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
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.
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).
