A convenient synthesis of bioactive cyclohexenephosphonates

Influenza virus infection and the shikimic acid pathway are two of many examples of microbe-host interactions and microbial biosynthetic pathways that are interesting for investigation by means of small molecules. A particularly interesting structural motif common to both is the cyclohexenecarboxylic acid. In the former, this structural motif has been employed as a mimetic of the sialyl cation intermediate and forms the scaffold of the anti-influenza drug and neuraminidase inhibitor Oseltamivir (or TamifluTM). In the latter pathway, crucial modifications towards aromatic amino acids are carried out via shikimic acid, a cyclohexenecarboxylic acid, as a substrate. A straightforward method to replace the carboxylate moiety in such structures with a phosphonate would provide access to a wide variety of mimetics, for instance monoesters, that still retain a negative charge under physiological conditions usually required for bioactivity. The aim of this research project was to develop an efficient synthesis of the cyclohexenephosphonate scaffold from chiral pool precursors via two key steps, a Hunsdiecker-Barton iododecarboxylation followed by a palladiummediated coupling step to introduce the phosphonate moiety, thus giving a convenient access to interesting bioactive molecules. This approach has successfully been applied to the shikimic acid to afford ‘phospha’-shikimic acids and 3-dehydro-‘phospha’-shikimic acids, and further development of this strategy has led to the synthesis of ‘phospha’-Tamiflu and its derivatives from an Oseltamivir precursor.