Synthesis of OSM-S-412

[david1597]

Hi All,

My name is David Smith and I have joined the project this week, working as a postdoc in Mat Todd's lab at The University of Sydney.

I'm starting with the synthesis of OSM-S-412 (MMV1557865). This was the compound which was previously produced biosynthetically (#513) with potency of 9 nM. We need more of this compound to evaluate further.

I propose the route below. A negative is that there are a large number of steps. Positives are that we have access to the starting material, and by using the benzyl protecting group twice, only one deprotection step is required at the end.

Any thoughts or comments would be appreciated.

[mcoster]

Hi @david1597, Nice! Hope it goes well. I was contemplating this the other day. Would you consider C-arylation of diethyl malonate as an alternative route to your diethyl 2-arylmalonate, eg. A General and Mild Copper-Catalyzed Arylation of Diethyl Malonate. Edward J. Hennessy and and Stephen L. Buchwald* Organic Letters 2002 4 (2), 269-272

A bit more convergent and maybe more analogue friendly?

Also: You probably need a stronger reducing agent than NaBH₄ to reduce the esters, eg. LiAlH₄, LiBH₄, DIBAL. It's often hard to get better than 50% yields from mono-benzylation of diols - formation of the benzylidene acetal, followed by redn with DIBAL is an alternative.

[drc007]

Hi @david1597, Do you need to protect the diol? I suspect it would only react once in the displacement? Is commercially available

[MFernflower]

I wonder if you could (provided you have time) produce a prodrug of this compound? (coupling the phenol functionality via Williamson with ethylchloroformate to form a carbonate on the benzene ring?)

Also I second Mark's idea of using the copper based method as p-iodophenol is extremely cheap

[david1597]

Great - thanks everyone! Really useful to have comments so quickly - based on the above I have changed the proposal to the one below.

@mcoster @MFernflower I now plan to use that Cu method, it was also suggested by another postdoc here in our group. Thanks.

@mcoster The benzylidene acetal route looks a lot neater - this is also now incorporated.

@drc007 I'm not sure on the diol protection...I was following a similar route that @edwintse used to make the parent MMV693155. When I get to that stage, I'll try a small-scale on the diol and see if I can do it directly on the diol. I planned to avoid the commercially available compound you indicated as the removal of the methyl ether group would require more harsh conditions in the final step.

@MFernflower Sure! I can do the prodrug at the end.

[MFernflower]

Chris Swain (@drc007) suggested that we do not use carbonate's for prodrugs and instead use an amino acid based approach (like an n-benzoylglycine ester of the phenolic functionality) to increase solubility @david1597

[MFernflower]

@david1597 Here is another possible molecule to bring up with Dr.Todd

[david1597]

Yep, it's a good idea! Coincidentally, @edwintse and @mattodd discussed this just yesterday, and @edwintse has already commenced synthesis of the similar molecule below.

[mattodd]

Yes. That idea was literally less than 24 hours old, so had not yet made it here. The extended chain in @MFernflower 's suggestion is not so easy to come by as the symmetrical diol. So let's start with that.

[cdsouthan]

This all sounds great. JFTR, as mentioned in https://github.com/OpenSourceMalaria/OSM_To_Do_List/issues/533 this OSM-S-412 replenishment task offers a great opportunity to rigourously test reproducability. At the risk of mentioning the obvious, be careful not to completely "run out" of the original 412 (do MMV have any left?). This means we then have the chance to systematically compare old-vs-new, not only for the identical NMR and suchlike but also to assay them both side-by-side.

JFTR (18 Aug) unless I've missed it somewhere @david1597 I cannot find the SMILES and InChIs for OSM-S-412 MMV1557865 for the search checking I wanted to do in PubChem and SciFinder. I know its a recent compound but since it is now our S4 front runner (pending re-rest) it would be good to get it into the https://github.com/OpenSourceMalaria/OSM_To_Do_List/issues/533 Master List

[david1597]

@cdsouthan The SMILES and InChIs are in the master list next to OSM-S-412. Do you mean locating them here or elsewhere? Apologies if I have misunderstood, I'm still relatively new to the various systems we have.

[cdsouthan]

OK @david1597 thats fine

[david1597]

This compound was included in the recent shipment to Dundee (OpenSourceMalaria/Series4#10 ).

I'm currently repeating the final hydrogenation step to get more material to ship for other testing, should it's potency is confirmed. For some reason the yield was really poor from the first benzyl deprotection attempt and a lot of starting material was recovered.

[mcoster]

Basic/coordinating nitrogens, such as pyridines and related heterocycles, poison Pd catalysts. Ways to minimise this include:

1. Use hydrogen bonding solvent, eg. EtOH (you probably already are)
2. Use AcOH as solvent or co-solvent
3. Add 1 equiv. HCl

[david1597]

@mcoster Thanks for the tips for the Bn deprotection - I never got back to you to say it worked. Already was in EtOH, but as you suggested a 50/50 mix of EtOH and AcOH worked better. Although the OSM-S-412 has just been made via a different route (OpenSourceMalaria/Series4#23) I have other compounds ready for debenzylation so will continue with this method. Thanks :)

[david1597]

Closing this issue.

OSM-S-412 has been successfully synthesised - see OpenSourceMalaria/Series4#23.