[clemi2310]

Good morning everyone,

I am trying to modify my synthetic pathway of a diketo ester. To make it short, the classical route involves a methyl ketone with an oxalate. I wondered if the reaction could work between an ester and a pyruvate (acting as the methyl ketone).

I have tried bases such as tBuOLi and NaH.

In TLC, it seems there's still a lot of starting material but in LCMS analysis there is no starting material detectable (after coinjections of the commercial starting material with the crude)

What do you think?



Thank you for your answers!!

[Dan]

in LCMS analysis there is no starting material detectable (after coinjections of the commercial starting material with the crude)

What do you think?

If there is no SM by LCMS then presumably there is product that cospots with SM under your TLC conditions. What is the mass of the new peak by LCMS? Why are you giving up the classical route?

[clemi2310]

We want to giving up the classical route because the synthesis of our methyl ketone is a linear 9 step process.

 At the second step, we have an ester, and if this does work, it would transform the synthetic route into a 4 step synthesis ! (project of designing biologically active molecules). I wondered if this new route would work in order to optimize, and have a new pathway for designing diketo acids (pyruvate used for that has never been described)

The mass of the new peak in LCMS is not the one from the product (mass expected 207, and we only got 152 (SM so maybe a fragment)
Maybe it is a fragment, we tried different voltages without success.

I can say a new product has formed, but I am not sure it is the diketoester because usually with the classical route we see it in mass signal.

Thank you for your answer !

[clarkstill]

Do you formally deprotonate all of the pyruvate before adding the pyridinyl ester? If not you might run into issues - I'd imagine the neutral pyruvic ester is much more electrophilic than the pyridinyl ester, so you might get homo-Claisen type products...

I'm not sure the pKa of your pyruvate and whether LiOtBu will irreversibly deprotonate it, but my guess is that it won't. Maybe try LDA instead?

I've also done a very similar procedure in the past, and found that I got much better yields by adding to the aldehyde, then oxidizing up to the ketone with MnO2. 2-Pyridinecarboxaldehyde is commercially available and cheap, and the aldehyde should be much more electrophilic than anything else in the pot so would solve any chemoselectivity issues.

[clemi2310]

What we do is: we put pyruvate + ester together, then we add the base.

With ester + base we observed a reaction by TLC, so that's why we thought the pyruvate and the ester would not react before the base is added.

Regarding deprotonation of pyruvate alone, I think it will react on itself no?

As bases, we also tried NaH, and we are thinking of using LiHMDS.

I agree with you regarding the aldehyde pathway, but the goal here, is to simplify our 9 steps synthetic pathway which doesn't not involve an aldehyde, and if we try to synthetize it we add a supplementary step which is not the goal. Complicated process haha !!

Thank you for your suggestions !

[Dan]

For a formal deprotonation I would try adding the pyruvate slowly via syringe pump to a mixture of strong base and ester. This should minimise the concentration of (non-deprotonated) pyruvate and hopefully minimise self-condensation.

Can you find any literature reactions involving pyruvate esters as nucleophiles in crossed aldols? The high electrophilicity of pyruvate may be a confounding issue here.

[clemi2310]

Thank you for this advice, we will try in this order.

I'm afraid you are right regarding the eletrophilicity of pyruvate. I have not been able to find any paper or conditions involving pyruvate as nucleophile.

I was wonderering if it could work in some particular conditions, can we have some additives to force the reaction?
we will try by adding slowly first, then we will see

[clemi2310]

Hello everyone !

I found recently a new paper about the design of a pyruvate used for its nucleophilic properties where the electrophilic part is hindered.

It is used to generate pyruvate enolate for arylation and alkylation. And it is working. So I wanted to apply this to my reactions and perform the crossed claisen condensation attached to this post. However, nothing seems to happen.

I tried different conditions  to screen solvants and bases on the scaffold attached:

LiHMDS in THF, RT --> starting material
KOH in THF, RT --> starting material
KOH in EtOH, RT --> starting material
tBuOLi in DMF, RT --> starting material
NaH in THF, RT --> starting material and something more polar with mass 220 and 345 (acid ?)

I wonder if you had some suggestions, because contrary to the methyl pyruvate trials I really think it can work with this protected pyruvate ester.

How to displace the equilibrium ? In terms of heating or proporitions equivalent (ester in excess?)

Thank you for your help,

Clémence

[wildfyr]

What about running this at ethanol distillation temperatures? or neat/high boiling solvent and under vacuum?

Remove ethanol from the system somehow to force the reaction.

[Babcock_Hall]

Pyruvate sometimes acts as a nucleophile in water.  See for example, Arnold and Kaplan, Journal of Biological Chemistry, Vol. 249, No. 2, Issue of January 25, pp. 652-655, 1974.  However, unless one can work in buffered aqueous solutions, I don't think that this will lead to a practical synthesis.