A concise and flexible synthesis of the potent anti-influenza agents tamiflu and tamiphosphor.

the treatment of influenza, is an orally administrated prodrug which is readily hydrolyzed by hepatic esterases to give the corresponding carboxylic acid 2 as the active inhibitor of neuraminidase on the influenza virus. As the side effects of tamiflu cause teenage patients to suffer from mental disorders, and with the emergence of drug-resistant strains of avian flu, the development of new chemical entities to combat influenza viruses are urgently needed for the battle against the threat of pandemic flu. We recently reported that tamiphosphor (3) is a promising drug against both avian flu and human influenza. Tamiphosphor, in which the carboxyl group in oseltamivir is replaced with a phosphonate group, interacts strongly with the three arginine residues of neuraminidase, and is more potent against the wild-type neuraminidases of H1N1 and H5N1 viruses. In addition, the guanidine analogue 4 is an effective inhibitor (Ki= 19 nm) of the H274Ymutant of H5N1 neuraminidase. Furthermore, our preliminary study indicates that tamiphosphor is also orally bioavailable and protects mice against lethal influenza viruses. By comparison of the survival rate and mean survival time of infected mice (data not shown), tamiphosphor is found to be more effective than tamiflu against the H1N1 human influenza virus and at least equally effective against the recombinant H5N1 (NIBRG14) virus. The current industrial synthesis of tamiflu relies on naturally occurring shikimic acid as a starting material. However, the availability of consistently pure shikimic acid may be problematic. One of the drawbacks of this large-scale synthesis lies in the manipulation of the potentially explosive azide reagent and intermediates. Several new synthetic methods for the preparation of tamiflu have been developed without using shikimic acid. To establish the cyclohexenecarboxylate core structure of tamiflu, various types of Diels– Alder reactions have been applied. For example, Karpf and co-workers have carried out the Diels–Alder reaction between an appropriately functionalized furan and acrylate, followed by enzymatic resolution, to obtain the chiral intermediate for the synthesis of tamiflu. In one approach by Shibasaki and co-workers, the Diels–Alder reaction of 1trimethylsilyloxy-1,3-butadiene with fumaryl chloride was utilized to construct the core structure; however, separation of the racemic mixture of a key intermediate (by HPLC on a chiral stationary phase) was required. Alternatively, the catalytic enantioselective Diels–Alder reactions developed by the research groups of Corey and Fukuyama afforded the required chiral cyclohexenecarboxylates for the synthesis of tamiflu. In another approach by the research group of Shibasaki, a meso-aziridine derivative of 1,4-cyclohexadiene was prepared and subjected to a catalytic asymmetric ring-opening reaction with trimethylsilyl azide, which served as the platform methodology for the synthesis of tamiflu. Karpf and co-workers used Ru/Al2O3-catalyzed hydrogenation of a substituted isophthalic diester to provide the cyclohexane core where all the substituents and the diester are disposed cis to one another. Themeso diester was then enzymatically hydrolyzed to an optically active monoacid, which serves as the key intermediate for the synthesis of tamiflu. Kann and co-workers [9] demonstrated the synthesis of tamiflu by starting with the amination of a chiral cationic iron complex of cyclohexadienecarboxylate, which was obtained by separation of the diastereomers formed with (1R,2S)-2-phenylcyclohexanol. Trost and Zhang reported a palladium-catalyzed asymmetric allylic amination of 5-oxabicyclo[3.2.1]hexen-4-one as a key step in the synthesis of tamiflu. Scheme 1. Retrosynthetic strategy for anti-influenza agents starting from bromoarene cis-1,2-dihydrodiol (5). Boc= tert-butyloxycarbonyl.