Synthesis of a Phosphonic Acid Analogue of N‐Acetyl‐2,3‐didehydro‐2‐deoxyneuraminic Acid, an Inhibitor of Vibrio cholerae Sialidase

Abstract The synthesis of the phospha analogue 10 of DANA ( 2 ) is described. Bromo‐hydroxylation of the known 11 (→ 12 and 13 ) followed by treatment of the major bromohydrin 13 with 1,8‐diazabicyclo[5.4.0]undec‐7‐ene (DBU) gave the oxirane 14 ( Scheme 1 ). Depending on the solvent, TiBr 4 transformed 14 into 16 or into a 15 / 16 mixture. Reductive debromination of 16 (→ 17 ), followed by benzylation provided 18 . Oxidattve decarboxylation (Pb(OAc) 4 ) of the acid, obtained by saponification of 18 , yielded the anomeric acetates 19 and 20 . While 19 was inert under the conditions of phosphonoylation, the more reactive imidate 22 , obtained together with 23 from 19 / 20 via 21 ( Scheme 2 ), gave a mixture of the phosphonates 24 / 25 and the bicyclic acetal 26 . Debenzylation of 24 / 25 and acetylation led to the acetoxyphosphonates 27 / 28 . Since β‐elimination of AcOH from 27 / 28 proved difficult, the bromide 34 was prepared from 27 / 28 by photobromination and subjected to reductive elimination with Zn/Cu (→ 35 ; Scheme 3 ). This two‐step sequence was first investigated using the model compounds 30 and 31 . Transesterification of 35 , followed by deacetylation gave 10 , which is a strong inhibitor of the Vibrio Cholerae sialidase.