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High‐Yielding Synthesis of the Anti‐Influenza Neuraminidase Inhibitor (−)‐Oseltamivir by Two “One‐Pot” Sequences
Author(s) -
Ishikawa Hayato,
Suzuki Takaki,
Orita Hideo,
Uchimaru Tadafumi,
Hayashi Yujiro
Publication year - 2010
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201001108
Subject(s) - chemistry , michael reaction , moiety , amide , organic chemistry , aldol reaction , reagent , curtius rearrangement , medicinal chemistry , catalysis
Abstract The efficient asymmetric total synthesis of (−)‐oseltamivir, an antiviral reagent, has been accomplished by using two “one‐pot” reaction sequences, with excellent overall yield (60 %) and only one required purification by column chromatography. The first one‐pot reaction sequence consists of a diphenylprolinol silyl ether mediated asymmetric Michael reaction, a domino Michael reaction/Horner–Wadsworth–Emmons reaction combined with retro‐aldol/Horner–Wadsworth–Emmons reaction and retro Michael reactions, a thiol Michael reaction, and a base‐catalyzed isomerization. Six reactions can be successfully conducted in the second one‐pot reaction sequence; these are deprotection of a tert ‐butyl ester and its conversion into an acyl chloride then an acyl azide, Curtius rearrangement, amide formation, reduction of a nitro group into an amine, and a retro Michael reaction of a thiol moiety. A column‐free synthesis of (−)‐oseltamivir has also been established.