School Contributions - 2023

[kym834]

    > Pulling to a new issue for further discussion @JuliaSarju

Hello! Julia from the Uni of York here. We have a group of 6 very interested year 3 chem undergrad students who are keen to contribute. We are planning to follow @mattodd suggestion to vary the aniline. Could we have some help identifying the first few options to try or what to avoid?

Originally posted by @JuliaSarju in https://github.com/OpenSourceMycetoma/Series-1-Fenarimols/issues/83#issuecomment-1357536632

[kym834]

Hi @JuliaSarju, Welcome!

Just pulled this over to here so we can discuss outside of the other meeting minutes and discussions :)

In terms of what to avoid - we have a list of compounds that have already been made or are currently being synthesised.

For the first few options to consider:

We'd love to explore walking the nitrogen around the ring so

• 2-aminopyridine, 3-aminopyridine and 4-aminopyridine

And possible see the important of the methyl group so

• m-toluidine

Other options would be nitro groups as we can reduce them later and further modify through the amine so

• 2-Amino-5-nitropyridine, 2-amino-4-nitropyridine and 2-amino-3-nitropyridine.

[MFernflower]

Amantadine might be a interesting coupling partner @kym834

[bebi78]

As @MFernflower suggested, a few reductive amination products (in addition to mine dubbed DNDI0004039860 by DNDi, see below) might be prepared from aryl aldehydes and pyridyl-substituted 2-aminothiazoles. Just to see if there is any antifungal activity for such compounds.

[mattodd]

Hi @JuliaSarju @kym834 How about we try to meet up online ASAP to discuss, along with @PaulMcKeatingSevenoaks @Whitgift and any other school that might want to come along. It'd be really good to divvy up targets and explore a block of structures, share experience in the synthetic route etc. Jan 17th. 18th. 19th or 20th? Could people suggest some possibles?

[PaulMcKeatingSevenoaks]

Hi @JuliaSarju @kym834 @Whitgift @mattodd - 17th and 19th are better for me - can do most times those days. Thanks!

[JuliaSarju]

19th is better for me as I'll have a 3 yo with me on the 17th. I could do anytime accept 2-3 on the 19th.

[bebi78]

@mattodd 19th is OK for me.

[mattodd]

OK, let's go for 1pm UK time on the 19th. We can use https://ucl.zoom.us/j/4808072370 . I'll reach out to @Whitgift by email. The aim of this meeting is to talk through synthetic plans and ensure that each group has a clear aminothiazole target(s). All good?

[MFernflower]

I will attend the meeting

[JuliaSarju]

Great. Looking forward to it! Julia @ York

[PaulMcKeatingSevenoaks]

Sounds good!

[bebi78]

A short basis for tomorrow's discussion from my side.

https://doi.org/10.1016/j.bmc.2013.08.048

[MFernflower]

@bebi78 A few questions:

If you replace thiourea with normal urea would you get the oxygen analogue of the compounds?

Might be worth trying to replace one of the aldehyde with acetophenone and seeing if that product is active?

[bebi78]

@MFernflower Urea seems to be not reactive enough for analogous oxazole synthesis. Br of 1 was substituted by OH and treated with cyanamide to prepare the corresponding amino-oxazole in the mentioned article. Acetophenones might surely be another option. Reductive amination with NaBH4 would then lead to racemic mixtures. The single enantiomers might differ in their activity, in case there is any activity. Aside separation of enantiomers by chiral chromatography or crystallisation, chiral hydrides can be used then to prepare enantiopure products.

[JuliaSarju]

Hiya, here is a link to an open google slide summarising our plan: https://docs.google.com/presentation/d/11RgivJDmrgEZGQlzjICQam-5Ni2zjMyY3mogPS5ChiA

[MFernflower]

@bebi78 https://www.sigmaaldrich.com/US/en/technical-documents/technical-article/chemistry-and-synthesis/cross-coupling/2-picoline-borane

[bebi78]

@MFernflower 2-Picoline-borane is more expensive than NaBH4, but might be a good alternative under ´´green chemistry´´ conditions, and maybe also for problematic starting compounds with low solubility or stability.

