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

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 B_3,6 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.