beta-lactams from D-erythrose-derived imines: A convenient synthesis of 2,3-diamino-2,3-dideoxy-D-mannonic-acid derivatives

The D-manno-configured N-anisylated beta-lactam 40, the beta-lactam carboxy lic acids 4 and 43, and the corresponding phosphonic-acid isosters 49 and 5 0 have been synthesized from D-glucose in 8-10 steps, respectively None of these compounds exhibited a significant inhibitory activity in vitro agains t the sialidases of Vibrio cholerae, Salmonella typhimurium, Influenza A (N 9), and Influenza B virus. Cycloaddition of the in situ generated imines de rived from the D-erythroses 6, 16, and 17 with the ketene: from mesyloxyace tyl chloride (20) gave the 2-mesyloxy-D-hexono-1,3-lactams 25, 27a/b, 28a/b /c, and 29 in 23, 69, 57, and 90% yield, respectively (Scheme 3). Transform ation of 27a/b and 29 (> 85%) to the corresponding azides, followed by oxid ative N-deprotection, gave 30a/b (45%) and 34 (80%). Subsequent alkylation of the ring N-atom in 31a with benzyl bromoacetate and dibenzyl (triflyloxy methyl)phosphonate 46 gave the carboxylate 41 (77%) and the phosphonate 47 (55%; Schemes 4 and 5). Hydrogenolysis of 41 gave the beta-lactam amino aci d 43, besides its hydrolysis product 44. Reductive N-acylation of the azido group in 41 (93%), followed by hydrogenolytic debenzylation, yielded the 2 -trifluoroacetamido N-(carboxymethyl)-beta-lactam 4 (56%). Similarly, 47 ga ve the 2-trifluoroacetamide 48 (89%), and hence, the 2-amino-N-(phosphonoyl methyl)-beta-lactams 49 (40%) and 50, resulting from deacylation of 49 (14% ). Aminolysis and carbamoylation of the protected beta-lactams 31a and 35 l ed to the 2,3-diamino-2,3-dideoxy-D-mannonamides 51 and 53, respectively (S cheme 6).