Palladium-catalyzed intramolecular C-O bond formation
S I Kuwabe1, K E Torraca, S L Buchwald
1Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Journal of the American Chemical Society
|December 6, 2001
Summary
Palladium catalysis enables efficient synthesis of oxygen heterocycles from aryl halides. This mild method preserves alcohol optical purity and is key to synthesizing the antidepressant MKC-242.
Area of Science:
- Organic Chemistry
- Medicinal Chemistry
- Catalysis
Background:
- Palladium-catalyzed cross-coupling reactions are vital in organic synthesis.
- Intramolecular etherification offers a route to oxygen heterocycles.
- Developing mild and efficient synthetic methods is crucial for drug discovery.
Purpose of the Study:
- To develop a novel palladium-catalyzed intramolecular etherification of aryl halides.
- To synthesize oxygen heterocycles under mild reaction conditions.
- To apply this method in the synthesis of the antidepressant MKC-242.
Main Methods:
- Palladium-catalyzed intramolecular etherification using di-tert-butylphosphinobiaryl ligands.
- Employing weak bases like cesium carbonate (Cs(2)CO(3)) or potassium phosphate (K(3)PO(4)).
- Coupling enantioenriched alcohols without loss of optical purity.
Main Results:
- Successful synthesis of various oxygen heterocycles.
- Reaction tolerates a wide range of functional groups.
- Enables synthesis of polyfunctionalized substrates due to mild conditions.
- Key step in the synthesis of MKC-242 achieved in 40% overall yield.
Conclusions:
- A novel and efficient palladium-catalyzed method for oxygen heterocycle synthesis.
- The method is mild, versatile, and preserves stereochemical integrity.
- Demonstrates utility in the total synthesis of a clinically relevant antidepressant.
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