Symmetry-based design for the chemoenzymatic synthesis of oseltamivir (Tamiflu) from ethyl benzoate.

A short chemoenzymatic formal synthesis of oseltamivir from ethyl benzoate has been achieved. The key steps involve a toluene dioxygenase-mediated dihydroxylation, hetero-Diels-Alder cycloaddition, and generation of C4 acetamido functionality. The formal synthesis of oseltamivir is achieved in ten steps and incorporates a unique translocation of the olefin with concomitant elimination of the C2 hydroxy group (see scheme).