Manganese(III) Promoted Cyclization of N-alkenyl-N-(2-hydroxyethyl) amides to Iso-Oxacepham Potent β-Lactamase Inhibitors

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,Poland

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.

Cite this article as:

Punda Paweł , Schielmann Marta and Makowiec Slawomir *, Manganese(III) Promoted Cyclization of N-alkenyl-N-(2-hydroxyethyl) amides to Iso-Oxacepham Potent β-Lactamase Inhibitors, Letters in Organic Chemistry 2017; 14 (5) . https://dx.doi.org/10.2174/1570178614666170321123252