Synthesis of Pyrrolidine Analogues of N-Acetylneuraminic Acid as Potential Sialidase Inhibitors

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 Ki = 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 NaBH4 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 (192023) 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 via29 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 LiBH4/HBF4. 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).

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