Infections are becoming the leading cause of death worldwide. In 2019 alone, microbial infections caused 13.7 million deaths worldwide, of which at least 1.27 million were directly linked to infections with antibiotic-resistant bacteria. β-Lactam antibiotics remain the most effective weapon against bacterial infections, but due to frequent and often improper use, bacteria are increasingly developing resistance to them. The most clinically relevant mechanism of resistance to β-lactam antibiotics is inactivation by β-lactamases. While effective inhibitors exist for serine β-lactamases, only monobactams remain effective against bacteria that are expressing metallo-β-lactamases. Therefore, in this master’s thesis, we have developed and optimized a multi-step synthetic route to desmethoxysulfazecin, a precursor to the only naturally occurring monobactam with antibacterial activity (i.e. sulfazecin).
Desmethoxysulfazecin was synthesized via a multi-step asymmetric synthetic route. The synthesis of the requisite amine was initiated from L-serine, which was protected on the amino group (-NH2) with a tert-butyl carbamate; the free carboxyl group (COOH) was then coupled with an amine protected by a benzyl ether group. The nitrogen atom of the newly formed amide was then linked to the C-3 carbon on the β-lactam ring. A second tert-butyl carbamate protecting group was then added onto the secondary nitrogen, and after removing the benzyl ether by hydrogenation, the sulfonation of the nitrogen atom in the β-lactam ring was achieved. Finally, both tert-butyl carbamate protecting groups were cleaved under acidic conditions, enabling the isolation of amine 7a.
The synthesis of the carboxylic acid sidechain began with 2-pyrrolidone-5-carboxylic acid, whereas its free COOH group was first protected as benzyl ether and the amino group with benzyl carbamate protecting group. The pyrrolidone ring was then opened, and the free carboxyl group was coupled with tert-butyl ester-protected D-alanine, which was subsequently deprotected to isolate free carboxylic acid 12. Compounds 7a and 12 were then coupled into an amide, after which the benzyl and benzyl carbamate protecting groups were simultaneously removed, yielding compound 21. All compounds obtained during the synthesis were evaluated using nuclear magnetic resonance (NMR), and new compounds were further analysed using mass spectrometry.
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