Analogues of Sialic Acids as Potential Sialidase Inhibitors. Synthesis of C 6 and C 7 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)Me 2 SiO group and hydrogenation (→ 26 ; Scheme 1 ). Chain extension of 26 by reaction with Me 3 SiCH 2 MgCl 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 2 C 5 conformation, the analogous N ‐Ph derivatives 46 and 17 adopt a 5 C 2 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 NaBH 3 CN afforded the (fluoromethyl)piperidine 52 , while reductive amination of 51 with H 2 /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.