Metalated nitriles: internal 1,2-asymmetric induction
Fraser F Fleming1, Wang Liu, Somraj Ghosh
1Department of Chemistry and Biochemistry, Duquesne University, Pittsburgh, PA 15282-1530, USA. flemingf@duq.edu
The Journal of Organic Chemistry
|March 14, 2008
Summary
This study reveals a new method for highly diastereoselective alkylations of nitriles. This approach efficiently creates hindered quaternary centers with excellent stereocontrol, advancing asymmetric synthesis.
Area of Science:
- Organic Chemistry
- Asymmetric Synthesis
- Stereoselective Reactions
Background:
- Alkylation reactions are fundamental in organic synthesis for forming carbon-carbon bonds.
- Achieving high diastereoselectivity in acyclic systems, particularly for installing quaternary centers, remains a significant challenge.
Purpose of the Study:
- To develop a highly diastereoselective method for alkylating conformationally constrained acyclic nitriles.
- To understand and exploit the conformational preferences that govern stereoselectivity in nitrile alkylations.
- To provide a versatile route for the synthesis of hindered quaternary stereocenters.
Main Methods:
- Investigated diastereoselective alkylations of various C- and N-metalated nitriles with vicinal dimethyl groups and adjacent phenyl or trisubstituted alkene substituents.
- Analyzed the influence of conformation on stereochemical outcomes, implicating a reactive conformation that minimizes allylic strain.
- Screened acyclic nitriles and esters to identify key structural requirements for high selectivity and developed a predictive model.
Main Results:
- Achieved exceptionally high diastereoselectivity in alkylations of constrained acyclic nitriles.
- Demonstrated efficient installation of quaternary centers, including complex tertiary-quaternary-tertiary stereocenters using isopropyl iodide.
- Developed a predictive model for stereoselectivity, explaining observed diastereomers and accounting for differences with ester alkylations.
Conclusions:
- Identified key structural features for high 1,2-asymmetric induction in metalated nitrile alkylations.
- Addressed the challenge of asymmetric alkylations with acyclic metalated nitriles.
- Provided a versatile and robust method for synthesizing hindered quaternary centers with excellent stereocontrol.
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