The 8 -- proposed synthesis Haverford College

[rbroadrup-HC]

Proposed synthetic routes have been developed in collaboration with students as part of an organic chemistry class I teach at Haverford College. The molecules are seen as being desirable targets as per #390. This Issue has been created for community feedback on the routes, which can then be attempted in the lab by us or others.

CC1=NC=C(OCC(O)C2=CC=CC=C2)N3C1=NN=C3C4=CC=C(OC(F)F)C=C4
InChI=1S/C21H18F2N4O3/c1-13-19-25-26-20(15-7-9-16(10-8-15)30-21(22)23)27(19)18(11-24-13)29-12-17(28)14-5-3-2-4-6-14/h2-11,17,21,28H,12H2,1H3
ASWYMQOLUDKKDJ-UHFFFAOYSA-N

[drc007]

I presume there is a deprotonation first before alkylation in the first step?

[rbroadrup-HC]

Scheme corrected to include base in first step and to update reference.

[MFernflower]

@rbroadrup-HC Looks like anything but halogens or hydrogen in the 8 position causes issues - Might want to shelve this one?

[mattodd]

No, this was factored in - we need ways to access this compound. It'd be useful to measure metabolic stability, particularly in the Aldehyde Oxidase assay, where blocking groups next to aromatic N might be useful. And if we can put a methyl there we might be able to adapt the chemistry to put other things there too. One possibility is that if the potency is reasonable then perhaps we could use the chemistry to put a biotin there for pull-down.

[MFernflower]

That is very very interesting. Is there any computational way to access AO stability? As for ideas that have not be tried for the 8 position - HCF2O or CF3 perhaps? maybe even bromine?

@rbroadrup-HC
@mattodd

[drc007]

I'm not aware of computational studies but I've written a summary here http://www.cambridgemedchemconsulting.com/resources/ADME/aldehyde_oxidase.html

Typically electron-deficient N-heterocycles are a potential flag.

[mattodd]

Closing since taken on to #429