[MFernflower]

@JuliaSarju @kym834 @mattodd I think the compounds made from bromo acetophenone were inactive - I assume some substituted phenyls will be okay though

[kym834]

Sorry I wasn't able to make the meeting - if there is a recording or some minutes please share, and I'll catch up.

@JuliaSarju - this looks great! Can I just clarify, how many compounds your team will be making? From the pyridines and a-bromoketones you've got in the plan there is 8 total combinations (see below). If you can let us know (by number is probably easiest) then I can add the compounds to the currently being synthesised wiki page :smiley:

[JuliaSarju]

@kym834 Thank you for the figure :) Yes, we are planning to synthesise those 8 initial targets. We may have time to include more targets in March, We were wondering about introducing an aryl bromide group followed by a Pd-cross coupling. Julia

[mattodd]

A MycetOS sub-meeting was held on 19th Jan 2023 with @mattodd @JuliaSarju @PaulMcKeatingSevenoaks @bebi78 @Whitgift @MFernflower and David Schofield (Hampton School).

@JuliaSarju (Uni York) will have 3rd year chem students (working on an integrated Masters) working in Feb/March, potentially with more sessions later. Eight targets were shared above, which are now being pursued. These examine the impact of walking the pyridine nitrogen around the amino pyridine ring. Addition of an aryl bromide is possible, which could be used in subsequent Suzuki couplings, though logD may suffer with another directly-appended Ar ring.

• [x] @JuliaSarju to conduct SciFinder search to verify novelty of these compounds.
• [x] @mattodd to share a Labarchives account with @JuliaSarju to allow for student sharing.

Whitgift target needed. Students are already sharing on Labarchives.

Sevenoaks target needed.

@bebi78 shared a homologous series (above). Attractive since no need to purify after first step, and amides will be easy. Which structures would be novel? @bebi78 to advise? @bebi78 kindly offered to provide some starting materials/reagents for the schools/teams who might want to try this route. Could the route also be employed with a benzylamine in place of an aniline?

@MFernflower suggested oxazoles, too. Are these known, and possess activity? Another possible set/target?

[bebi78]

@mattodd @PaulMcKeatingSevenoaks @Whitgift , Hampton School Here are some first target suggestions for the reductive amination and amide project. (the 2-benzyloxybenzylamine scaffold was found active in a DNDi trypanosoma project)

[PaulMcKeatingSevenoaks]

Thank you @bebi78. I think we are going to look at the amides initially, and see if we can make that happen. Then we should have time to look at the reductive amination process, maybe...

[MFernflower]

@PaulMcKeatingSevenoaks @bebi78 other possible acids to couple to the amine

2,4-Dichlorobenzoic acid

Hydrocinnamic acid

[mattodd]

My gut feeling here would be that everyone should stick with the same core motif and chemistry at this stage - i.e. that @Whitgift and @PaulMcKeatingSevenoaks should go after the same synthetic scheme as @JuliaSarju so that everyone can compare notes. So, vary the aniline or something like it. e.g. aminocyclohexane (as per @MFernflower suggestion) or benzylamine, taking us to @bebi78's kind of molecules, but via the original route. Provided they have not been examined to date and are ideally novel according to SciFinder.

I think at this stage we just need 3 molecules, right? One each for Whitgift, Sevenoaks and Hampton.

However, I think @Whitgift have already bought 2-Bromo-4-nitoacetophenone, meaning they are aiming for one of these molecules @kym834 ?

Let's make a decision on these, sketch them up, and let the students have a go at getting them. Final opinions?

[MFernflower]

@mattodd Phenethylamine is cheap and would give us a novel molecule might be worth a try?

