Ruthenium-catalyzed azide-alkyne cycloaddition reactions for the synthesis of novel tricyclic compounds and synthetic receptors

Licentiate thesis, 2024

The ruthenium-catalyzed azide-alkyne cycloaddition (RuAAC) allows the synthesis of 1,4,5-
trisubstituted 1,2,3-triazoles. This translates into a synthetic flexibility which enhances the
scope of possible applications of this reaction, both in terms of synthetic methodology
development, but also in other fields, such as the preparation of synthetic receptors. This thesis
has focused on the use of the RuAAC reaction in two different contexts.
In Part I of this thesis, the RuAAC reaction was employed together with a ruthenium-catalyzed
hydrogen borrowing reaction to develop a double cyclization strategy, which resulted in an
atom economic assembly of tricyclic 1,5-fused 1,2,3-triazole piperazines from a proline
scaffold. The RuAAC-cyclization process was characterized by mild reaction conditions,
attaining up to 99% yield of the desired products. Additionally, the utilization of intramolecular
hydrogen borrowing reaction on these RuAAC products afforded fused triazole piperazines in
varying yields, ranging from moderate to good. This methodology holds promise for the
synthesis of natural product analogues as well as bioactive compounds, suggesting broader
implications for drug discovery and chemical biology.
Another application of the RuAAC reaction lies in the design of synthetic receptors for
biosensing applications. In response to the growing need for rapid and efficient diagnostic tools
targeting antibiotic-resistant bacteria, Part II of this focuses on the development of a novel class
of biosensors, where synthetic receptors are employed for recognition and graphene will serve
as a sensing platform. Traditional diagnostic methods often rely on complex biomolecules such
as antibodies or enzymes acting as receptors, posing challenges in accessibility and
functionalization. To address this, the use of synthetic organic receptors is proposed. In this
novel class of receptors, differently functionalized 1,4,5-trisubstituted 1,2,3-triazoles will serve
as building blocks (monomers) to construct oligomers, given their ability to function as
isosteres for peptidic bonds. Click chemistry, and in particular the RuAAC reaction offers an
efficient method for a modular synthesis of the required triazole monomers, promising a
versatile platform for receptor design. To synthesize the target oligomers, a Sonogashira
reaction was initially used to create internal alkynes, which were subsequently employed as
substrates for the ruthenium-catalyzed azide-alkyne cycloaddition. This process enabled the
production of structurally diverse monomers. Next, these monomers were combined through
amide coupling to form dimers which were further reacted with additional monomers to
produce trimers. The obtained trimers are currently being tested for their interactions with
biomolecules, using UV/Vis and fluorescence spectroscopy. A pyrene-appended trimer was
also designed for immobilization of the synthetic receptor onto graphene, to create the final
biosensor platform.