Rapid Enantioselective and Diastereoconvergent Hybrid Organic/Biocatalytic Entry into the Oseltamivir Core

A formal synthesis of the antiviral drug (-)-oseltamivir (Tamiflu) has been accomplished starting from m-anisic acid via a dissolving metal or electrochemical Birch reduction. The correct absolute stereochemistry is efficiently set through enzyme-catalyzed carbonyl reduction on resultant racemic α,β-unsaturated ketone. screen broad ketoreductase (KRED) library identified several that deliver desired allylic alcohol with nearly perfect facial selectivity at new center for each antipodal substrate, indicating enzyme also able to completely override inherent diastereomeric bias in substrate. Conversion complete, d-glucose serving as terminal hydride donor (glucose dehydrogenase). For resulting secondary alcohol, O/N-interconversion then effected either by synfacial [3,3]-sigmatropic imidate rearrangement direct, stereoinverting N-Mitsunobu chemistry. Both stereochemical outcomes have confirmed crystallographically. α,β-unsaturation introduced an α-phenylselenylation/oxidation/pyrolysis sequence yield targeted (S)-N-acyl-protected 5-amino-1,3-cyclohexadiene carboxylates, key advanced intermediates oseltamivir pioneered Corey (N-Boc) and Trost (N-phthalamido), respectively.