[somethingtoxic]

ABT-089

Seems simple enough, right, but not for me apparently...

*rereads ochem chapters*

Can anybody genuinely help?

[Doc Oc]

The pyrrolidine probably comes from proline.  If you can buy that methylpyridine with a fluorine where it needs to be connected to the oxygen it might be as simple as trying an SNAr reaction, but I don't know how cooperative that pyridine nitrogen will be.

[hohoshark]

i think use proline is reasonable,but the N-H must be protected, cause the N is more nuclephile than O, maybe.

[MissPhosgene]

3-Hydroxy-2-methylpyridine plus proline derivative (very easily made from proline).

[MissPhosgene]

Hoboshark is right. protect the nitrogen.... may not be as reactive as one might think, but it could be necessary.

[johnnyd]

Protecting the nitrogen is just giving yourself work mate. Firstly, pKa of protonated pyridine is around 5 so its not that nucleophilic. Secondly, and more importantly, any attack by this substituted pyridine on your proline derivative (acid chloride, anhydride whatever) will be reversible. In fact it'll speed up your reaction! Nucleophilic catalysis???

[Doc Oc]

I think you're misinterpreting the synthesis we're suggesting.  We're talking about the proline nitrogen, and the carboxyl group would have to be reduced down to the alcohol.

[johnnyd]

Major apologies! I see where you're coming from now. The problem is the synthesis of the proline acid chloride derivative because it will react with itself as it is formed if the nitrogen is not protected. I've finally caught up 

I'd still try and avoid the protection and deprotection steps though. You could prob take the 3-hydroxy-2-methyl pyridine (I haven't checked but this seems to be commercially available?) in solution add a coupling reagent like DCC, and add proline itself dropwise over the course of a day. The proline will react as it is added to the solution and because the alcohol is in such a large excess this should (might?!) mask the fact that the nitrogen is more nucleophilic. Possibly increase the temperature too in order to further move away from a kinetically controlled system.

I think its worth trying in that it would save 3 steps...

Care is needed on the reduction as well. The proton at the stereocentre is reasonably acidic and you may racemize. Form the dithiane and cleave with Rainey Ni might work.

[MissPhosgene]

3-hydroxy-2-methyl pyridine is commercially available.