Diversity-orientated approach toward oseltamivir analogs utilizing iron carbonyl chemistry

ORGN 182

Karen M Bromfield, bromfiel@chalmers.se1, Henrik Gradén1, Daniel Hagberg1, Thomas Olsson2, and Nina Kann, kann@chalmers.se1. (1) Department of Chemical and Biological Engineering / Organic Chemistry, Chalmers University of Technology, Kemivagen 10, S-41296 Gothenburg, Sweden, (2) Medicinal Chemistry, AstraZeneca R & D Mölndal, Pepperedsleden 1, 43183 Mölndal, Sweden

Oseltamivir phosphate, the active constituent in TamifluTM, is a neuraminidase inhibitor used for the treatment of influenza A and B. To date the main synthetic routes for the preparation of oseltamivir have employed (-)-quinic acid or (-)-shikimic acid as the precursors. This study however, is focused on the synthesis of oseltamivir analogues of high diversity using cationic iron carbonyl chemistry. Different nucleophiles can be employed in the initial  reaction with the cation (Nu), the ethyl ester moiety or a suitably activated ester can be converted to different esters or amides (X), while variation of the acylating reagent (R1) and introduction of different ring substituents via the nucleophile (R2) used for the aziridine ring-opening allow even further derivatisation. The results we have achieved so far in the application of iron carbonyl chemistry for the synthesis of oseltamivir will be presented.