Sugar‐Based Synthesis of Tamiflu and Its Inhibitory Effects on Cell Secretion

Abstract

Tamiflu is currently the most effective drug for the treatment of influenza, but the insufficient supply and side-effects of this drug demand urgent solutions. We present a practical synthesis of Tamiflu by using novel synthetic routes, cheap reagents, and the abundantly available starting material D-glucal. The strategy features a Claisen rearrangement of hexose to obtain the cyclohexene backbone and introduction of diamino groups through tandem intramolecular aziridination and ring opening. In addition, this synthetic protocol allows late-stage functionalization for the flexible synthesis of Tamiflu analogues. By using the synthesized Tamiflu and its active metabolite (oseltamivir carboxylate), we investigated their influences on neuroendocrine PC12 cells in various aspects. It was discovered that oseltamivir carboxylate significantly inhibits the vesicular exocytosis (regulated secretion) of PC12 cells, and suggests a mechanism underlying the Tamiflu side-effects, in particular its possible adverse influences on neurotransmitter release in the central nervous system.

α‐ und β‐Lipomycin: Totalsynthesen auf der Grundlage sequentieller Stille‐Kupplungen und Zuordnung der absoluten Konfiguration aller stereogenen Zentren

“…Ihm folgte sofort eine β‐Eliminierung von LiOMe, womit D ‐Digitoxal ( D ‐ 28 ; Stufe g47) fertiggestellt war. Abschließend wurde zum Glycal 9 bis( tert ‐butyldimethylsilyliert) (Stufe h, 63 % Ausbeute) 48…”

The evolution of Tamiflu synthesis, 20 years on: Advent of enabling technologies the last piece of the puzzle?

“…Affordable and abundantly available sugars such as d -xylose, [ 101 ] d -ribose, [ 102 ] D-mannitol, [ 103 ] D-glucal, [ 104 ] and d -glucose [ 105 ] have also been used as starting material for Tamiflu 1a synthesis [ 1 , 2 , 24 , 26 ] However, sugar dependent synthetic procedures are characteristically long (12–22 steps) accompanied with extensive chromatographic purification (9–16 operations) and low yields (2.6–15%). Herein, Liu and coworkers’ D-glucal procedure, [ 104 ] Wong et al. d -xylose procedure [ 101 ] and Kongkathip et al.…”

Synthetic Advancement of Neuraminidase Inhibitor “Tamiflu”

“…Sugar‐based synthesis of Tamiflu by Ma and co‐workers : Tamiflu synthesized from this group began with glucal derivative 276 , obtained from glucose, (Scheme ) involved the oxidation to an aldehyde by DMP or Swern reagents and Wittig methylenation to get 277 . The Claisen rearrangement of the generated aldehyde 278 which on successive oxidation, esterification generated 279 .…”