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

• Published in: Letters in organic chemistry Vol. 14; no. 5; pp. 337 - 346
• Main Authors: Punda, Pawel, Schielmann, Marta, Makowiec, Slawomir
• Format: Journal Article
• Language: English
• Published: SHARJAH Bentham Science Publ Ltd 01.06.2017
• Subjects: Chemistry; Chemistry, Organic; Physical Sciences; Science & Technology; radical cyclizations; FREE-RADICAL CYCLIZATIONS; beta-lactams; beta-lactamase inhibitors; iso-oxacephams; 1-OXACEPHAMS; REACTIVITY; ISOCEPHEMS; cyclization; N-alkenylamides; IN-VITRO ACTIVITY; ENAMIDES
• DOI: 10.2174/1570178614666170321123252
• ISSN: 1570-1786

Background: beta-Lactams are still a subject of interest of organic chemists. The main reason for this interest is due to their application as a chemotherapeutic. beta-Lactam antibiotics are still the most commonly used drugs in bacterial infections. Method: Methods using 4-exo-trig radical cyclization leading to beta-lactams are an alternative to classical Staudinger`s beta-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 beta-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 beta-lactamase inhibitory activity was confirmed on bacterial beta-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 beta-lactamase inhibition was observed in case of four synthesized compounds.