4-alkylated monobactams. Chiral synthesis and antibacterial activity

Article abstract of DOI:10.1016/S0040-4020(01)92151-9

The synthesis of 4-alkylated monobactams by a variety of procedures is described. Two complementary procedures have been developed for the chiral synthesis of monobactams: (1) sulfonation of 4-alkyl-3-(protected)amino-2-azetidinones with various complexes of SO₃; and (2) cyclization of β-mesyloxyacyl sulfamates derived from β-alkyl-β-hydroxy-α-amino acids. The most general procedure involves introduction of the alkyl group via a Grignard reaction on 6-APA-derived sulfones 23 or 24 followed by sulfonation. For the specific case of (3S,trans-)-3-amino-4-methylmonobactamic acid (48), cyclization of the β-mesyloxyacyl sulfamate 40 derived from (L)-threonine is the preferred route. The introduction of 4-alkyl groups into monobactams results in a decrease in activity against gram-positive bacteria, an increase in activity against gram-negative bacteria, and an increase in β-lactamase stability. Increasing the size of the alkyl group beyond methyl results in diminished intrinsic antibacterial activity. 4β-Alkylmonobactams display better β-lactamase stability than their 4α-counterparts.