Progress on the Synthesis of Suggested Compounds

[edwintse]

Thank you again to the winners for all the interesting suggestions for new active compounds (#19)! With so many different steps, I've been multitasking as much as possible to make these compounds as quickly as I can so in case you have been wondering where we are currently at with this, I've put together the scheme below which outlines that progress that I have made thus far. The coloured arrows represent the status of the reactions (green = done, blue = in progress, red = not yet started). I'll try to update this scheme as I knock off more of the intermediates. Final compounds and their suggesters are in the shadowed boxes. All the experimental information can be found in my ELN.

[edwintse]

UPDATE: The two compounds in green (Optibrium/Intellegens and Davy Guan) were successfully synthesised and sent for potency evaluation at the end of last week. We should be getting the results back before the one-day meeting on the 31st where they will be shared.

Regarding the remaining two compounds:

• The nitrile reduction step for Exscientia's compound proved troublesome. We have found an alternative starting material which removes the need to do this step. I'll complete this compound once we receive the reagent.
• The coupling of the pyrrole alcohol with the core was relatively messy and in low yield. Due to the cost of the pyrrole acid starting material we have decided to pursue the second suggestion from Giovanni. The starting materials are very cheap so there are two options to make the target compound: 1) protection/deprotection as for the first compound which has more steps but would be cleaner, or 2) direct coupling with the diol which will be messier but require less steps. I'll give option 2 a go first.

[gcincilla]

Very good @edwintse, thank you for the update.
I would have a question: so, we should consider our molecule containing the pyrrole group as synthetically not accessible or you will do other attempts?

[edwintse]

@gcincilla I think the pyrrole compound is still synthetically accessible but based on the relative cost of the required starting material/the the synthesis required if we were to make the material, we decided not to buy more for now. I may have a few mg that I might be able to purify from my first reactions so it's possible I'll still have it made. If not, it will go on the desired compounds list.

[edwintse]

UPDATE: I've just finished making the remaining two compounds and have sent them for evaluation. By the time we get the results back we should have written most of the paper so the last thing should be putting in the potencies and making any comments about the results.

[edwintse]

UPDATE: We are going to try making a few extra compounds that should hopefully add the results for the paper. They are shown as Set 2 in the bottom of the scheme. I'm currently working on making the amino derivative of the Exscientia compound. Shouldn't be too hard and I should have it by next week. We've ordered in the furan SM and that should be a quick synthesis too.

Regarding the furan one, I tried to do the Boc protection using what I had left of the acid SM (~20 mg) but it wasn't the smoothest reaction and I only have ~10 mg of crude product. I think I might put this on hold for the time being but perhaps this would be a good target for @Seb470 to try making, @alintheopen? The pyrrole acid SM isn't the cheapest (we got it for $150 USD from Combi-Blocks + shipping) so maybe you could have a go at making it, or a derivative, instead

[Seb470]

Thanks @edwintse. I've discussed with Alice. I would like a few compounds that I can make for my project that other people aren't making. For the pyrrole (I assume furan was a mistake) Boc protection one, do you mind if I try to synthesise it?

Also how would I go about finding compound you aren't planning on working on? I know some in Molomics are labelled synthesis candidates so I assume you are looking at those? If so, would I be free to try synthesise the other ones (I'll let you know).

Best,

Sebastian

[gcincilla]

@Seb470, just a clarification: as specified in the project summary page in Molomics technology, molecules tagged as "synthesis candidate" are compounds that are considered interesting by somebody, they deserve special attention, but their synthesis was still not decided. It would be good if you and other synthetic chemists could evaluate the "synthetic accessibility" and possibly also the "chemical stability" of such compounds. To do that you have simply to go into the molecule info card (i.e. clicking on its code or structure), click on the "Evaluate" tab, and evaluate such properties. In this way we can prioritize those molecules.
Compounds whose synthesis has been decided by OSM should be tagged as "to synthesize".

[edwintse]

UPDATE: Exscientia 1b has now been completed. I'm still waiting on the starting material for Molomics 1c but that should be a quick two reactions. This will likely replace Molomics 1a in the paper and the synthesis of it can be pursued later.

[BenedictIrwin]

This looks good, sorry for the delay on new suggestions here, have been very ill for the last ~11 days. Ben

[BenedictIrwin]

I'm trying to set up remote working, it might take a few days to coordinate with others so won't be able to continue working on the suggestion for some time.

[edwintse]

@BenedictIrwin That's totally fine. It seems everything will be slowing down a bit for a while so no need to worry.