Atroposelective Arene-Forming Alkene Metathesis using Small Molecule Catalysts and Artificial Metalloenzymes

Jončev, Zlatko. Atroposelective Arene-Forming Alkene Metathesis using Small Molecule Catalysts and Artificial Metalloenzymes. 2022, Doctoral Thesis, University of Basel, Faculty of Science.

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Atropisomers arise due to hindered rotation about a single bond. These compounds have gained significant importance because of their structural diversity in natural products. Amongst others, biaryl systems emerged as a significant class as the most frequently encountered atropisomers. The structure of biaryls dictates the behavior of the dynamic of the rotation with substituents in the vicinity of the axis having the most significant effect on the barrier of rotation. Three or four ortho substituents typically lead to a high energy barrier to rotation, which renders some atropisomers practically indefinity configurationally stable. Understanding the connection between structure and rotational profile of atropisomers has led to widespread adoption in stereoselective catalysis, medicinal chemistry, and biology among other fields. This distinct trend in the application of configurationally restricted compounds is coupled with the development of methods for their creation, rendering enantioselective synthesis of atropisomers highly valuable.
Stereoselective arene-formation represents a powerful methodology that utilizes the thermodynamic stability of aromatic rings as the driving force behind the reaction. As an otherwise reversible transformation, alkene metathesis has benefited from this strategy. Fascinated by the remarkable alkene metathesis reaction, we examined the ability of in situ formed molybdenum binolate complexes to selectively convert triene substrates in an arene-forming atroposelective alkene metathesis to access 2-methoxybinaphthalenes. Triene substrates were accessed via a short synthetic sequence, and the (E) isomer was crystallized or chromatographically purified and used as such. In situ formed molybdenum catalytic systems bearing electron-deficient binols can trigger a remarkably efficient and highly atroposelective catalysis to obtain methoxy substituted biaryls in up to 99% yield with excellent stereocontrol of up to 98:2 e.r. (Scheme 1).The absolute configuration of the binaphthalene product and the binol ligand, combined with the experimentally supported critical role of the methoxy group, was utilized to propose a tentative stereoselectivity model (Scheme 2). Coordination of the methoxy group to the molybdenum metal center is proposed in the anti alkylidene intermediate as the main factor contributing to substrate preorganization during the stereocontrol of the biaryl axis.
Atroposelective Metathesis using Artificial Metalloenzymes
Artificial metalloenzymes have benefited from the intrinsic reactivity of metal ions combined with highly arranged spatial orientation and tunable structure of protein scaffolds. These catalysts complement natural enzymes and expand the repertoire of new-to-Nature reactions representing an exciting opportunity for targeted delivery of drugs. Multiple strategies for anchoring catalytically active metal centers have emerged, among which biotin-streptavidin (biot-SAV) supramolecular assembly represents a privileged scaffold.
The development of catalysts for alkene metathesis paved the way for this transformation to become a very powerful method for formation of double bonds, natural product synthesis, and polymer synthesis. In the context of artificial metalloenzymes, several protein scaffolds have been modified to include various Grubbs-Hoveyda type alkene metathesis catalysts that can promote ring-closing metathesis or ring-opening metathesis polymerization. Intrigued by the concept of artificial metalloenzymes for metathesis, also known as metathases, we examined the ability of supramolecularly assembled biot-Ru-SAV to catalyze the atroposelective metathesis of water-soluble triene system and form configurationally stable binaphthalenes (Scheme 3). Triene substrate was designed to increase the water solubility by incorporating the polar ammonium group on the terminal carbon of the double bond of the side chain. Supramolecular biot-Ru-SAV metathase can stereoselectively promote first atroposelective arene-forming metathesis of the water-soluble triene system, converting it to a binaphthalene product. Site-directed mutagenesis of SAV at positions S112 and K121 showed that hydrophobic amino acid residues are the most beneficial for the selectivity of the product obtained. Binaphtalene was obtained in a low 12% yield with good selectivity of 81:19 e.r. as a preliminary result.
Advisors:Sparr, Christof and Ward, Thomas R. R. and Leroux, Frédéric R.
Faculties and Departments:05 Faculty of Science > Departement Chemie > Chemie > Bioanorganische Chemie (Ward)
05 Faculty of Science > Departement Chemie > Chemie > Organische Chemie (Sparr)
UniBasel Contributors:Sparr, Christof
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:14792
Thesis status:Complete
Number of Pages:xiv, 260
Identification Number:
  • urn: urn:nbn:ch:bel-bau-diss147928
edoc DOI:
Last Modified:09 Sep 2022 05:48
Deposited On:02 Sep 2022 09:47

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