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Synfacts 2014; 10(3): 0225
DOI: 10.1055/s-0033-1340699
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart · New York

Synthesis of (–)-Oseltamivir

Contributor(s):
Philip Kocienski
Mukaiyama T, Ishikawa H, Koshino H, Hayashi Y * Tohoku University, Sendai, Kumamoto University and RIKEN, Wako, Japan
One-Pot Synthesis of (–)-Oseltamivir and Mechanistic Insights into the Organocatalyzed Michael Reaction.

Chem. Eur. J. 2013;
19: 17789-17800
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Publication History

Publication Date:
17 February 2014 (online)

 
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Key words

oseltamivir - neuraminidase inhibitors - asymmetric Michael addition - organocatalysis

Significance

A remarkably short and efficient gram-scale synthesis of the neuraminidase inhibitor (–)-oseltamivir is reported featuring an organocatalytic Michael addition as the first step. The ­sequence requires only one pot and was achieved without evaporation of solvent or solvent exchange. The overall yield for the gram-scale synthesis was 28% from the (Z)-nitroalkene B.


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Comment

A thorough investigation of the mechanism of the initial Michael addition established optimum conditions which include (1) the use of a bulky O-silyl-substituted diphenylprolinol catalyst (C), (2) chlorobenzene as the solvent, and (3) the addition of formic acid to accelerate the reaction and to increase diastereo- and enantioselectivity. This represents a substantial improvement on an earlier synthesis (H. Ishikawa et al. Chem. Eur. J. 2010, 16, 12616).


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