Stereodivergent synthesis of oligo-1,2-naphthylenes and studies towards the total synthesis of naphthacemycin B1

Lotter, Dominik. Stereodivergent synthesis of oligo-1,2-naphthylenes and studies towards the total synthesis of naphthacemycin B1. 2019, Doctoral Thesis, University of Basel, Faculty of Science.


Official URL: http://edoc.unibas.ch/diss/DissB_13292

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Nature is taking advantage of the complex polyketide synthase machinery to assemble, cyclize and modify numerous polyketide natural products.[1] Many of these compounds show antibiotic properties, making them interesting targets for studies of their biosynthesis, bioactivity and also potential total syntheses. Among these natural polyketides many atropisomeric compounds can be found, of which some have a unique way of forming the stereogenic axis. The involved key step in the biosynthesis of this rare class of atropisomeric natural products was proposed to be atroposelective arene-forming aldol condensation rather than the often-found oxidative dimerization (Scheme 1).[2] A synthetic counterpart of nature’s aldol condensation was developed in our group, enabling the synthesis of various compounds with a configurationally stable axis.[3] Besides other scaffolds, oligo-1,2-naphthylenes with two consecutive axes were synthesized with an enantioselective and a substrate-controlled diastereoselective arene-forming aldol condensation.[4] These structurally interesting oligomers can be valuable scaffolds for placing substituents in a precise and predictable spatial relationship.
Stereodivergent Synthesis of Oligo-1,2-naphthylenes:
Due to the configurationally stable axes between the subunits of oligo-1,2-naphthylenes, synthetic issues arise from the exponential growth of potential diastereomers. In this thesis, we therefore addressed this issue and aimed for the development of a diastereodivergent, atroposelective arene-forming aldol condensation, enabling the synthesis of different diastereoisomers of oligo-1,2-naphthylenes with different lengths.[5]
An iterative chain elongation sequence consisting of a C10 building block addition, an in situ double-oxidation and the arene-forming aldol condensation enabled an efficient assembly of the oligomers.[6] The key transformation – the arene-forming aldol condensation – was achieved under substrate stereocontrol to obtain a series of oligomers with a non-helical secondary structure. Subsequently, the inherent substrate-stereocontrol was efficiently inverted with amine- or ion-pairing catalysis to obtain helically shaped oligomers with up to four consecutive stereogenic axes. This synthesis represents the first example of a stereodivergent method for the synthesis of compounds with multiple elements of axial chirality. The properties of the corresponding oligomers were subsequently studied and provided the first insight into the structure of configurationally stable oligo-1,2-arylenes. These analyses revealed a densely packed helical secondary structure, confirming low flexibility and high configurational stability and hence making the oligo-1,2-naphthylenes a valuable molecular scaffold for various applications. In different collaborations first applications – as mono-dentate phosphine ligands for gold- and palladium-catalysis, as bridge between a photosensitizer and an electron-donor, and as catalysts for asymmetric epoxidations – have been studied and promising preliminary results have been achieved.
Studies Towards the Total Synthesis of Naphthacemycin B1:
With the arene-forming aldol condensation being inspired by the biosynthesis of polyketides, we were strongly interested in the structure of fasamycin congeners, which are proposed to be formed in an atroposelective arene-forming aldol condensation.[2] Applying the synthetic methods developed in our laboratories would give an insight into the biosynthesis of these compounds, and moreover enable the very first stereoselective total synthesis of a member of this class of natural products.[3] To achieve an efficient total synthesis we aimed to develop an (enolendo)-exo-trig aldol cyclization, hence avoiding an exo-cyclic carbonyl group, as it is formed in the established (enolexo)-exo-trig arene-forming aldol condensation.[7,8]
The studies towards the total synthesis of the fasamycin congener naphthacemycin B1 led to the development of a new reductive Friedel-Crafts cyclization, enabling an efficient assembly of the dihydro-anthracene core-structure. The desired (enolendo) cyclization was achieved with three different model substrates, though yet unselective. The first substrate, containing an acetonyl side-chain, was successfully cyclized with sodium amide as base and a secondary amine catalyst to obtain the corresponding binaphthalene. The same product was obtained with a substrate with an a-bromo acetonyl side chain through an interesting phosphine mediated titanium enolate formation. Finally, also a substrate containing a b-keto ester side chain was efficiently cyclized to the tetra-ortho-substituted biaryl in a Lewis acid mediated reaction. Based on these results, the ongoing studies in the group focus on the stereoselective synthesis of naphthacemycin B1.
Advisors:Sparr, Christof and Mayor, Marcel
Faculties and Departments:05 Faculty of Science > Departement Chemie > Chemie > Organische Chemie (Sparr)
UniBasel Contributors:Lotter, Dominik and Sparr, Christof and Mayor, Marcel
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:13292
Thesis status:Complete
Number of Pages:1 Online-Ressource (xiv, 327 Seiten)
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edoc DOI:
Last Modified:01 May 2021 01:30
Deposited On:13 Nov 2019 14:18

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