Title:Manganese(III) Promoted Cyclization of N-alkenyl-N-(2-hydroxyethyl) amides to Iso-Oxacepham Potent β-Lactamase Inhibitors
VOLUME: 14 ISSUE: 5
Author(s):Paweł Punda, Marta Schielmann and Slawomir Makowiec*
Affiliation:Department of Organic Chemistry, Faculty of Chemistry, Gdańsk University of Technology, Narutowicza 11/12, 80 233 Gdańsk, Department of Pharmaceutical Technology and Biochemistry, Faculty of Chemistry, Gdańsk University of Technology, Narutowicza 11/12, 80-233 Gdańsk, Department of Organic Chemistry, Faculty of Chemistry, Gdańsk University of Technology, Narutowicza 11/12, 80 233 Gdańsk
Keywords:β-lactams, β-lactamase inhibitors, iso-oxacephams, radical cyclizations, N-alkenylamides, cyclization.
Abstract:Background: β-Lactams are still a subject of interest of organic chemists. The main reason
for this interest is due to their application as a chemotherapeutic. β-Lactam antibiotics are still the most
commonly used drugs in bacterial infections.
Method: Methods using 4-exo-trig radical cyclization leading to β-lactams are an alternative to classical
Staudinger`s β-Lactams formation. We prepared N-alkenyl-N-(2-hydroxyethyl)amides to check the
action of internal nucleophile. In the next step, with use of Mn(OAc)3 promoted radical cyclization 3-
carbamoyl, 3-tiocarbamoyl and 3-phosphoryl β-lactams containing intramolecular nucleophile were prepared.
These intermediates were able to induce the second ring closing through a carbocation trapping.
Results: Iso-oxacepham derivatives were synthesized by the 4-exo-trig radical cyclization as innovative
one-pot approach. Subsequent cyclization process of N-alkenyl-(2-hydroxyethyl)amides to 7-
substituted iso-oxacephams was described. Influence of carbamoyl, thiocarbamoyl and phosphoryl
moieties located on C-7 position of iso-oxacephamic scaffold on β-lactamase inhibitory activity was
confirmed on bacterial β-lactamases from group C.
Conclusion: In this paper, we describe alternative approach for the synthesis of 7-substituted isooxacepham.
The hypothetic reaction mechanism for the second ring closing was confirmed. The β-
lactamase inhibition was observed in case of four synthesized compounds.
