First research update: Introductions, arrylpyrroles and sulfonates.

02 Oct
Published by Matin

Hello all,
I just wanted to introduce myself, I'm Matin and I started at the Todd lab in Sydney at the end of July and after 2 months I'm doing my first update on Synaptic Leap, I'll be talking about experiments which have been recorded in my lab book which can be found here.
During the first week I was directed towards this paper which would allow me to synthesise product sA on the current Arrylpyrrole wanted list using the following reaction path:
My lab book entry for this reaction can be found here.
The carboxylic acid starting material had already been made by Paul at the Sydney lab here, so it was a simple matter of retracing Paul's steps up to the carboxylic acid then using the coupling technique to get to the product.
This reaction worked well, with HNMR, CNMR and IR spectra suggesting that the desired compound was produced and it has now been sent for elemental analysis for confirmation.                                                   
I then set my sights on another compound on the list, the sulfonamide sE, which was previously worked on by Paul in the Sydney lab (link to his lab book here) he hasn't had much success with his aproach so I looked at other ways of doing it. One interesting method would have been to use DABSO combined with a grignard on the pyrrole as a means of sulfonating the pyrrole, it seemed a bit tricky to put the grinard on the pyrrole so more simpler ways were looked at first.

The approach I settled on was to sulfonate the pyrrole using sulfur trioxide-pyridine followed by forming a sulfonyl chloride to then react with a suitable amine to form the final compound. This would be the first step of the reaction:
Method can be found here.
When I tried this reaction here, the HNMR spectra of the product seems to be indicating that the sulfonate has added into both the 3 and 4 positions.

For my next attempt I will reduce the amount of of the Sulfur trioxide-pyridine complex used and see if that will stop it from adding into both positions. If this all goes to plan I will then be looking at different methods of chlorinating the sulfonate.
Thanks for reading my first update, and don't forget to leave feedback.
Matin Dean


MatTodd's picture

I still think that reaction is amazing. Can you briefly describe the precedence you've found for it, and any related reactions, including links to the relevant papers where possible?

And if you've sulfonated the lower case twice, Alice suggested we take that compound on too, which is a great idea. So don't throw it out...

The use of sulfur trioxide pyridine is looking promising. I was wondering have you considered forming the sulfonamoyl chloride and treating this with the pyrrole? Maybe using pyridine or 4-DMAP as a nucleophilic catalyst?

cdsouthan's picture

Inspired by being featured with the gang in Chemistry World  and PubChem pushing towards 50 mill, I would like to catch up with any searching you might think useful.   Can I request an SAR update/refresh  of say the "top ten" ?  Just a simple table would do of SMILES, InChIKey and IC50s.   If you have any outstanding "% inhbition" figures I'd suggest getting IC50s done so they are comparable.  I'd also suggest re-submiting at least your top-five for IC50s, so that time-separated  duplicates will provide some idea of variance.  

MatTodd's picture

Sure - I'm in Sydney this week. I'll get together with the local team and get this posted. I think the % inhibition figures are mostly for low-actives, though I do think we are waiting on a very early set of numbers from the Ralph group if memory serves. We're expecting biological data for the latest set of compounds in a week or so from Vicky's group, and that may inform our discussion, so we should wait till then - if the latest compounds (near neighbour thiazolidinone set) are good-looking (since we've made them more soluble) then they become of greater interest. Let'd revisit when we know. I'm not too concerned about resubmitting IC50s, but it's something we could do if there's a consensus that this is necessary. The reasons are: 1) early figures for the first round carried out by several labs were quite consistent, meaning spatial variance (another form of temporal variance..) is low, and b) the labs doing the evaluation have these assays running all the time, meaning there is unlikely to be a lot of variability in set-up. And degradation of compounds over time could presumbly be assessed by NMR. But very happy to vote on it.

cdsouthan's picture

Sounds fine but would still suggest in the gentlest possible way that it's imprudent to assume 1) or b) untill you accumulate  a substancial collated data set that defines this variance statistically.  The pharmacophore work is also dependant on this as you know.