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Nouvelle approche synthétique vers des analogues de l'avibactam et cyclisations de N-alkoxyurées insaturées initiées par des réactifs d’iode(III) hypervalent

Abstract : The current dire situation of antimicrobial resistances urges synthetic chemists to design new molecules that can fight these resistances. Hence, the diazabicyclo-octanes β-lactamase inhibitors are of particular interest, as they can preserve the current therapeutic arsenal by restoring the activity of β-lactam antibiotics. Thus, avibactam was very recently approved by the FDA and the EMA in combination with ceftazidime (a 3rd generation cephalosporin antibiotic) for the treatment of severe Gram-negative bacteria infections. Structurally, these compounds are characterized by a bicyclic framework featuring a cyclic N-hydroxylated urea motif that is key to its activity. Yet, only few methods exist to easily access this singular type of saturated heterocycles. The aim of this project was to develop a new synthetic approach to acces a new range of avibactam analogues. For this, we developed chemoselective iodine(III)-mediated cyclizations of unsaturated N-alkoxyureas. We were able to optimize and study three different cyclizations that proceed through distinct mechanisms to yield oxazolidinone oximes, or N-oxyimidazolidinones from the same substrates. The different modes of cyclization can be triggered using a combination of the iodine(III) and a halide salt or TEMPO, under reaction conditions which are operationally simple and easily tunable. In parallel, we also devised asymmetric synthesis of a key monocyclic intermediate which should yield avibactam analogues, through a new synthetic route that relies on the methodology we developed.
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Submitted on : Friday, January 10, 2020 - 3:45:08 PM
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Laure, Peilleron. Nouvelle approche synthétique vers des analogues de l'avibactam et cyclisations de N-alkoxyurées insaturées initiées par des réactifs d’iode(III) hypervalent. Chimie organique. Université Paris-Saclay, 2019. Français. ⟨NNT : 2019SACLS408⟩. ⟨tel-02435157⟩

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