Phosphonic‐Acid Analogues of the N‐Acetyl‐2‐deoxyneiiraniinic Acids: Synthesis and Inhibition of Vibrio cholerae Sialidase

The phosphonic acids 3 and 4 were prepared to compare their inhibitory activity on Vibrio cholerae sialidase with the one of the corresponding N‐acetyl‐2‐deoxyneuraminic acids 5 and 6. Thus, hydrogenation and benzylation of methyl N‐acetyl‐2,3‐didehydro‐2‐deoxyneuraminate (1MeNeu2en5Ac; 7) gave a mixture of the fully O‐benzylated benzyl and methyl esters 9 and 10, the partially O‐benzylated benzyl and methyl esters 11 and 12, and the fully O‐and N‐benzylated benzyl and methyl esters 13 and 14 (Scheme 1). Transesterification of 9 to 10 and hydrolysis of 10 gave the acid 15. Oxidative decarboxylation of 15 with Pb(OAc)4 gave a 1:9 mixture of the α‐and β‐D‐glycero‐D‐galacto‐acetates 16 and 17. Phosphonoylation of 17 with P(OMe)3 and Me3SiOTf gave a 1.3:1 mixture of the phosphonates 18 and 19, which were deprotected to give the (4‐acetamido‐2,4‐dideoxy‐D‐glycero‐α‐and β‐D‐galacto‐octopyranosyl)phosphonic acids 3 and 4, respectively. The acid 6 was obtained by epimerization of the tert‐butyl ester 23 with lithium N‐cyclohexylisoproylamide and deprotection. The phosphonic acids 3 (Ki 5.5 10‐5 M) and 4 (Ki 2.3.10−4 M) are stronger inhibitors of Vibrio cholerae sialidase than the anomeric N‐acetyl‐2‐deoxyneuraminic acids 5(Ki 2.3 10−3 M) and 6. Both 3 and 4 inhibit the Vibrio cholerae sialidase, while only the carboxylic acid 5, possessing an equatorial COOH group is an inhibitor.