Total Syntheses of Natural Metallophores Staphylopine and Aspergillomarasmine A

Abstract

Staphylopine was discovered and functionally evaluated as a novel type of metallophore that Staphylococcus aureus employs to acquire multiple divalent transition metals. Aspergillomarasmine A (AMA), with a similar structure to staphylopine, was recently identified as an inhibitor of metallo-β-lactamases NDM-1 and VIM-2. Herein, we report a unified approach using Mitsunobu reaction as a key step to accomplish the concise and efficient total syntheses of staphylopine and AMA. We also elucidate the similar broad-spectrum metal chelation properties between staphylopine and AMA.

Aminocarboxylic acids related to aspergillomarasmine A (AMA) and ethylenediamine-N,N′-disuccinic acid (EDDS) are strong zinc-binders and inhibitors of the metallo-beta-lactamase NDM-1

“…6 This finding was followed by reports describing the chemical synthesis of AMA and its structural analogues. [7][8][9][10][11] Among them, synthetic routes using either a key N-nosyl protected aziridine intermediate 10 or a cyclic sufamidate 9 furnished AMA in relatively few steps and the highest reported yields (overall yields of 28% and 19% respectively).…”

Synthesis of Two Epimers of Pseudopaline

“…By the time this article was prepared, Zhang et al published the asymmetric synthesis of 4a and 4b , along with the attribution of the ( S,S,S ) configuration (the one of 4b ) to the natural product. This synthesis relies, as the one the same authors proposed for compound 3 , on the conversion of the amino groups in sulfonamides which are engaged, in turn, in an asymmetric Tsuji–Trost and a Fukuyama–Mitsunobu reactions. This elegant strategy presents anyhow some drawbacks, as it requires harsh deprotection conditions and a series of oxidations involving highly toxic reagents (i.e.…”

“…Recently, Zhang et al proposed a synthesis for 3 and 4 . Their strategy, similarly to the synthesis that we previously published for compound 5 , relies on the conversion of amines in sulfonamides, followed by N ‐alkylations for the construction of the main chain of the molecule.…”

Approaches for the discovery of metallo‐β‐lactamase inhibitors: A review

“…Inspired by AMA, Zhang synthesized a series of AMA derivatives. These compounds show varying degrees of synergy in combination with meropenem (). There are also some metal chelators, such as 1,4,7,10‐tetraazacyclod‐odecane‐1,4,7,10‐tetraacetic acid (DOTA, Figure .3) and 1,4,7‐triazacyclononane‐1,4,7‐triacetic acid (NOTA, Figure .4) (Somboro et al., ), which can also restore the activity of meropenem in different MBL‐producing bacterial strains.…”