Two Approaches toward the Formal Total Synthesis of Oseltamivir Phosphate (Tamiflu): Catalytic Enantioselective Three-Component Reaction Strategy and l‑Glutamic Acid Strategy

Two independent formal total syntheses of oseltamivir phosphate were successfully achieved: the first utilized a copper-catalyzed asymmetric three-component reaction strategy, and the second utilized l-glutamic acid γ-ester as a chiral source to install the correct stereochemistry. Both strategies u...

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Bibliographic Details
Published in:Journal of organic chemistry 2013-04, Vol.78 (8), p.4019-4026
Main Authors: Alagiri, Kaliyamoorthy, Furutachi, Makoto, Yamatsugu, Kenzo, Kumagai, Naoya, Watanabe, Takumi, Shibasaki, Masakatsu
Format: Article
Language:English
Subjects:
Catalysis
Glutamic Acid - chemistry
Molecular Structure
Oseltamivir - chemical synthesis
Oseltamivir - chemistry
Stereoisomerism
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Summary:Two independent formal total syntheses of oseltamivir phosphate were successfully achieved: the first utilized a copper-catalyzed asymmetric three-component reaction strategy, and the second utilized l-glutamic acid γ-ester as a chiral source to install the correct stereochemistry. Both strategies used Dieckmann condensation to construct a six-membered ring core, after which manipulation of the functional groups and protecting groups accessed Corey’s intermediate for the synthesis of oseltamivir phosphate. While the first synthesis was accomplished via four purification steps in 25.7% overall yield, albeit with moderate optical purity (76% ee), the second strategy achieved the synthesis via six purification steps in 19.8% overall yield with perfect enantiocontrol.
ISSN:0022-3263
1520-6904
DOI:10.1021/jo400360j