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

Virendra Tiwari (1) , Douglas Powell (2) , Sylvain Broussy (3) , David Berkowitz (1)

1 University of Nebraska–Lincoln
2 OU - University of Oklahoma
3 CiTCoM - UMR 8038 - Cibles Thérapeutiques et conception de médicaments

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

Domaines: Chimie; Sciences du Vivant [q-bio]

Virendra Tiwari, Douglas Powell, Sylvain Broussy, David Berkowitz. Rapid Enantioselective and Diastereoconvergent Hybrid Organic/Biocatalytic Entry into the Oseltamivir Core. Journal of Organic Chemistry, 2021, 86 (9), pp.6494-6503. ⟨10.1021/acs.joc.1c00326⟩. ⟨hal-03241859⟩