Hung's PhD Project at the University of Sydney

[fantasy121]

Hi All, My name is Hung and I am doing my PhD at the University of Sydney in organic chemistry and science communication. As part of my project, I will join in the drug discovery progress for mycetoma and investigate methodologies to effectively communicate scientific information to the community using mycetoma as a case study/example. For the drug discovery section of my PhD project, I will be synthesising more compounds as candidates against mycetoma, which I will include down below. You can now access my current LabArchives notebook from here. More information will be added as I progress through my synthesis. All my Honours notes are still available for viewing as well. I’ve updated the result section for my Honours thesis to include the latest biological assay result done by @wwjvdsande . I also ran LogD calculations for these compounds to give a general idea of which might be promising in terms of favourable in vivo results, as originally suggested by @bendndi My LogD calculation are from Chemicalize.org by ChemAxons. Below is an overview of the molecules I plan to synthesise for the next few months. I chose EPL-BS0178 (and its precursor) as a starting point because it has a good in vivo result and a small LogD value. I am also fairly experienced in making this kind of motif Four of the mods are molecules from the OSN to-do list (P4_D_MXF004–6,9). The majority of the modification consists of ring-locked and aliphatic ring conversion. For P4_D_MXF004 and P4_D_MXF009, I want to synthesise a version of them where they look identical to the starting points except for the ring lock; it would be interesting to see how this constraint would affect biological activity. If you think there are other molecules I should look at, I’m open to hear your opinions as well. I also will tackle more molecules from the OSN list once I am done with my current ones.

[fantasy121]

Looking forward to working with everyone.

[MFernflower]

Cyclohexyl phenyl ketone and dicyclohexylketone (Can be made in house see new post) are pretty cheap from sigma so might be worth reacting those with the pyridine-lithium compound @fantasy121 to make weird bendy analogues of fenarimol

[fantasy121]

Thanks @MFernflower . These ones look like easy picking in terms of synthesis. I'll try to include these in my workflow in a logical manner.

[MFernflower]

TCI also carries this interesting precursor: https://www.tcichemicals.com/eshop/en/us/commodity/D3557/

@fantasy121

[mattodd]

Looks good. I'm assuming all compounds are novel? For numbering, remember the debate about compound IDs in OpenSourceMycetoma/Series-1-Fenarimols#6. I'm always OK with these being assigned to compounds that are targets as well as compounds that have definitely been made, but others here will argue for them being assigned only on completion of the synthesis. I mention this only because some of your targets have no codes, and some have codes from @bendndi . At some point a mycetos code will be needed.

[MFernflower]

@mattodd Issue with the compounds @fantasy121 is making - I designed them so there names in the OSN list ended up becoming an amalgamation of my code-names for them (MXF stands for "Mandrake eXtreme Fenarimol") and what names @bendndi assigned them

E.G one is named P4_D_MXF009 while other compounds not designed by me are assigned numbers like P4_B_004

[MFernflower]

@fantasy121 I hate being that guy but I did notice a small error in one of the synthesis schemes

[fantasy121]

@MFernflower Thank you for spotting that. That’s one of two reactions I’m working on tomorrow so good timing 🙂. It was meant to be Cl- but I have have to Br- version of that starting material so I just used that instead. Copy and paste error. @mattodd they are all novel as I have checked them against what’s available in the Epichem library. Re: codes. Compounds will be coded with HPDXXX-Y as I’m preparing to synthesise them (gathering methods and doing HIRACs). Each compound I make shall gain HPDXXX-Y which will be the internal code I use for my ELN in addition to any other codes they might already have such as EPL-BS or P4_D_MXF etc. Once full characterisation is achieved, my molecules will also be ready to gain their MycetOS unified codes as well.

[fantasy121]

Here are my current targets for synthesis. They're a little more down-to-earth compared to the ones I proposed initially up there so that I can get started while getting ready for some more difficult ones.

I have some issues with the cyclohexyl and piperidyl candidates being hard/expensive to source. Still looking for synthesis alternatives for these. After that I will use the synthesis route for the aromatic tertiary alcohol but substitute some of the rings with their aliphatic counterparts.

[MFernflower]

I found an interesting way to make dicyclohexylketone from materials you should have in the lab:

@fantasy121

[fantasy121]

Thanks @MFernflower. I usually go from aldehyde + organolithium to give me a secondary alcohol, then oxidise that with manganese dioxide. I will have a look to see if this offers improvement over my usually method, especially with aliphatic rings.

