Novel asymmetric synthesis of oseltamivir phosphate (Tamiflu) from (-)-shikimic acid via cyclic sulfite intermediates

Article abstract of DOI:10.1016/j.tetasy.2011.09.014

A novel asymmetric synthesis of oseltamivir phosphate 1 from the naturally abundant (-)-shikimic acid via 3,4-cyclic sulfite intermediate 3 (Scheme 1) is described. Target compound 1 was obtained in 39% overall yield from this nine-step synthesis, and the characteristic step of the synthesis is the regio- and stereospecific nucleophilic substitution with sodium azide at the allylic (C-3) position of 3,4-cyclic sulfite 3. Since the yield of the direct-aziridine-formation from the unprotected dihydroxyl azide 4 was not satisfactory, two improved preparations of the established compound 7 via protected 3,4-cyclic sulfites 10 and 13 (Scheme 2) have been developed. In these two improved preparations, compound 7 was obtained from 3,4-cyclic sulfite 3 in 7-steps in 64% or 62% overall yield, respectively. Copyright