Noncanonical polyketide cyclization and stereoselective synthesis of configurationally stable Csp2-Csp3 atropisomers

Witzig, Reto Matthias. Noncanonical polyketide cyclization and stereoselective synthesis of configurationally stable Csp2-Csp3 atropisomers. 2019, Doctoral Thesis, University of Basel, Faculty of Science.


Official URL: http://edoc.unibas.ch/diss/DissB_13447

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Noncanonical Polyketide Cyclization
The restricted rotation about a single bond results in stereoisomers that are called atropisomers.
Most prominent are biaryl atropisomers, which have emerged to one of the most frequently used
scaffolds in stereoselective catalysis. These stereoisomers result from a rotationally restricted Csp2-
Csp2 single bond that can exhibit substantial configurational stabilities if sufficiently substituted
with sterically demanding groups in the ortho-position. However, the increased steric demand is
often accompanied with difficulties in the preparation and therefore the stereoselective synthesis
of biaryl atropisomers still remains challenging.
The arene-forming aldol condensation is a fundamental reaction in the biosynthesis of aromatic
polyketides. Strictly controlled by the polyketide synthases, the highly reactive poly-b-carbonyl
substrates are diverged into a countless number of aromatic natural products through selective
cyclization reactions. Fascinated by the eminent cyclization control, we examined the ability of
small-molecule catalysts to selectively convert noncanonical hexa-carbonyl substrates in a double
arene-forming aldol condensation culminating in the atroposelective synthesis of tetra-orthosubstituted
biaryls. The hexa-carbonyl substrates were accessed in a four-fold ozonolysis enabling
a late-stage introduction of all carbonyl functions in one step. Secondary amine catalysts capable
to form an extended hydrogen-bonding network triggered the noncanonical polyketide cyclization
in order to obtain tetra-ortho-substituted biaryls in up to 93% yield and with an excellent
stereocontrol of up to 98:2 e.r. The utile hydroxy functions in the 3,3’-position of the binaphthalene product were readily
converted into aryl substituents by a triflation and Suzuki cross-coupling reaction. The obtained
binaphthalene dicarbaldehyde enabled the straight-forward access to a diene ligand, a [5]helicene
as well as the highly valuable Maruoka catalyst in excellent yields. These transformations clearly
demonstrated the importance of the established method.
Stereoselective Synthesis of Csp2-Csp3 Atropisomers
Previous stereoselective catalysis aimed at achieving selectivity for one out of two stereoisomers
per stereogenic element (2n). Much less explored, but even more intriguing from a stereochemical
perspective, are atropisomers arising from the restricted rotation about Csp2-Csp3 axis. In this
exciting unprecedented stereochemical scenario, one out of six stereoisomers (>2n) arising from
such a rotationally restricted axis is potentially obtained selectively.
To achieve high configurational stability of Csp2-Csp3 atropisomers represents a great challenge
for the studies of these captivating rotational isomers, and previous investigations of the rotational
barrier and isomer-interconversions have been studied after separating racemic mixtures. In this
thesis, we intended to contribute to this research field by the development of a [2+2+2]-
cyclotrimerization for the first stereoselective synthesis of atropisomers resulting from a
rotationally restricted Csp2-Csp3 single bond. To suitably evolve stable atropisomeric products, an
adamantyl terminated trialkyne was converted into all three possible diastereoisomers of the Csp2-
Csp3 atropisomeric product. The low configurational stability of the stereoisomers first prevented
their stereoselective preparation, but detailed analysis of the rotational profile enabled to design
and synthesize a carbonyl derivative, which provided cyclotrimerization products that exhibit
remarkable configuration stability even at temperatures up to 100 °C. A rhodium catalyzed
[2+2+2]-cyclotrimerization permitted the first stereoselective synthesis and the reaction was
optimized for the (ap)-stereoisomer, which could be accessed in good yields of up to 75% and a
high enantiomeric ratio of 93:7 e.r. In addition to the selective preparation of the (ap)-
conformer, a second diastereoisomer was synthesized in enantioselectivities of up to 85:15 e.r. as
a preliminary result.
Advisors:Sparr, Christof and Ward, Thomas R.
Faculties and Departments:05 Faculty of Science > Departement Chemie > Chemie > Organische Chemie (Sparr)
UniBasel Contributors:Sparr, Christof and Ward, Thomas R.
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:13447
Thesis status:Complete
Number of Pages:1 Online-Ressource (xi, 341 Seiten)
Identification Number:
edoc DOI:
Last Modified:01 Sep 2021 01:30
Deposited On:16 Dec 2019 13:17

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