CATAFLU.OR · OrganoCATAlytic approaches towards easily synthesized, economical, and high yielding oseltamivir derivatives

Despite widespread immunization, influenza still kills thousand of people, and costs to US, Europe and Asia enormous amount of money in term of healthcare expenses and productivity losses. While immunization remains an important approach to prevent influenza, small-molecule antiviral agents represent a novel opportunity for effective prevention and therapy of flu. Inhibitors of neuraminidase, essential enzyme for viral replication in all three classes of influenza viruses, has been recently found. Two of these inhibitors have reached the market, namely, zanamivir (GSKBs Relenza (1) in July 1999, and oseltamivir phosphate (Gilead Bs Tamiflu (2), also marketed by Roche) in October 1999. The recent healthy problem related to avian flu, has increase the public demand for stockpiles of Tamiflu, both as a reasonable frontline therapy against a possible flu pandemic and as a preventive agent. However, natural sources of drug (Shikimic acid) are scarcely, and increasing demand for oseltamivir phosphate has placed further pressure on Roche and the chemical community in general to develop new routes to the drug that do not involve complex natural products. In addition, the described synthesis are expensive and difficult. Moreover, in this synthesis use of hazardous azide-based reagents was necessary. New routes to Tamiflu have been recently described, but more than 12 steps in one case and 17 in another are needed. In order to find new drug candidates, cut the drug costs and improving availability as well as efficiency, new chemical synthesis are necessary. We propose a new domino reaction based on an organocatalytic approach to the synthesis of new Tamiflu derivatives. The chemistry involved in this project is easy to perform, and well adapt to industrial contest. Moreover, new chemical structures will be prepared and evaluated as potential drug against virulent and mutated flu viruses.