[Molecules: 11] [Related articles/posters: 009 063 060 084 061 ]

New b-lactam analogues as antimicrobial agents: design and synthesis

Reuben Jih-Ru Hwu,* Shwu-Chen Tsay, Zahra Ranezani and Gholam H. Hakimelahi

Organosilicon and Synthesis Laboratory, Institute of Chemistry, Academia Sinica, Nankang, Taipei, Taiwan 11529, ROC and Department of Chemistry, National Tsing Hua University, Hsinchu, Taiwan 30043, ROC

Abstract

The cis-configurated race-(6RS,7RS)-3-hydroxy-8-oxo-7-(2-phen- oxyacetamido)-4-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid as well as rac-(6RS,7RS)-3-hydroxy-8-oxo-7-(2-phenoxy- acetamido)-4-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and rac-3-methyl 2-hydrogen (6RS,7RS)-8-oxo-7-(2- phenylacetamido)-4-oxa-1-azabicyclo[4.2.0]oct-2-ene-2,3- dicarboxylate were synthesized. The key step involves chlorination of the corresponding carbonions of rac-tert- butyl 3-{[cis-4-oxo-3-(2-phenoxyacetamido)azetidin-2-yl] methylthio}-3-oxopropanoate, rac-tert-butyl [cis-4-oxo-3- (2-phenoxyacetamido)azetidin-2-yl]methyl propanedioate, and rac-1-benzyl 4-methyl 2-[cis-4-(hydroxymethyl)-2-oxo-3- (phenylacetamido)azetidin-1-yl]-3-(phenylsulfonyl)butane- dioate with CF₃SO₂Cl followed by internal alkylation. Our newly synthesized b-lactams were found to possess biological activity aganist several pathogenic microorganisms in vivo. The pathogenic microorganisms include S. aureus (FDA 209P), E. coli (ATCC39188), S. typhi (O-901), Ps. aeruginosa (1101-75), and K. pneumoniae (NCTC418).

Electronic activation of the lactam moiety in rac-3- methyl 2-hydrogen (6RS,7RS)-8-oxo-7-(2-phenylacetamido)-4- oxa-1-azabicyclo[4.2.0]oct-2-ene-2,3-dicarboxylate resulted in a remarkably enhanced biological activity.

Scheme 1 Reagents and conditions: (a) CF₃SO₂Cl, Et₃N, CH₂Cl₂. b) CF₃CO₂H, CH₂Cl₂, 25 ^oC

Scheme 2 Reagents and conditions: (a) ClCOCH₂CO₂CH₂Ph, pyridine, CH₂Cl₂. b) CF₃SO₂Cl, Et₃N, CH₂Cl₂.

Scheme 3 Reagents and conditions: (a) CF₃SO₂Cl, Et₃N, CH₂Cl₂: 90% for 9 -> 11, 80% for 10 -> 12.

Scheme 4 Reagents and conditions: (a) CF₃SO₂Cl, Et₃N, CH₂Cl₂: 95% for 13 -> 16, 75% for 14 -> 17, no reaction with 15.

Scheme 5 Reagents and conditions: (a) ClCOCH₂CO₂Bu^t, pyridine, CH₂Cl₂: 40% for 4 -> 20, 58% for 18 -> 21, 70% for 19 -> 22. b) CF₃SO₂Cl, Et₃N, CH₂Cl₂: 60% for 20 -> 23 -> 26, 70% for 21 -> 24 -> 27, 46% for 22 -> 25 -> 28. c) Bu₄NClO₄, CF₃CO₂H, CH₂Cl₂: 80% for 26 -> 29, 85% for 27 -> 30.

Scheme 6 Reagents and conditions: (a) 1. CF₃SO₂Cl, Et₃N, CH₂Cl₂; 2. DBU. b) H₂ (50 psi), PdCl₂, AcOEt.