Many drugs and other biologically active molecules contain basic nitrogen groups that, in their physiological protonated state - and often constrained into intricate ring systems - contribute to the binding of the agent to its protein target. The major theme of this proposal is to develop new synthetic methods that utilize alkyl azides for the synthesis of cyclic nitrogen containing compounds, and to use those methods for the synthesis of biologically relevant compounds. Work in previous grant periods has resulted in the discovery and examination of three broadly useful reactions (the inter- and intramolecular Schmidt reactions of alkyl azides, and the insertion reaction of hydroxyalkyl azides) and has also demonstrated the utility of the reactions in complex molecule synthesis. We have obtained preliminary data that demonstrates how the Schmidt reaction can be linked with other powerful reactions, such as the Diels-Alder cycloaddition, the aldol condensation, and conjugate addition reactions, to provide one-step syntheses of complex lactams from very simple starting materials. We propose to develop these processes, concentrating on matters of scope, efficiency, and stereoselectivity. These new reactions will also be used to synthesize a variety of alkaloids in biological classes that range from NMDA antagonists to cytotoxic agents. The specific targets proposed include the antitussive agent neostenine, several members of the cylindricine family of natural products, the frog-derived indolizidine 223A, and pinnaic acid.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM049093-13
Application #
6929638
Study Section
Medicinal Chemistry Study Section (MCHA)
Program Officer
Schwab, John M
Project Start
1993-05-01
Project End
2009-04-30
Budget Start
2005-05-01
Budget End
2006-04-30
Support Year
13
Fiscal Year
2005
Total Cost
$266,829
Indirect Cost
Name
University of Kansas Lawrence
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
076248616
City
Lawrence
State
KS
Country
United States
Zip Code
66045
Fehl, Charlie; Hirt, Erin E; Li, Sze-Wan et al. (2015) Temperature dependence of turnover in a Sc(OTf)3-catalyzed intramolecular Schmidt reaction. Tetrahedron Lett 56:3137-3140
Szostak, Roman; Aubé, Jeffrey; Szostak, Michal (2015) Determination of Structures and Energetics of Small- and Medium-Sized One-Carbon-Bridged Twisted Amides using ab Initio Molecular Orbital Methods: Implications for Amidic Resonance along the C-N Rotational Pathway. J Org Chem 80:7905-27
Szostak, Roman; Aubé, Jeffrey; Szostak, Michal (2015) An efficient computational model to predict protonation at the amide nitrogen and reactivity along the C-N rotational pathway. Chem Commun (Camb) 51:6395-8
Singh, Gurpreet; Meyer, Angelica; Aubé, Jeffrey (2014) Stereodivergent synthesis of enantioenriched 4-hydroxy-2-cyclopentenones. J Org Chem 79:452-8
Szostak, Michal; Aubé, Jeffrey (2013) Chemistry of bridged lactams and related heterocycles. Chem Rev 113:5701-65
Motiwala, Hashim F; Fehl, Charlie; Li, Sze-Wan et al. (2013) Overcoming product inhibition in catalysis of the intramolecular Schmidt reaction. J Am Chem Soc 135:9000-9
Motiwala, Hashim F; Gulgeze, Belgin; Aube, Jeffrey (2012) Copper-catalyzed oxaziridine-mediated oxidation of C-H bonds. J Org Chem 77:7005-22
Liu, Ruzhang; Gutierrez, Osvaldo; Tantillo, Dean J et al. (2012) Stereocontrol in a combined allylic azide rearrangement and intramolecular Schmidt reaction. J Am Chem Soc 134:6528-31
Gutierrez, Osvaldo; Aube, Jeffrey; Tantillo, Dean J (2012) Mechanism of the acid-promoted intramolecular schmidt reaction: theoretical assessment of the importance of lone pair-cation, cation-ýý, and steric effects in controlling regioselectivity. J Org Chem 77:640-7
Painter, Thomas O; Thornton, Paul D; Orestano, Mario et al. (2011) In situ generation and intramolecular Schmidt reaction of keto azides in a microwave-assisted flow format. Chemistry 17:9595-8

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