Synthesis of Pyrrolidine Analogues of <i>N</i>‐Acetylneuraminic Acid as Potential Sialidase Inhibitors

Abstract

Abstract The pyrrolidine derivatives 3 , 4 , and 5 were prepared from the methyl ester 7 of Neu2en5Ac via lie pyrrolidine‐borane adduct 33 . They inhibit Vibrio cholerae sialidase competitively with K i = 4. 4 10 −3 M, 5. 3 10 −3 M, and 4. 0 10 −2 M, respectively. Benzylation of 7 gave the fully O ‐benzylated 8 besides 9, 10 , and 11. Ozonolysis and reduction with NaBH 4 of 8 and 9 gave the 1, 4‐diols 12 and 15 , the hydroxy acetates 13 and 16 , and the furanoses 14 and 17 ( Scheme 1 ), respectively. The diol 12 was selectively protected (→ 19 → 20 → 23 ) and transformed into the azide 27 by a Mitsunobu reaction. Selective base‐catalysed deprotection of the diacetate 22 , obtained from 12 , was hampered by an easy acetyl‐group migration. The mesylate 28 proved unstable. The azide 27 was transformed via 29 into the ketone 30 ( Scheme 2 ). Hydrogenation of 30 gave the dihydropyrrole 31 and, hence, the pyrrole 32. The adduct 33 was obtained from 30 by a Staudinger reaction (→31) and reduction with LiBH 4 /HBF 4 . It was transformed into the pyrroudine 34 . The structure of 34 was established by X‐ray analysis. Reductamination of the pyrrolidine‐borane adduct with glyoxylic acid gave 40 and, hence, 3. N ‐Alkylation afforded 44 and, hence, the phosphonate 4. The acid 5 was obtained from 33 by acylation (→ 47 ) and deprotection ( Scheme 4 ).