Proton donor acidity controls selectivity in nonaromatic nitrogen heterocycle synthesis
Simon Duttwyler1, Shuming Chen, Michael K Takase
1Department of Chemistry, Yale University, New Haven, CT 06520, USA.
Science (New York, N.Y.)
|February 9, 2013
Summary
This study introduces a new method for synthesizing highly substituted piperidines, crucial for drug discovery. The reaction
Area of Science:
- Organic Chemistry
- Medicinal Chemistry
- Synthetic Chemistry
Background:
- Piperidines are core structures in many natural products and pharmaceuticals.
- Developing efficient synthetic routes for substituted piperidines is vital for drug discovery.
- Existing methods may lack regiochemical control or require complex starting materials.
Purpose of the Study:
- To develop a novel, regioselective method for synthesizing highly substituted piperidine derivatives.
- To demonstrate tunable regiochemistry controlled by acid strength.
- To provide a theoretical basis for the observed selectivities.
Main Methods:
- Rhodium-catalyzed carbon-hydrogen bond activation to form dihydropyridines.
- Regio- and diastereoselective protonation of dihydropyridines under kinetic or thermodynamic control.
- Nucleophilic addition to generated iminium ion intermediates.
- X-ray crystallography and Density Functional Theory (DFT) calculations for structural and mechanistic insights.
Main Results:
- A cascade reaction efficiently converts starting materials to dihydropyridines.
- Tunable regiochemistry of piperidine synthesis achieved by varying acid strength.
- High regio- and diastereoselectivity observed in iminium ion formation and subsequent nucleophilic addition.
- Experimental and computational data elucidated the mechanisms behind the observed selectivities.
Conclusions:
- The developed methodology offers a versatile and controllable route to highly substituted piperidines.
- This approach facilitates the synthesis of diverse piperidine scaffolds for pharmaceutical applications.
- The mechanistic understanding aids in further optimization and application of the synthetic strategy.
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