Towards Higher Generations of Linear Tröger's Base Analogues

Abstract

This project work was done at the Centre for Analysis and Synthesis (CAS)at the Department of Chemistry at Lund University in cooperation with the Universität Leipzig in the period of November 2011 to April 2012. In that time the synthesis of the precursor leading to the so called tris-Tröger's base was accomplished. Starting point of the synthesis was 4-bromo-3-methylaniline, which was functionalized in para-position to the methyl group with an iodine residue, followed by a condensation reaction to the Tröger's base. Two dierent reactions were tested for the removal of the iodine moiety. The dehalogenation
with zinc powder and HCl in EtOH proved to be the more suitable than the
lithiation with n-BuLi and exchange with a proton. The bromine substituents were transformed into amine groups via a Buchwald-amination and were subsequently protected with TMS-groups. The racemic mixture was lithiated with t-BuLi and further reacted with R-menthyl chloroformate. The corresponding diastereomers of the Tröger's base were formed and separated with column chromatography. With the single diastereomer at hand the ester was reduced to an alcohol with LAH.

From there the next steps would have been the alkylation of the hydroxyl
groups, the deprotection with TBAF and the monoprotection by triuoroacetic anhydride to achieve a desymmetrization. This would have been necessary for the following condensation with paraformaldehyde in TFA that leads to the tris-Tröger's base. This molecule should have been the subject of further isomerization studies. Optimization of the syntheses and the full characterization of the compounds were also in the focus of this project.

Abstract

Popular Science Summary
The aim of this project was the synthesis of the tris-Tröger's base, a molecule with three Tröger’s base units
and four aromatic rings fused together linearly. Because syn-syn-tris-Tröger's bases have a unique concave
structure, the idea stands to reason, that if several bases in syn-syn conformation are combined in a linear way
a helical structure will be taken. These helical nanotubes generated by this novel approach could be integrated
into membranes for mass transport or if they intercalate preferentially with cancer DNA it could be used for
cancer treatment.
When the target molecule would be synthesized, not only its structure would have been of interest, which
should be determined by X-ray diffraction analysis, but also its behaviour in non-aqueous acidic conditions.
Under these conditions isomerization should occur and three different diastereoisomers would be possible
(syn-syn, anti-anti, syn-anti), with syn-syn being the preferred one. It is of great importance to determine which
one is preferably formed, if and how one can influence this equilibrium, so one has a tool at hand to
interconvert these diastereomers.
Starting from the 4-bromo-3-methylaniline the wanted tris-Tröger’s base should be synthesized in ten reaction
steps. Seven reaction steps were carried out and the optimization of the reaction conditions and the scale-up
were at the focus of the work. The target molecule was almost obtained. Its structure determination via X-ray
diffraction analysis is still pending, as well as the studies concerning its isomerisation behaviour.

• author: Klische, Michaela
• supervisor: Sami Dawaigher
• organization: Department of Chemistry
• course: KEMP31 20121
• year: 2012
• type: H2 - Master's Degree (Two Years)
• subject: Chemistry
• keywords: Organisk kemi
• language: English
• id: 3222074
• date added to LUP: 2012-12-11 15:55:52
• date last changed: 2012-12-11 15:55:52