Synthetic strategies for oseltamivir phosphate

We review here the synthetic strategies for oseltamivir phosphate, an important orally active anti-influenza drug. The Roche synthesis utilized naturally occurring shikimic acid as a starting material. Introduction of the 1-ethylpropyloxy (3-pentyloxy) functionality by regioselective reduction of the acetal and iterative ring-opening reactions with azide to introduce nitrogen functionalities were the key steps. Corey and Fukuyama's syntheses utilized catalytic asymmetric Diels-Alder reactions as the starting points, whereas Shibasaki and Kanai's synthesis began with an asymmetric aziridine-opening reaction with TMSN3 catalyzed by a polymetallic gadolinium complex. These three syntheses demonstrate the power of asymmetric catalysis in pharmaceutical synthesis. Although Kann's synthesis required resolution to provide an enantiomerically pure intermediate, the properties of chiral iron-diene complexes were elegantly utilized. Yao and Fang's syntheses started from abundant natural chiral sources: L-serine and D-xylose, respectively. Specifically, Fang's study identified new analogues of oseltamivir with higher potency against several neuraminidases, including oseltamivir-resistant mutants. Despite the relatively small molecular size, oseltamivir synthesis highlights an important frontier in organic synthesis.