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An efficient chemoenzymatic approach to (S)-gamma-fluoroleucine ethyl ester
John Limanto1, Ali Shafiee, Paul N Devine
1Department of Process Research, Merck Research Laboratories, Merck & Co., Inc., P.O. Box 2000, Rahway, New Jersey 07065, USA. john_limanto@merck.com
The Journal of Organic Chemistry
|March 12, 2005
Summary
This study presents an efficient asymmetric synthesis for (S)-gamma-fluoroleucine ethyl ester. A key lipase-catalyzed reaction provides a novel route to this valuable fluorinated amino acid derivative.
Area of Science:
- Organic Chemistry
- Asymmetric Synthesis
- Biocatalysis
Background:
- Fluorinated amino acids are crucial building blocks in medicinal chemistry.
- Developing efficient enantioselective synthetic routes is essential for accessing pure enantiomers.
Purpose of the Study:
- To describe an asymmetric synthesis of (S)-gamma-fluoroleucine ethyl ester.
- To utilize enzymatic catalysis for a key stereoselective transformation.
Main Methods:
- Lipase-catalyzed dynamic ring-opening of 2-(3-butenyl)azlactone with ethanol.
- Enzymatic kinetic resolution to achieve high enantiomeric excess.
- Deprotection and salt formation to isolate the final product.
Main Results:
- Achieved 84% enantiomeric excess (ee) in the key lipase-catalyzed step.
- Synthesized (S)-gamma-fluoroleucine ethyl ester in 75% yield.
- Isolated the final product with >97% ee.
Conclusions:
- Demonstrated a practical and efficient asymmetric synthesis of (S)-gamma-fluoroleucine ethyl ester.
- Highlighted the utility of lipase-catalyzed reactions in producing enantiomerically pure fluorinated compounds.
- Established a viable method for accessing valuable fluorinated amino acid derivatives.