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

Abstract

Influenza is a serious respiratory disease responsible for significant morbidity and mortality due to both annual epidemics and pandemics; its treatment involves the use of neuraminidase inhibitors. (−)-Oseltamivir phosphate (Tamiflu) approved in 1999, is one of the most potent oral anti-influenza neuraminidase inhibitors. Consequently, more than 70 Tamiflu synthetic procedures have been developed to date. Herein, we highlight the evolution of Tamiflu synthesis since its discovery over 20 years ago in the quest for a truly efficient, safe, cost-effective and environmentally benign synthetic procedure. We have selected a few representative routes to give a clear account of the past, present and the future with the advent of enabling technologies.

Continuous flow asymmetric synthesis of chiral active pharmaceutical ingredients and their advanced intermediates

“…(−)-Oseltamivir is a neuraminidase inhibitor which is broadly employed for the treatment of influenza. 78 Importantly, due to its broad-spectrum antiviral activity, it was clinically investigated against SARS-CoV-2 79 in various in clinical trials. 80 Although, there are numerous synthetic routes developed, 78 the asymmetric synthesis of (−)-oseltamivir is challenging due the presence of three contiguous stereocenters within the cyclohexene ring.…”

“… 78 Importantly, due to its broad-spectrum antiviral activity, it was clinically investigated against SARS-CoV-2 79 in various in clinical trials. 80 Although, there are numerous synthetic routes developed, 78 the asymmetric synthesis of (−)-oseltamivir is challenging due the presence of three contiguous stereocenters within the cyclohexene ring. Continuing their long-standing interest in the synthesis of this medication, 81 the Hayashi group reported the continuous flow telescoped synthesis of (−)-oseltamavir in 2017 ( Scheme 10 ), 82 which was in fact the first multistep one-flow process involving enantioselective organocatalysis as key step to introduce asymmetry.…”

The aminoshikimic acid pathway in bacteria as source of precursors for the synthesis of antibacterial and antiviral compounds

“…Oseltamivir phosphate (Tamiflu) is one of the most potent oral anti-influenza neuraminidase inhibitors used to treat both seasonal and pandemic influenza (Sagandira et al., 2020 ; Tompa et al., 2021 ). Shikimic acid was initially used as the substrate for the chemical synthesis of Tamiflu by Gilead Sciences in 1995, codeveloped and marketed with F. Hoffmann-La Roche Ltd., and released commercially in 1999 (Sagandira et al., 2020 ).…”

Anti-Influenza Strategies Based on Nanoparticle Applications

“…Over the years, oseltamivir-and zanamivir-resistant (neuraminidase inhibitors, NAIs) strains have been described [127][128][129]. Strains resistant to NAIs are less frequent and for that reason oseltamivir and zanamivir are widely used, and new methods of their synthesis continue to be developed [130,131]. Another used NAI is peramivir, formerly region-restricted to China, Japan, South Korea, and the USA [25].…”