Issue Date: July 23, 2007
Another Practical Route to Tamiflu
The threat of an influenza pandemic has prompted an increase in demand of the flu-fighting drug (-)-oseltamivir phosphate, marketed by Roche as Tamiflu (shown). Unfortunately, the compound's costly commercial production, which includes a tedious purification of the shikimic acid starting material and several explosive intermediates and reagents, makes the drug expensive and therefore out of reach for developing countries. Consequently, chemists have been working toward a simpler, less expensive route to Tamiflu. Now, Tohru Fukuyama and coworkers at the University of Tokyo report a synthesis of the compound starting from pyridine (Angew. Chem. Int. Ed. 2007, 46, 5734). The route, which proceeds in 5.6% overall yield, features an asymmetric Diels-Alder reaction, a bromolactonization, a Hofmann rearrangement, and a domino transformation of a bicyclo[2.2.2] system into an aziridine intermediate. The synthesis uses inexpensive and commonly used reagents, eschews tedious chromatographic purifications, and has the potential to generate a wide range of Tamiflu analogs.
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