Phosphonylation of Disulfonimides

[purplepeopleether]

I'm doing research on the phosphonylation of disulfonimides for the synthesis of novel enzyme inhibitors. Has anyone ever done similar research?

[John Cuthber]

Is that product missing an R on the Nitrogen?

I'm afraid that's as much help as I can be.

[Horza2002]

Assuming that your not trying to remove the R group as well, then this type of reaction, in theory this reaction is possible. The proton next to the sulphonyl will be reasonably acidic so you could deprotonate it and then use it as a nucleophile.

[hypervalent_iodine]

I myself don't do this sort of research, but the reaction is plausible if you ignore the missing R group. Did you have a particular question relating to this reaction or did you just want to know if people are doing it/if it has been done before? A good way to find out if this has been done previously is to do a search by molecule in scifinder (if you have access to it).

Edited January 27, 2011 by hypervalent_iodine

[mississippichem]

What kind of enzymes are you you inhibiting?

[purplepeopleether]

Im not sure if the R on the Nitrogen should be there in the product or not, but this the the scheme that was drawn by my organic chemistry professor. I figured that I would need a strong base (some of the research that I have been looking at used n-BuLi) but I'm just having a hard time figuring out what the electrophile would best look like, theoretically. I've searched on scifinder for similiar molecules to the product, but unfortunately have not had great success. As for the enzyme that I'm trying to inhibit, I wasn't told of a specific enzyme or group of enzymes by my organic chemistry professor. I'm just trying to figure out what would work best theoretically and then see if I can actually make it. This is a research project that I am doing as a chemistry major in my freshman year of undergrad, so any help would be greatly appreciated! Thanks in advance!

[hypervalent_iodine]

Im not sure if the R on the Nitrogen should be there in the product or not, but this the the scheme that was drawn by my organic chemistry professor. I figured that I would need a strong base (some of the research that I have been looking at used n-BuLi) but I'm just having a hard time figuring out what the electrophile would best look like, theoretically. I've searched on scifinder for similiar molecules to the product, but unfortunately have not had great success. As for the enzyme that I'm trying to inhibit, I wasn't told of a specific enzyme or group of enzymes by my organic chemistry professor. I'm just trying to figure out what would work best theoretically and then see if I can actually make it. This is a research project that I am doing as a chemistry major in my freshman year of undergrad, so any help would be greatly appreciated! Thanks in advance!

 

I think you need to talk to your professor. For starters, you need to clear up the issue relating to the missing R group (it's almost definitely meant to be there). Secondly, I think you should ask him which enzyme you are inhibiting. I fail to see how you 'theoretically' work out what would work best without knowing what you need to make work. Or perhaps I'm misinterpreting the aim of this assignment. On that note, since this is an assignment, I don't think it's exactly fair that we tell you the answer straight up. That being said, Horza has pretty much given you your answer relating to the first step and you seem to be on the right track with that. What you should try and do is see if you can find what the pKa of the proton you're removing is - if you can't find the exact molecule on scifinder, try looking up very similar derivatives. In terms of the pKa, you could even just look up a simple methane sulphonamide to get an idea of what you'll need (though you are correct in that you'll need a strong base). If you can find that, you should be able to find a suitable base. With respect to the electrophile, you need to think why would you need the electrophile? What is it doing? As a hint, it relates to what happens when you react your sulphonamide with the phosphorous group and what subsequently happens to the leaving group (the Cl ion).

[Horza2002]

Just a thought, it could be that R is a protecting group (i.e a BOC group). If the hydrogen was present on the nitrogen, when you add the strong base (n-BuLi would probably be a good one to try) you would deprotonate the N-H bond. This proton is more acidic than the ones you would try to remove on the sulphonyl groups.

[hypervalent_iodine]

Just a thought, it could be that R is a protecting group (i.e a BOC group). If the hydrogen was present on the nitrogen, when you add the strong base (n-BuLi would probably be a good one to try) you would deprotonate the N-H bond. This proton is more acidic than the ones you would try to remove on the sulphonyl groups.

 

In this case, given the product the OP is after, I doubt it's a boc/fmoc, etc. group. I suspect it's a case of a magical, missing R group of nondescript nature.

[mississippichem]

I would be way more worried about protecting those sulfones from reduction. Purplepeopleether, whatever you do, you need a very non- reducing base as those sulfones are very easy to reduce to sulfoxides or thiols.

[hypervalent_iodine]

Hmm, that's true. I wouldn't use BuLi anyway. I should think that it'll add to the sulphone as a nucleophile as opposed to acting as a base.

[Horza2002]

Not sure it would act as a nucleophile seeing as BuLi is a hard nucleophile whereas sulphones are soft electrophiles. I be more worried about reducing them

[mississippichem]

I'm fairly sure n-butyl lithium will reduce them all the way to the thiol. Though I'm not sure what affect the amino nitrogen has on that.

[hypervalent_iodine]

Not sure it would act as a nucleophile seeing as BuLi is a hard nucleophile whereas sulphones are soft electrophiles. I be more worried about reducing them

 

Ha, yeah, I realised that after I'd posted it and gone to bed. Oh wells.