Atroposelective and transannular catalyst-controlled polyketide cyclizations

Fäseke, Vincent C.. Atroposelective and transannular catalyst-controlled polyketide cyclizations. 2019, Doctoral Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_13293

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In polyketide biosynthesis, an intricate enzymatic machinery produces a myriad of complex aromatic core structures by folding and correspondingly cyclizing pre-assembled polyketide chains. As a result, aromatic polyketides possess a specific oxygenation pattern in their carbon backbones, which are often further diversified by tailoring processes such as glycosylations or oxidative transformations. The structural versatility of this class of natural products leads to unique molecular architectures and allowed to uncover highly potent antibiotic and anticancer drug-candidates. Atropisomeric polyketide scaffolds are among the most important structural motifs for bioactive congeners and may provide a well-defined design for novel organocatalysts or ligands for transition-metal catalysis.
Intrigued by the efficient construction of aromatic molecules by aldol cyclization cascades, we were inspired to employ biomimetic polycarbonyl substrates to perform stereoselective arene- forming aldol condensations by small-molecule catalysts. As a first part of this thesis, the development of an atroposelective arene-forming aldol condensation for the preparation of axially chiral aromatic amides was accomplished, which may provide novel chiral scaffolds for medicinal chemistry or catalysis.
The glyoxylic amide substrate enabled the de novo construction of axially chiral aromatic amides, involving the stereospecific transfer of the stereochemical information of the tetrazole catalyst into the configuration of the aryl–carbonyl bond. The remarkably fast arene-formation with a subsequent carbaldehyde reduction allowed the isolation of the corresponding configurationally stable aromatic amides with excellent atroposelectivity.Encouraged by the high reactivity of the glyoxylic amide substrate, we next prepared valuable tetra-ortho-substituted biaryls enantioselectivly from noncanonical hexacarbonyl substrates, with a unique 1,2-dicarbonyl functionality. These polyketides inspired substrates were readily accessible by a fourfold ozonolysis of biindene precursors. The twofold arene-forming aldol condensation was subsequently catalyzed by an aminoethanol proline catalyst controlled by a suitable hydrogen-bond network to fold the polycarbonyl substrate, leading to the desired aldolization mode and an excellent enantioinduction. Furthermore, the isolated di-ortho- carbaldehyde substituted biaryl scaffolds bear the ideal pattern of functional groups for further transformation to various valuable chiral molecular architectures such as the Maruoka catalyst and a [5]-helicene.
As a next step towards catalytic polyketide cyclizations, we focused on the development of a novel biomimetic methodology, enabling control of folding modes of highly reactive canonical polyketide substrates by applying their macrocyclic congeners. This strategy to reduce the number of conformational states was envisaged to allow for controlled transannular aldol cyclizations, triggering cascades to generate aromatic polyketides identical to naturally folded polyketide chains.
With the macrocyclic hexa-!-carbonyl substrate, formed through a twofold ozonolysis of the 1,4-diene precursor, the transannular aldol cyclization led to an intramolecular hemi-acetal
folding mode S folding mode F
intermediate that was selectively transformed in a retro-Claisen condensation to chromenone and further aromatic hexaketide products. In basic media, the typical folding modes of aromatic polyketides products generated by bacteria (folding mode S) and fungi (folding mode F) were obtained. In contrast, with acidic conditions the chromenone scaffold is exclusively formed. With the development of the symmetric model substrate, we proceeded to perform keto- processing leading after the first aldol cyclization already to in total five different aldol addition intermediates. Preliminary results provide a proof of concept that small-molecule catalysts enable control of the cyclization processes.
Advisors:Sparr, Christof and Baudoin, Olivier
Faculties and Departments:05 Faculty of Science > Departement Chemie > Chemie > Organische Chemie (Sparr)
UniBasel Contributors:Sparr, Christof and Baudoin, Olivier
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:13293
Thesis status:Complete
Number of Pages:1 Online-Ressource (XI, 326)
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edoc DOI:
Last Modified:31 Mar 2021 01:30
Deposited On:14 Nov 2019 09:39

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