Stereoselective Total Synthesis of Racemic BCX-1812 (RWJ-270201) for the Development of Neuraminidase Inhibitors as Anti-influenza Agents

Abstract

A convergent and versatile racemic total synthesis of the anti-influenza agent BCX-1812 (RWJ-270201) was accomplished on the basis of a sequence of stereoselective reactions. Despite intensive research to develop neuraminidase inhibitors to treat infections due to influenza, currently available agents are still in the need of optimization with respect to selectivity and potency, as well as to minimize adverse effects. Our synthetic approach, introduced in this report, is highly exploitable for further derivatization due to flexibility that will eventually accommodate diversified substituents. In addition, the size of the core ring can be varied depending on the size of the diene used for the preparation of the key cycloadduct 10 using an acylnitroso-based hetero-Diels-Alder reaction. Elaboration of 10 to methyl ester 14 followed by a precedented [3+2] dipolar cycloaddition gave bicyclic isoxazoline 17 in a regio- and stereoselective fashion. Incorporation of the peripheral guanidino group and subsequent deprotection provided the target molecule. The details of the synthesis are described herein.

1,3-Dipolar cycloadditions: applications to the synthesis of antiviral agents

“…4 So, new broadspectrum antivirals must be developed because the cost and the risk to a rapid drug resistance of the antivirals targeted against single viruses are very elevated. 60 Genomics helps scientists to find targets at every viral stage and also provides crucial data for understanding the drugvirus effective interaction. Closely, the organic synthetic chemists are dedicating many efforts to design and prepare potential drugs once targets have been identified.…”

“…In this occasion, to 55 resolve the racemic mixtures of compound 61, (R)-(−)-1,1'-binaphthyl-2,2'-diyl-hydrogen phosphate was employed providing the required diastereomeric salt in good yield and excellent enantiomeric excess at the end of the process (98.8%). In this work, a comparison of the X-ray structures of 60 dicarboxylic acid 55 and the binding site of the HCV polymerase was surveyed. The bulkier tert-butyl substituent on the benzamide caused movement in the side chain of Leu384 allowing inhibitors to bind deeper into the pocket an increase their antiviral power.…”

“…Azides, nitrones, and azomethine ylides are the most employed dipoles giving rise to nitrogenated five membered ring heterocycles. Particularly interesting is the enantioselective approach to them using 60 substoichiometric amounts of chiral catalysts.…”

The Effect of Indium(III) Triflate in Oxone-Mediated Oxidative Methyl Esterification of Aldehydes

“…For the assurance, the reaction was carried out with 5 mol % of In(OTf) 3 , which furnished only a 32% yield (Table 1, Entry 7). The reaction was also confirmed using 10 mol % of Zn(OTf) 2 and Mg(OTf) 2 , and the result was moderately diminished yields in both cases (Table 1, Entries 8 and 9). The blank experiment without Lewis acid was then followed, which yielded 56% at reflux and 55% at room temperature based on our reaction method and isolating procedure (Table 1, Entries 10 and 11).…”

Therapeutic Activity of Intramuscular Peramivir in Mice Infected with a Recombinant Influenza A/WSN/33 (H1N1) Virus Containing the H275Y Neuraminidase Mutation

“…In addition to these interesting pharmacokinetics properties, peramivir demonstrated a particularly strong NA-inhibitory activity due to its conformation, which fits very well within the NA active site (6). Indeed, the negatively charged carboxylate group forms conserved hydrogen bonds with residues R118, R292, and R317 (N2 numbering) of the active site whereas the acetamido group binds to the hydrophobic pocket formed by I222 and W118 (6,25). On the other hand, the positively charged guanidinium group forms strong hydrogen bonding and electrostatic interactions with E119, D151, and E277 (25).…”