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Synthesis, structure and inhibitory activity of a stereoisomer of oseltamivir carboxylate

Sartori, Andrea and Dell'Amico, Luca and Battistini, Lucia and Curti, Claudio and Rivara, Silvia and Pala, Daniele and Kerry, Philip S. and Pelosi, Giorgio and Casiraghi, Giovanni and Rassu, Gloria Maria Rita and Zanardi, Franca (2014) Synthesis, structure and inhibitory activity of a stereoisomer of oseltamivir carboxylate. Organic & Biomolecular Chemistry, Vol. 12 (10), p. 1561-1569. ISSN 1477-0520. Article.

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DOI: 10.1039/C3OB42069H

Abstract

A stereodivergent plan is presented leading to all eight stereoisomers of oseltamivir carboxylate (OC). Key chemical manoeuvers are (1) a three-component vinylogous Mukaiyama–Mannich reaction, which sets the whole carbon skeleton and heteroatom substituents, and (2) an intramolecular, silylative Mukaiyama aldol reaction, which creates the targeted carbocycle. The viability of the plan was demonstrated by the first total synthesis of 4-epi-oseltamivir carboxylate (6), accessed in 15 steps from glyceraldehyde, o-anisidine and pyrrole siloxydiene precursors. Compound 6 inhibits influenza A virus strains H1N1 and H3N2 at the µM level, about 150 000-fold less than the OC reference, testifying that the stereodisposition of the C4 acetamido function is key for enzyme recognition. Guided by in-depth structural evaluation including NMR solution studies, molecular mechanics simulations, docking analyses and X-ray crystallography, rationalization of the biological verdict was established.

Item Type:Article
ID Code:10295
Status:Published
Refereed:Yes
Uncontrolled Keywords:Oseltamivir carboxylate, Mukaiyama-Mannich reaction, x-ray crystallography, influenza A virus
Subjects:Area 03 - Scienze chimiche > CHIM/06 Chimica organica
Divisions:002 Altri enti e centri di ricerca del Nord Sardegna > CNR-Consiglio Nazionale delle Ricerche > Istituto di chimica biomolecolare, Sassari
Publisher:Royal Society of Chemistry
ISSN:1477-0520
Deposited On:14 Nov 2014 13:05

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