for Amine ?- and ?-C-H Functionalization. Chemistry 22:18179-18189
Kang, YoungKu; Seidel, Daniel (2016) Decarboxylative Annulation of ?-Amino Acids with ?-Nitroaldehydes. Org Lett 18:4277-9
Chen, Weijie; Seidel, Daniel (2016) Redox-Annulation of Cyclic Amines and ?-Ketoaldehydes. Org Lett 18:1024-7
Zhu, Zhengbo; Seidel, Daniel (2016) An Ugi Reaction Incorporating a Redox-Neutral Amine C-H Functionalization Step. Org Lett 18:631-3
Kang, YoungKu; Chen, Weijie; Breugst, Martin et al. (2015) Asymmetric Redox-Annulation of Cyclic Amines. J Org Chem 80:9628-40

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