Synthetic Advancement of Neuraminidase Inhibitor “Tamiflu”

Abstract

Tamiflu (oseltamivir phosphate), clinically working antiviral chiral drug, is most effective against the infectious disease caused by both influenza A and B. It is also the last resort drug for the treatment of N1H1 virus infection at a high cost with minimal global availability. The current industrial method uses natural (‐)‐shikimic acid obtained from Chinese star anise and coffee beans, hence the limited natural resource and scarcity restricted the Tamiflu production. While most of the synthetic methods reported were composed of natural chiral pools and relatively low‐cost reagents, however, the industrial process is fundamentally limited to the use of hazardous azide or tedious purification methods. In case of an influenza outbreak, producing the Tamiflu according to its demand may be difficult. This document detailed the synthetic progress of chemistry over the last two decades emphasizing the starting materials, hazards of reagents, time needed, number of steps, and overall yields etc. for the interest in academia as well as industrial research.

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

“…As reflected in this review and complimented by the published reviews, [ [1] , [2] , [3] , [22] , [23] , [24] , [25] , [26] , [27] , 47 ] both the shikimic acid-free and azide chemistry-free approaches are mostly low yielding compared to their competitors despite their ingenuity in Tamiflu assembling. Having solved the shikimic acid availability concerns over the years by developing more efficient extraction and purification processes or alternatively by fermentation using genetically engineered E.coli bacteria, [ 25 , [28] , [29] , [30] ] the use of hazardous azide chemistry needs more attention.…”

“…Tamiflu was discovered by Gilead Sciences in 1995, patented in 1996, co-developed with F. Hoffmann-La Roche Ltd and marketed by F. Hoffmann-La Roche and commercially launched in November 1999 [ [16] , [17] , [18] , [19] , [20] , [21] ] In the early years of its discovery, (−)-shikimic acid was used as starting material for the synthesis of Tamiflu and furthermore, the current and only industrial synthetic route still uses (−)-shikimic acid. In response to an increasing threat of an influenza pandemic, diverse synthetic approaches have been developed and very insightful reviews of their relative merits have been published [ [1] , [2] , [3] , [22] , [23] , [24] , [25] , [26] , [27] ] However, there were legitimate (−)-shikimic acid availability concerns in the early years of the development of this drug. Shikimic acid, which is a natural product isolated from a plant of Chinese star anise was unavailable in consistent purity and enough quantity, which prompted extensive studies into (−)-shikimic acid free synthetic routes in both industry and academia.…”

Dearomatization of aromatic asmic isocyanides to complex cyclohexadienes

“…Dearomatizations are strategic transformations for assembling complex cyclic, bridged, or spirocyclic scaffolds because multiple bonds are forged from readily available aromatics ( 1 ) 2 – 4 . Numerous dearomatizations have featured as key steps in the synthesis of prized bioactive targets 5 – 9 where brevity is paramount, such as in the syntheses of the anti-viral drug oseltamivir (Tamiflu, 2 ) 10 and the pain management opiate oxycodone ( 3 ) 11 (Fig. 1 ).…”

Potential Antioxidant and Anti-Inflammatory Function of Gynura procumbens Polyphenols Ligand

“…In contrast, polyphenols, which are secondary metabolites of plants, have a long history as drugs due to their distinct aromatic structures, and compared to chemically synthesized drugs, they show reduced or no toxicity [5]. Therefore, interest has increased in the development of plant materials, such as aspirin [6], developed through willow bark, artemisinin [7], which is found in Artemisia annua L. and used as a treatment for malaria, and Tamiflu [8], which is synthesized through star anise; and research using plant materials is being actively conducted [9].…”