Synthesis of Glucuronic, Mannuronic, and Galacturonic Acid‐Derived Imidazoles as Inhibitors of Bovine Liver β ‐Glucuronidase

The gluco‐, manno ‐, and galacto ‐configured imidazopyridine‐5‐carboxylates 5 – 7 , respectively, were synthesized and evaluated as inhibitors of bovine liver β ‐glucuronidase. The gluconolactam 15 was transformed into the gluco ‐ and manno ‐imidazoles 5 and 6 in nine steps and in an overall yield of 9 and 12%, respectively. Oxidation and esterification of the selectively protected gluco ‐ and manno ‐configured hydroxymethyl‐imidazopyridines 23 and 25 , respectively (both obtained from gluconolactam 15 ), provided the benzhydryl esters 24 and 26 , respectively. Hydrogenolysis afforded the gluco ‐imidazopyridine‐carboxylic acid 5 and the manno ‐isomer 6 . Similarly, the hydroxymethyl‐imidazopyridine 33 , obtained from galactonolactam 27 , was subjected to oxidation, esterification, and deprotection to afford the galacto ‐configured imidazopyridine‐carboxylate 7 in ten steps from the galactonolactam 27 and in an overall yield of 13%. The gluco ‐configured imidazole 5 is the strongest known inhibitor of β ‐glucuronidases ( K i  = 12 n M ), while the manno ‐ and galacto ‐configured imidazoles 6 and 7 are micromolar inhibitors of bovine β ‐glucuronidase. The small difference between the inhibitory strength of the imidazopyridine‐carboxylic acid 5 and the tetrazolopyridine‐carboxylic acid 1 , and the difference between the configurational selectivity of 5 – 7 as compared to the unselectivity of the corresponding lactams 3 and 4 are discussed.