High‐Yielding Synthesis of the Anti‐Influenza Neuraminidase Inhibitor (−)‐Oseltamivir by Two “One‐Pot” Sequences

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.

Organocatalytic Conjugate Addition in Stereoselective Synthesis

“…56,57 This synthesis is impressive in terms of both practicability and chemical efficiency. It takes advantage of the addition of aldehyde 92 to the vinyl nitroester 93.…”

Eintopfreaktionen beschleunigen die Synthese pharmazeutischer Wirkstoffe

“…Im Unterschied zur klassischen Eintopfreaktion oder der "teleskopierten Synthese", [11] [12] und konnte später auf zwei aufeinanderfolgende Eintopfreaktionen verdichtet werden (Schema 2). [13] Bei der Planung einer "ununterbrochenen Abfolge von Reaktionen" ist die Verwendung von niedrig siedenden Lösungsmitteln sowie Reagentien, die selbst flüchtig sind oder flüchtige Nebenprodukte erzeugen, angeraten. Die Entfernung flüchtiger Bestandteile im Hochvakuum verhindert die Akkumulation reaktiver Nebenprodukte, die einen Überschuss an Reagentien in den darauffolgenden Schritten erforderlich machen.…”

Modeling the Relationships Between Molecular Structure and Inhibition of Virus-Induced Cytophatic Effects: Anti-Hiv-1 and Anti-H1n1 (Influenza A) Activities as Examples

“…The spread and treatment of this disease is combated with vaccination and anti-influenza drugs. Several compounds targeting the virus neuraminidase have been synthesized, tested and approved for use in humans as anti-influenza agents [35][36][37] . Recently, a large group of angelicin derivatives was synthesized and tested as inhibitors of the influenza A/WSN/33 (H1N1) virus strain induced cytopathic effect 38 .…”