[bebi78]

I strongly suggest to use the simple, well-established and published 2-step procedures for the reductive amination and amide synthesis target compounds at first, instead of trying out other procedures which might fail for these target compounds. In terms of substituents I would additionally suggest target compounds with any kind of trifluoromethyl substituents, but I don't have the corresponding benzoic acids in stock. Must be purchased then by @PaulMcKeatingSevenoaks

[PaulMcKeatingSevenoaks]

My gut feeling here would be that everyone should stick with the same core motif and chemistry at this stage - i.e. that @Whitgift and @PaulMcKeatingSevenoaks should go after the same synthetic scheme as @JuliaSarju so that everyone can compare notes. So, vary the aniline or something like it. e.g. aminocyclohexane (as per @MFernflower suggestion) or benzylamine, taking us to @bebi78's kind of molecules, but via the original route. Provided they have not been examined to date and are ideally novel according to SciFinder.

I think at this stage we just need 3 molecules, right? One each for Whitgift, Sevenoaks and Hampton.

However, I think @Whitgift have already bought 2-Bromo-4-nitoacetophenone, meaning they are aiming for one of these molecules @kym834 ?

Let's make a decision on these, sketch them up, and let the students have a go at getting them. Final opinions?

Happy to do one of the amines - e.g. aminocyclohexane derivative via the route used by @kym834

[kym834]

@PaulMcKeatingSevenoaks, would you like me to out your school down next to the cyclohexane analogue as has been suggested above? Below is what the final target molecule would be:

And starting materials would be aminocyclohexane as the aniline replacement and keeping the original 2-(bromoacetyl)pyridine hydrobromide:

[kym834]

@kym834 Thank you for the figure :) Yes, we are planning to synthesise those 8 initial targets. We may have time to include more targets in March, We were wondering about introducing an aryl bromide group followed by a Pd-cross coupling. Julia

@JuliaSarju, cool! I've added these compounds to the list of compound currently being synthesised. Good luck!

[kym834]

However, I think @Whitgift have already bought 2-Bromo-4-nitoacetophenone, meaning they are aiming for one of these molecules @kym834 ?

@mattodd, Whitgift had let me know that they have purchases this compound and I've now added it to the list of compound currently being synthesised.

[PaulMcKeatingSevenoaks]

@PaulMcKeatingSevenoaks, would you like me to out your school down next to the cyclohexane analogue as has been suggested above? Below is what the final target molecule would be:

And starting materials would be aminocyclohexane as the aniline replacement and keeping the original 2-(bromoacetyl)pyridine hydrobromide:

@kym834 Yes please - thank you.

[mattodd]

York ELN created @JuliaSarju https://tinyurl.com/YorkChemELN. Have at it!

[kym834]

@PaulMcKeatingSevenoaks - if you would like to have a meeting to discuss the logistics of how to do the synthesis and ask any questions, I'm more than happy to set up a time. I've been doing these with @Whitgift and think it's been really helpful for them in preparing for the sessions, problem solving any issues that arise and come up with work arounds that suit the facilities and resources that you have etc. We also have some more step-by-step procedure, probing questions and some background resources that we can share as well to help support student learning and understanding of the project.

I'm not sure who to tag for Hampton - but if you would also like to join or set up a separate meeting please let me know :)

[PaulMcKeatingSevenoaks]

@PaulMcKeatingSevenoaks - if you would like to have a meeting to discuss the logistics of how to do the synthesis and ask any questions, I'm more than happy to set up a time. I've been doing these with @Whitgift and think it's been really helpful for them in preparing for the sessions, problem solving any issues that arise and come up with work arounds that suit the facilities and resources that you have etc. We also have some more step-by-step procedure, probing questions and some background resources that we can share as well to help support student learning and understanding of the project.

I'm not sure who to tag for Hampton - but if you would also like to join or set up a separate meeting please let me know :)

Hi @kym834 - yes please, all of that would be helpful!

Thanks Paul

[kym834]

@PaulMcKeatingSevenoaks I'll send an email so we can work out a time that works - save all these poor souls getting notifications about it.