Potential compounds to synthesise

[fidiris]

Further to the first set of compounds prepared by Jessica Baiget and those inherited from GSK I think it would be sensible to focus synthetic efforts towards three key areas.

1. I would like to look at making subtle changes to the aromatic ring as it seems to be key for reactivity.

2. We'll also need to investigate different tethers as this hasn't been explored yet.

3. Different amine analogues can be made to see if we get any improvement in activity in comparison to the morpholine scaffold.

Ideally, most of these compounds will be synthesised according to the general synthetic route, however, deviations from this approach are envisaged, especially as we change the tether.

Any suggestions on other molecules to make or tips on synthetic strategies to access these compounds will be appreciated.

The original active hit - OSTBS83 will also be synthesised to be used as a reference sample.

[fidiris]

Update

Over the past 2 months I've synthesised and characterised the compounds listed below. Some are from the original list proposed back in March with some new additions as well. I should have a few more compounds prepared/purified in the coming few weeks and will continue working my way through the original list and add more analogues. OSTBS83 is the original active hit and OSTBS98 is a known inactive.

My ELN details the procedures used to access these compounds. Generally, compounds containing a very electron deficient phenyl ring are challenging to access as the last amide coupling step is low yielding (see below). For aniline substrates which don't contain a hydroxy group, I've adopted a direct acylation with chloroacetyl chloride, followed by a nucleophilic substitution with morpholine to access these scaffolds in excellent yields. Experiment ID's are detailed in the scheme below.

[fidiris]

Update - See below the 15 compounds I've synthesised and purified to date for OSTB series 3. I'm hoping to finish of this series in the coming months. The compounds I'm currently working on are highlighted. I'm currently using the T3P mediated amide coupling approach and preparing the corresponding amine tethered carboxylic acids as described in my previous comment.

12 of the compounds - OSTBL1-10, OSTBS83 and OSTBS98 have been dropped off to our collaborators (Professor Tim McHugh) at the Centre for Clinical Microbiology at UCL. Looking forward to getting some updates soon!

[MFernflower]

@fidiris @mattodd Has the racemic alcoholic compound been tested? I think you could reduce the original hit with sodium borohydride!

[MFernflower]

@fidiris @mattodd I'd also be curious about a hydrocarbon linker if it's not already been tried

SMILES strings for all three proposed analogues:

OC1=C(CCCN2CCOCC2)C(Cl)=C(Cl)C=C1Cl Hydrocarbon 1 OC(CN1CCOCC1)NC1=C(O)C(Cl)=CC(Cl)=C1Cl Amino Alcohol OC1=C(CC(=O)CN2CCOCC2)C(Cl)=C(Cl)C=C1Cl Hydrocarbon 2

[MFernflower]

@fidiris it appears that ELN link is broken? Just redirects to labarchives company page

[fidiris]

@MFernflower here is the Link to my ELN. The link on the Wiki seems to be working for me but I'll update it.

In terms of the hemiaminal structure proposed - Hemiaminals, especially acyclic ones tend to be very unstable and synthetically I wouldn't be able to make it directly from the original hit. Amides (in general) can't be reduced with sodium borohydride and require stronger reducing agents such as lithium aluminum hydride. In that case, you wouldn't reduce the amide to the hemiaminal. You would get the amine. Milder conditions employing triflic anhydride and Hantzsch esters would also yield the corresponding amine (aniline in this case).

Other reducing agents commonly used to reduce amides such as DIBAL-H would give you the aldehyde (i.e. fragmenting the structure). Therefore, from a synthetic prospective, I don't think it would be feasible to make the structure from the original hit (although it may be interesting).

With regards to the two hydrocarbon structures, although they'd make nice additions to the SAR, synthetically I'm not sure how I'd make these structures.

In terms of the ketone, there is some work from Cacchi and co-workers reporting a Pd-catalysed route which combines propargylic carbonates and secondary amines.

Although the reaction seems to work well with electron poor aryl rings (i.e. ester functionality in para) it may not work with the highly electron deficient core structure that we have. Additionally, having carried out a retrosynthesis, (in my opinion) I don't think its synthetically feasible. A synthetic route to the key aryl iodide intermediate would need to be developed and all the steps would likely need optimisation.

We are currently waiting on more biological data for the 15 new analogues detailed above. When we get this back, we can think about what to make next.

Thanks for the suggestions! I'll keep them in mind.

[MFernflower]

@fidiris whoops! Forgot about the instability of that aminal compound! - has the amine linker molecule (lithal reduction product) been screened yet?

[fidiris]

@MFernflower no the amine hasn’t been screened yet but it’s an interesting compound and we could look at making it.

[MFernflower]

https://www.sigmaaldrich.com/catalog/product/aldrich/531642

https://www.sigmaaldrich.com/catalog/product/aldrich/a55004

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Buchwald-Hartwig route to the amine linker might also be possible??

[MFernflower]

@fidiris how many chlorines are needed on the aryl ring to keep potency? I'd reckon it'd only be the two para position ones? (might even be able to get away with keeping only the chlorine closest to the OH group!!!?!)