[MFernflower]

(Sorry for the reposting)

The paper calls for 2.3 equivalents of the solvated [they don't seem to say what solvent but I assume it's diethylether] Grignard mixed with 1 equivalent of CDI powder at -80c before allowing the mixture to warm to room temp and then a 1-hour hold at rt before recovering product

I do think this may need to be done in a RBF hooked up to a continuous vacuum pump (not inert gas!!) since I think it evolves CO2 with rather small amounts of CO

The only downside to this method seems to be that you can only make symmetric ketones

@fantasy121

[MFernflower]

@fantasy121 One final possible other product to make provided this CDI method works well and you have the time!

[fantasy121]

Thank you @MFernflower May I have the link to this paper as well please? I would like to learn more about this reaction. Seems to be similar in parts to the organolithium reaction I'm using right now but involves fewer steps.

[MFernflower]

^^^^^^^^^^^ https://www.thieme-connect.com/products/ejournals/pdf/10.1055/s-0029-1216815.pdf

[MFernflower]

My written instructions have been adapted from that paper - RBF hooked up to vac pump is preferable than nitrogen atmosphere because that mgbr cdi reaction might offgass some co2 @fantasy121

[MFernflower]

@fantasy121 Might be a good idea when you have time to spin this off into a separate issue - will be good to have for synthetic chemistry dossier @mattodd

[MFernflower]

I do wonder if this would work with organolithium reagents however - would save time as opposed to the mgbr ones @drc007

[MFernflower]

@fantasy121 Saw your having issues with general rxn solubility for the anthrone compound - Perhaps switch the solvent for the bromopyridine and anthrone from Et2O to THF?

the resultant THF/Hexane system should do the trick!

[fantasy121]

@mFernflower thanks. I added THF in the current reaction mix. To see if I could recover the anthrone, I’ve tried to extract the reaction with THF but it’s miscible with water - so troublesome in larger quantities.

[MFernflower]

I was wrong to assume that the thf would be completely free of water - xylene/hexane system if a redo is needed? @fantasy121

update: seems like anthrone rxn failed????????

[MFernflower]

(Reposted since email client chewed up formatting): @fantasy121 this is taking a stab in the dark since I don't know your purification equipment, but for the one that's derived from butyrophenone - since that's a liquid at RT perhaps injecting that directly into the reaction after adding the bromopyridine dissolved in ether into the lithium since butyrophenone and ether should mix

[fantasy121]

@MFernflower I have dried solution on tap with the Puresolv system here at my lab so I always use freshly dried ether or THF for my organolithium reactions. It's just that trying to extract the reaction mix with too much THF is kind of a pain. I have to see what I can get out of the crude of the anthrone reaction. It's not a complete failure I don't think. Re: butyrophenone reaction: I've been dissolving solid ketone into solvent first before injecting it into the aryllithium mix so definitely I would try to directly inject butyrophenone neat into the reaction mix. Thanks for spending your time on this.

[bendndi]

@MFernflower @fantasy121 To get around issues with THF miscibility with water in the work-up, you could try :

• • quenching the THF reaction directly with decent quantity of water (may crash your compound out directly so it can be filtered, the imidazole by-products will remain soluble in aqueous.)
• • quench with aq HCl / brine and extract with either DCM or EtOAc (i.e. saturate the aqueous layer with salt to reduce the THF miscibility, then use a polar non-miscible solvent for the extraction)
• quench with samll amount of water, then evaporate the THF, then do the work up normally using again DCM or EtOAc, water, brine etc.

Also for the reaction set up as long as your inert gas comes in via a line with a bubbler (e.g. schlenk line) or is via syringe / balloon technique, the evolution of gas from the reaction is of not issue. (that said I may be missing something but I dont see mechnaistically how this reaction evolves CO2 or CO gas...)

[MFernflower]

@fantasy121 @mattodd Might not be a bad idea to add in some sort of control compound for this run - I think something like Di(4-fluoro-phenyl)(pyridin-3-yl)methanol would be good provided you have 4,4'-fluorobenzophenone on hand

ClC1=CC=C(C=C1)C(O)(C=1C=NC=CC1)C1=CC=C(C=C1)Cl 4.09 Di-Cl compound

FC1=CC=C(C=C1)C(O)(C=1C=NC=CC1)C1=CC=C(C=C1)F 3.65 Di-F compound

[MFernflower]

I'm sorry to hear you are having issues oxidizing the phenyl(pyridin-3-yl)methanol - If I had to take a random guess perhaps try PIDA in DCM? @fantasy121 @mattodd

[fantasy121]

Update for up to COVID-19 shutdown of my progress so far