1062100-85-9Relevant articles and documents
Boronate, trifluoroborate, sulfone, sulfinate and sulfonate congeners of oseltamivir carboxylic acid: Synthesis and anti-influenza activity
Hong, Bei-Tao,Cheng, Yih-Shyun E.,Cheng, Ting-Jen,Fang, Jim-Min
, p. 710 - 721 (2019)
Tamiflu readily undergoes endogenous hydrolysis to give oseltamivir carboxylic acid (OC) as the active anti-influenza agent to inhibit the viral neuraminidase (NA). GOC is derived from OC by replacing the 5-amino group with a guanidino group. In this study, OC and GOC congeners with the carboxylic acid bioisosteres of boronic acid, trifluoroborate, sulfone, sulfinic acid, sulfonic acid and sulfonate ester were first synthesized, starting with conversion of OC to a Barton ester, followed by halodecarboxylation to give the iodocyclohexene, which served as a pivotal intermediate for palladium-catalyzed coupling reactions with appropriate diboron and thiol reagents. The enzymatic and cell-based assays indicated that the GOC congeners consistently displayed better NA inhibition and anti-influenza activity than the corresponding OC congeners. The GOC sulfonic acid congener (7a) was the most potent anti-influenza agent, showing EC50 = 2.2 nM against the wild-type H1N1 virus, presumably because the sulfonic acid 7a was more lipophilic than GOC and exerted stronger interactions on the three arginine residues (R118, R292 and R371) in the NA active site. Although the trifluoroborates, sulfones and sulfonate esters did not have acidic proton, they still exhibited appreciable NA inhibitory activity, indicating that the polarized B?F and S→O bonds still made sufficient interactions with the tri-arginine motif.
SYNTHESIS OF OSELTAMIVIR CONTAINING PHOSPHONATE CONGENERS WITH ANTI-INFLUENZA ACTIVITY
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Page/Page column 77-78, (2009/04/25)
Novel phosphonate compounds are described. The compounds have activity as neuraminidase inhibitors against wild-type and H274Y mutant of H1N1 and H5N1 viruses. The present disclosure also provides an enantioselective synthetic route to known neuraminidase inhibitors oseltamivir and the anti-flu drug Tamiflu, as well as novel phosphonate compounds, via D-xylose. Another efficient and flexible synthesis of Tamiflu and the highly potent neuraminidase inhibitor Tamiphosphor was also achieved in 11 steps and > 20% overall yields from the readily available fermentation product (1S-cis)-3-bromo-3,5- cyclohexadiene-1,2-diol. Most of the reaction intermediates were obtained as crystals without tedious purification procedures. The key transformations include an initial regio- and stereoselective bromoamidation of a bromoarene cis- dihydrodiol, as well as the final palladium-catalyzed carbonylation and phosphonylation.
