Skip to Main content Skip to Navigation
Journal articles

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

Abstract : 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.
Document type :
Journal articles
Complete list of metadata

https://hal-univ-paris.archives-ouvertes.fr/hal-03241859
Contributor : Hal Paris Diderot <>
Submitted on : Monday, May 31, 2021 - 10:00:03 AM
Last modification on : Wednesday, June 2, 2021 - 4:26:38 PM

File

 Restricted access
To satisfy the distribution rights of the publisher, the document is embargoed until : 2021-10-15

Please log in to resquest access to the document

Identifiers

Collections

Citation

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

Share

Metrics

Record views

16