Analogues of Sialic Acids as Potential Sialidase Inhibitors. Synthesis of C6 and C7 Analogues of N‐Acetyl‐6‐amino‐2,6‐dideoxyneuraminic Acid

Brigitte I. Glänzer, Zoltan Györgydeák, Bruno Bernet, Andrea Vasella

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Abstract

The piperidines 12–18, piperidmose analogues of Neu5Ac (1) with a shortened side chain, were synthesized from N‐acetyl‐D‐glucosamine via the azidoalkene 32 and tested as inhibitors of Vibrio cholerae sialidase. Deoxygenation at C(4) of the uronate 22, obtained from the known D‐GlcNAc derivative 20, was effected by β‐elimination (→ 23), exchange of the AcO at C(3) with a (t‐Bu)Me2SiO group and hydrogenation (→ 26; Scheme 1). Chain extension of 26 by reaction with Me3SiCH2MgCl gave the D‐ido‐dihydroxysilane 28, which was transformed into the unsaturated L‐xylo‐mesylate 29 and further into the L‐lyxo‐alcohol 30, the mesylate 31, and the L‐xylo‐azide 32. The derivatives 29–31 prefer a sickle zig‐zag and 32 mainly an extended zig‐zag conformation (Fig. 2). The piperidinecarboxylate 15 was obtained from 32 by ozonolysis (→ 33), intramolecular reductive animation (→ 34), and deprotection, while reductive animation of 34 with glycolaldehyde (→ 35) and deprotection gave 16 (Scheme 2). An intramolecular azide‐olefin cycloaddition of 32 yielded exclusively the fused dihydrotriazole 36, while the lactone 39 did not cyclize (Scheme 3). Treatment of 36 with AcOH (→ 37) followed by hydrolysis (→ 38) and deprotection led to the amino acid 18. To prepare the (hydroxymethyl)piperidinecarboxylates 12 and 17, 32 was first dihydroxylated (Scheme 4). The L‐gluco‐diol 40 was obtained as the major product, in agreement with Kishi's rule. Silylation of 40 (→ 42), oxidation with periodinane (→ 44), and reductive animation gave the L‐gluco‐piperidine 45. It was, on the one hand, deprotected to the amino acid 12 and, on the other hand, N‐phenylated (→ 46) and deprotected to 17. While 45 and 12 adopt a 2C5 conformation, the analogous N‐Ph derivatives 46 and 17 adopt a 5C2 and a B3,6 conformation, respectively, on account of the allylic 1,3‐strain. The conformational effects of this 1,3‐strain are also evident in the carbamate 47, obtained from 45 (Scheme 5), and in the C(2)‐epimerized bicyclic ether 48, which was formed upon treatment of 47 with (diethylamino)sulfur trifluoride (DAST). Fluorination of 40 with DAST (→ 49) followed by treatment with AcOH led to the D‐ido‐fluorohydrin 50. Oxidation of 50 (→ 51) followed by a Staudinger reaction and reduction with NaBH3CN afforded the (fluoromethyl)piperidine 52, while reductive amination of 51 with H2/Pd led to the methylpiperidine 55, which was similarly obtained from the keto tosylate 54 and from the dihydrotriazole 36. Deprotection of 52 and 55 gave the amino acids 13 and 14, respectively. The aniline 17 does not inhibit V. cholerae sialidase; the piperidines 12–16 and 18 are weak inhibitors, evidencing the importance of an intact 1,2,3‐trihydroxypropyl side chain.

Original languageEnglish
Pages (from-to)343-369
Number of pages27
JournalHelvetica Chimica Acta
Volume74
Issue number2
DOIs
Publication statusPublished - Mar 13 1991

ASJC Scopus subject areas

  • Catalysis
  • Biochemistry
  • Drug Discovery
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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