22748-45-4Relevant articles and documents
Rapid Enantioselective and Diastereoconvergent Hybrid Organic/Biocatalytic Entry into the Oseltamivir Core
Tiwari, Virendra K.,Powell, Douglas R.,Broussy, Sylvain,Berkowitz, David B.
supporting information, p. 6494 - 6503 (2021/05/06)
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.
Steric Course of the Reactions Catalyzed by 5-Enolpyruvylshikimate-3-phosphate Synthase, Chorismate Mutase, and Anthranilate Synthase
Asano, Y.,Lee, J. J.,Shieh, T. L.,Spreafico, F.,Kowal, C.,Floss, H. G.
, p. 4314 - 4320 (2007/10/02)
To probe the steric course of several reactions in the shikimate pathway, (1R,2R)-glycerol was synthesized and fed to cultures of Klebsiella pneumoniae mutant 62-1.The accumulated chorismic acid, labeled from endogenously formed (E)-phosphoenolpyruvate, was isolated and degraded by hydrogenation of the side-chain double bond and cleavage of the ether linkage to D,L-lactic-acid.Resolution of the latter and determination of the methyl group configuration in the two enantiomers demonstrated predominant E configuration of the chorismic acid.It follows that the addition and the elimination step in the 5-enolpyruvylshikimate-3-phosphate (ESP) synthase reaction proceed with opposite stereochemistry, i.e., anti/syn or syn/anti.Incubation of the above chorismic acid with anthranilate synthase produced pyruvate of predominantly S configuration, indicating stereospecific protonation on the re face of the side chain.Conversion of the (E)-chorismic acid into phenylalanine and tyrosine with whole cells of E. coli and configurational analysis of these amino acids by conversion into pyruvate carrying a chiral methyl group with phenylalanine hydroxylase and/or tyrosine phenol-lyase indicated that the chorismate mutase reaction proceeds via a chair transition state.
