Catalyst Controlled Divergent Transannular Polyketide Cyclizations and Selective Preparation of Stereoisomers with Threefold Stereogenicity

Raps, Felix Calvin. Catalyst Controlled Divergent Transannular Polyketide Cyclizations and Selective Preparation of Stereoisomers with Threefold Stereogenicity. 2021, Doctoral Thesis, University of Basel, Faculty of Science.

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Aromatic polyketides are generated in a divergent fashion from linear polyketide chains. These seemingly simple building blocks are selectively generated and cyclized by intricate enzymatic machinery controlling almost every step of the process. With the recent progress on small molecule catalysis and the diverse activation modes unveiled, the question arises whether aromatic polyketides could be prepared selectively in a small molecule- controlled fashion. In this thesis, the development and investigation of a macrocyclic polyketide is presented which possesses a reduced number of reactive conformers compared to its linear hexaketide congener. The behavior of the polyketide under various stoichiometric conditions are outlined and its selective transformations based on small molecule catalysts are described. A variety of folding patterns observed in Nature were observed and the products characterized. The intricate biosynthesis of aromatic polyketides has the toolset to selectively reduce the highly reactive intermediary polyketide chains, controlling the oxygenation of the resulting aromatic polyketide products. This process of selective reduction was addressed in the substrate synthesis of the macrocyclic polyketide, whereas control over the oxygenation-pattern of the cyclization products by small-molecule catalysis is described. Subsequently employed conditions of the previously developed ring-opening/ring-closing cascade selectively formed the aromatic polyketides.
Higher order stereogenicity is observed in scaffolds possessing non-classical stereogenic elements leading to (>2)n stereoisomers arising from n stereogenic elements. The isolation of stable, non-interconverting stereoisomers is well described for stereogenic axes which are restricted in rotation about a single bond. Recently, our group disclosed a strategy controlling the stereoisomeric ratio of a sixfold stereogenic element in a triptycene based scaffold via [2+2+2]-cyclotrimerization which is the first example of catalyst-controlled, stereoselective preparation of a non-binary stereogenic element. Inspired by the delicate control exceeding the dualism of stereogenic elements, in this thesis, the development of selective preparations of threefold stereogenic elements is outlined. A highly reactive alkyne was designed, and the selectivity of the intermolecular cycloadditions studied. The corresponding iptycene products bearing the threefold Csp3–Csp3 stereogenic axis were formed in full regioselectivity and diastereoselectivity. Furthermore, a stepwise approach was designed for the enantioselective preparation of the iptycene with a threefold stereogenic axis. The cycloaddition was performed with alkenes forming the intermediate Diels-Alder product with high conversions, enantiomeric excess and full diastereomeric excess. Preliminary studies on the subsequent oxidation to remove point stereogenic elements led to enantioenriched threefold stereogenic iptycenes in enantiomeric excess, retaining the diastereomeric ratio. In addition to the well investigated iptycene scaffolds with Csp3–Csp3 based stereogenic axes, 9-substituted fluorenes are known for twofold stereogenicity about a Csp2–Csp3 stereogenic axis. First modifications led to a semi-stable threefold stereogenic element which was investigated by NMR and chromatographic analyses, laying the foundation for future developments to further increase the barrier to enantiomerization.
Advisors:Sparr, Christof and Gillingham, Dennis and Müller, Michael
Faculties and Departments:05 Faculty of Science > Departement Chemie > Chemie > Organische Chemie (Sparr)
UniBasel Contributors:Raps, Felix and Sparr, Christof and Gillingham, Dennis
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:14548
Thesis status:Complete
Number of Pages:XVI, 281
Identification Number:
  • urn: urn:nbn:ch:bel-bau-diss145482
edoc DOI:
Last Modified:14 Dec 2021 05:30
Deposited On:13 Dec 2021 10:47

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