Szu-Han Chen
National Taiwan University, Taiwan
Title: Synthesis of Oseltamvir Using Diels–Alder Reaction of 1,3-Butadiene Bearing 2-Carboxy and 4-Alkoxy Substituenes
Biography
Biography: Szu-Han Chen
Abstract
Diels–Alder reactions are particularly useful for the total synthesis of pharmacologically active compounds and natural products. Not only does this strategy construct two new C–C σ-bonds in one step, but it also forms a cyclohexene system with good regio- and stereoselectivity http://medicinalchemistry.pharmaceuticalconferences.com/europe/up to four contiguous stereocenters. Using heteroatom-substituted electron-rich dienes, such as Danishefsky’s diene, usually promotes the normal electron-demand Diels–Alder reactions in highly regioselective fashion.
Tamiflu, the phosphate salt of oseltamivir, is a popular anti-influenza drug in clinical use. Diels–Alder reactions using 1,3-butadiene, 1-timethylsilyoxy-1,3-butadiene, furan, N-Boc-pyrrole and 1-Cbz-1,2-dihydropyridine have been successfully applied to react with appropriate dienophiles for construction of the cyclohexene core structure of oseltamivir.
We synthesized a novel diene precursor bearing both 3-pentoxy and ester groups. Dimerization of this diene was overcome by trapping it in situ using activated alkenes as the dienophiles. Inspired by Shibasaki’s work, we successfully synthesized a racemic mixture of oseltamivir via a sequence of reactions that comprise acyl azide formation and Curtius rearrangement. The synthesis of optically active oseltamivir via asymmetric Diels–Alder reaction is currently under investigation.