The synthesis and antibacterial activity of 3-[(Z)-2-alkoxyimino-2-(2-aminothiazol-4-yl)-acetamido]-2-azetidinone-l-sulfonic acid derivatives with a heteroatom-bound substituent at the 4-position are described. The effect of various 4-substituents on the antibacterial activity was examined. Some of these compounds showed excellent antibacterial activity especially against Gram-negative bacteria, including 63-lactamase-producing strains.Our earlier chemical modification of sulfazecinl,=' revealed that although some of the 4-unsubstituted 2-azetidinone-l-sulfonic acid derivatives with various 3-acylamino groups had improved antibacterial activity, these compounds generally lack the activity against 3-lactamase-producing strains.To correct for this deficiency we explored new derivatives having various 4-heteroatom-bound substituents". This paper deals with the synthesis and the antibacterial activity of 3-[(Z)-2-alkoxyimino-2-(2-aminothiazol-4-yl)acetamido]-2-azetidinone-l-sulfonic acid derivatives with 4-heteroatombound substituents. ChemistryReactions of the 4;3-methylsulfonyl compound (2Bb)°', or the 4a-acetoxy compound (2Aa) which is obtainable by hydrogenolysis of 3-benzyloxycarbonylamino derivative (1)°,-'' over Pd-black followed by tritylation with trityl chloride and triethylamine, with various nucleophiles (Y-) gave mixtures of the 4a-substituted-2-azetidinone derivatives (2Ac-h) and the 4,3-isomers (2Bc'h).The 4-methoxycarbonyllnethylthio derivatives (2Ae and 2Be) were converted into 4-carbamoylmethylthio derivatives (2Ai and 2Bi) by treatment with ammonia, and the 4,3-azido compound (2Bh) was transformed to the 4,3-triazolyl compounds (2Bj and 2Bk) by the 1,3-dipolar cycloaddition reactions' with methyl propiolate. 3-[2-(2-Aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-4-substituted -2-azetidinone-l-sulfonic acid derivatives (7a -k) were synthesized from these 3-tritylamino compounds (2A and 2B) as shown in Chart 2.