An unexpected elimination product leads to 4-alkyl-4-deoxy-4-epi-sialic acid derivatives

Abstract

A useful, unexpected β,γ-unsaturated-α-keto ester (ethyl (E)-5-acetamido-3,4,5-trideoxy-6,7:8,9-di-O- isopropylidene-D-manno-non-3-en-2-ulosonate 5) was isolated in 91% yield following ozonolysis and chromatographic purification of its enoate ester precursor ethyl 5-acetamido-2,3,4,5-tetradeoxy-6,7:8,9-di-O-isopropylidene-2-methylene- 4-nitro-D-glycero-D-galacto-nononate (6). When the 4R enoate ester (ethyl 5-acetamido-2,3,4,5-tetradeoxy-6,7:8,9-di-O- isopropylidene-2-methylene-4-nitro-D-glycero-D-talo-nononate, 7) was subjected to the same conditions, enone 5 was a minor product (18%) while the major product did not eliminate HNO2 but instead cyclized to form a five-membered ring containing a hemiaminal linkage between C-2 and the amide nitrogen on C-5 (9, 70%). Conjugate addition to enone 5 opens up the potential to generate 4-substituted sialic acid derivatives, a general route to such compounds that has not been previously reported. In a preliminary investigation of such a route, diethylzinc and dimethylzinc were added to enone 5 resulting in generation of 4-alkyl-substituted cyclic hemiaminal structures 11 and 13, which could be deprotected to form 2,7-anhydrosialic acid analogues 14 and 15. These products could then be converted to peracetylated glycals 16 and 17, the 4-methyl-substituted compound 17 being finally deprotected to give a 4-methyl- substituted analogue of the glycal of sialic acid (5-acetamido-2,6-anhydro-3,4,5-trideoxy-4-methyl-D-glycero-D-talo-non-2-enonic acid 18).Key words: conjugate addition, dialkylzinc reagent, sialic acid, ozonolysis, inhibitors.