Multigram-scale chemoenzymatic synthesis of diverse aminopolycarboxylic acids as potential metallo-β-lactamase inhibitors

Mohammad Faizan Bhat, Alejandro Prats Luján, Mohammad Saifuddin, Peter Fodran, Gerrit J. Poelarends*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Toxin A, a precursor to naturally occurring aspergillomarasmine A, aspergillomarasmine B, lycomarasmine and related aminopolycarboxylic acids, was synthesized as the desired (2S,2′S)-diastereomer on a multigram-scale (>99% conversion, 82% isolated yield, dr > 95 : 5) from commercially available starting materials using the enzyme ethylenediamine-N,N′-disuccinic acid lyase. A single-step protection route of this chiral synthon was developed to aid N-sulfonylation/-alkylation and reductive amination at the terminal primary amine for easy derivatization, followed by global deprotection to give the corresponding toxin A derivatives, including lycomarasmine, in moderate to good yields (23-66%) and with high stereopurity (dr > 95 : 5). Furthermore, a chemoenzymatic route was developed to introduce a click handle on toxin A (yield 72%, dr > 95 : 5) and its cyclized congener for further analogue design. Finally, a chemoenzymatic route towards the synthesis of photocaged aspergillomarasmine B (yield 8%, dr > 95 : 5) was established, prompting further steps into smart prodrug design and precision delivery. These new synthetic methodologies have the prospective of facilitating research into the finding of more selective and potent metallo-β-lactamase (MBL) inhibitors, which are urgently needed to combat MBL-based infections.

Original languageEnglish
Article number22
Pages (from-to)491-495
Number of pages5
JournalOrganic and Biomolecular Chemistry
Volume2024
Issue number3
Early online date12-Dec-2023
DOIs
Publication statusPublished - 2024

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