near neighbours sythesis

26 Jan
Published by ZoeH

I've been working for six weeks now with the Todd Research Group at Sydney University as part of an undergraduate summer research program. The aim of my project is to synthesise analogues of this group of hits from the  antimalarial dataset released by GSK. They are referred to here as 'near neighbours' because they share the arylpyrrole moiety present in the two hits (TCMDC 123812 and 123794) Paul has been working on, but have a thiazolodinone side chain. The major components of my project are:
1. Paal-Knorr synthesis to make an arylpyrrole from an aniline derivative and 2,5-hexanedione:

2. Vilsmeier-Haack reaction to convert the arylpyrrole into an aldehyde:

3. Condensation reaction to combine the aldehyde with a thiazolidinone previously synthesised by Paul:

 
Some of the arylpyrroles and aldehydes had already been made by Paul and Laura before I came, and the condensation reaction goes very smoothly. This has allowed quite easy synthesis of a collection of near neighbours with variaion in the R groups shown above (here is a summary page of all the compounds I have made so far, with links to the relevant blog entries).
4. Recently I have also started exploring variations at the thiazolidinone end of the molecule, either by adding to the near neighbour or making new starting thiazolidinones.
This has been trickier so far - and my inexperience is showing more as I move into reactions that someone else in the lab hasn't already done. This is a bit challenging for me - it was quite easy to get used to the near neighbour syntheses where the product usually just precipitated out, clean, after a few hours, but also an opportunity for me to learn to apply some of the concepts I have learned mostly in a fairly abstract way in lectures. All comments, suggestions, and gently pointing out that I'm being an idiot welcome! At the moment I'm also excited about sending off the compounds I have already made for preliminary testing against the malaria parasite, hopefully at the end of next week.