Regioselective Activation of Aminothiazole(iminoxyacetic acid)acetic Acid:  An Efficient Synthesis of the Monobactam Aztreonam

An efficient synthesis of the monobactam aztreonam [[2S-[2alpha,3beta(Z)]]-3[[(2-amino-4-thiazolyl)[(1-carboxy-1-methylethoxy)imino]acetyl]amino]-2-methyl-4-oxo-1-azetidinesulfonic acid] (1) by acylation of alpha-aminoazetidinone 22 with the regioselectively activated aminothiazoleiminoxyacetic diacid 15 or 18 is described. Reaction of benzhydryl ester 10 with N-hydroxybenzotriazole and dicyclohexylcarbodiimide followed by ester deprotection formed the monoacid amide 15. Alternatively, chemoselective transient silylation of, the diacid 9 followed by activation with N-hydroxysuccinimide formed active ester 18. Acylation of alpha-aminoazetidinone 22 with amide 15 or ester 18 produced aztreonam (1) in 75-85% yield.