Abstract
This thesis concerns the chemistry of polyether ionophores (PEI). PEIs are highly complex,
naturally occurring secondary metabolites of Streptomyces bacteria and belong to a family
of compounds called ionophores, that are capable of transporting ions across biological
membranes. Their narrow role within veterinary medicine contrasts with their potent
inhibitory activity against multidrug-resistant bacterial strains that offer a potential
solution in the face of emerging antimicrobial resistance. Largely due to their indiscriminate
toxicity, no human trails have, however, been reported to this date. By developing synthetic,
PEI-like molecules an increased selectivity is believed to be attainable, however
diversification of these highly complex molecules is intrinsically challenging. From a
methodological perspective, we hypothesized that the coupling between silyl enolates/silyl
ketene acetals with in situ formed oxocarbenium ions could be leveraged to enable efficient
synthesis of the prototypical attached ether rings that comprise core structural elements of
all PEIs. Furthermore, these couplings could be advantageously performed in an iterative
manner to rapidly access complex natural product-like molecules. The thesis presents the
development of this method and, as a proof of concept, its use to conduct a formal synthesis
of the well-known PEI, lasalocid acid A, as its enantiomer. In future biological studies, this
chemistry will allow us to investigate the role of chirality for the biological activity of
lasalocid and ultimately prepare synthetic PEI-like molecules with potential potent
antibiotic properties.
naturally occurring secondary metabolites of Streptomyces bacteria and belong to a family
of compounds called ionophores, that are capable of transporting ions across biological
membranes. Their narrow role within veterinary medicine contrasts with their potent
inhibitory activity against multidrug-resistant bacterial strains that offer a potential
solution in the face of emerging antimicrobial resistance. Largely due to their indiscriminate
toxicity, no human trails have, however, been reported to this date. By developing synthetic,
PEI-like molecules an increased selectivity is believed to be attainable, however
diversification of these highly complex molecules is intrinsically challenging. From a
methodological perspective, we hypothesized that the coupling between silyl enolates/silyl
ketene acetals with in situ formed oxocarbenium ions could be leveraged to enable efficient
synthesis of the prototypical attached ether rings that comprise core structural elements of
all PEIs. Furthermore, these couplings could be advantageously performed in an iterative
manner to rapidly access complex natural product-like molecules. The thesis presents the
development of this method and, as a proof of concept, its use to conduct a formal synthesis
of the well-known PEI, lasalocid acid A, as its enantiomer. In future biological studies, this
chemistry will allow us to investigate the role of chirality for the biological activity of
lasalocid and ultimately prepare synthetic PEI-like molecules with potential potent
antibiotic properties.
| Originalsprog | Engelsk |
|---|
| Udgivelsessted | Aarhus |
|---|---|
| Forlag | Aarhus University |
| Antal sider | 147 |
| Status | Udgivet - apr. 2024 |