July 03, 2022, 10:11:52 PM
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Topic: Enolate alkylation troubles  (Read 558 times)

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Offline kriggy

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Enolate alkylation troubles
« on: January 07, 2022, 05:50:05 AM »
Hey guys, Im running into troubles with selenylation of pyroglutamic acid derivative (scheme attached). My issue is that I only get traces of the mono-selenylated product which is the desired one while the majority is the bis-selenylated and unreacted starting material. The exact synthesis is reported in literature:

(1) Oba, M.; Ohkuma, K.; Hitokawa, H.; Shirai, A.; Nishiyama, K. Convenient Synthesis of Deuterated Glutamic Acid, Proline and Leucine via Catalytic Deuteration of Unsaturated Pyroglutamate Derivatives. J. Label. Compd. Radiopharm. 2006, 49 (3), 229–235. https://doi.org/10.1002/jlcr.1038.

and with different protecting groups:

(1) Moody, C. M.; Young, D. W. Investigation into Direct Use of Protected 3,4-Dehydropyroglutamates in Synthesis. J. Chem. Res. 2005, No. 7, 478–480. https://doi.org/10.3184/030823405774309087.

But only bis-alkylated product was obtained when reproducing the 1st synthesis.

I tried various hexamethylsilazane bases and bunch of other modification (whole reaction at -78°C, warming to RT then cooling, reverse addition...) with no success. We think the issue is that the mono-selenylated product is way more acidic than the starting material, therefore the unreacted enolate deprotonates the mono-selenylated product and then it reacts again. I tried stopping the reaction immidiately but already had the bis-selenylated as a major product. Im wondering if there is a way around this but I dont think I can think of one. I think alkylation with phenylselenic anhydride to get immidiate elimination might work but I feel the mono-SeOPh derivative will suffer from the same increased acidity therefore I will get bis-selenylated products again.

I tried quenching the enolate with TMSCl but that has poor reactivity.
I can picture multiple other syntheses to introduce the double bond but then it would require multiple more steps - protection, deprotection and oxidation of pyroglutamic alcohol with the double bond being reported to be unstable and the compound (dehydropyroglumate) dimerize during column chromatography.

Looking for any ideas because Im starting to get a bit desperate

Offline rolnor

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Re: Enolate alkylation troubles
« Reply #1 on: January 07, 2022, 07:28:04 AM »
We had a similar selenation question here some time ago, in this case it was solved by following the procedure exactly with fresh reagents. Have you done this?

Offline kriggy

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Re: Enolate alkylation troubles
« Reply #2 on: January 07, 2022, 08:47:45 AM »
We had a similar selenation question here some time ago, in this case it was solved by following the procedure exactly with fresh reagents. Have you done this?

Yes, learned my lesson :D.
 I followed the procedure exactly, although with lower loading of starting materials (they did grams) but the molar equivalents were same. Im going to re-try it again but I have doubts since in the paper they isolate the product in high yield yet no NMR or MS is provided making me feel that their procedure was in fact different or not as straightforward as they report.

I double checked all my starting materials (NMR of pyroglutamate and PhSeCl, both fine) I use oven or heatgun dried glassware, freshly distilled THF.  I borrowed some of the bases from other research groups but they seemed in good shape. I used KHMDS from new bottle.


Offline phth

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Re: Enolate alkylation troubles
« Reply #3 on: January 21, 2022, 06:01:22 PM »
They can be tricky due to the enolate character imparted by the alpha seleno group. In other words, the product is more reactive than the SM, so we see the byproduct. I would try another reagent. Scifinder this reagent if you can. There was a french paper that did the transformation with 2-phenyl-1-acetaldehyde (an extremely reactive product prone to over reaction) and the pictured reagent.  They didn't have problems, so I imagine it is just needing a special reagent. Maybe it wont work initially because of the pKa differences of morpholine-aldehyde and morpholine-amide.




Offline rolnor

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Re: Enolate alkylation troubles
« Reply #4 on: January 21, 2022, 11:41:52 PM »
If they dont give NMR its very strange, do they use the material in a second step? It looks difficult.

Offline kriggy

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Re: Enolate alkylation troubles
« Reply #5 on: January 25, 2022, 03:53:41 AM »
phth: do you have a reference for that paper?

I made it work in the end by the lit. conditions but I got fresh base. Still, the yield is <30% and is a mixture of multiple products.

rolnor: Its a mixture of diastereomers that might be the reason for it but yeah, its very strange and makes me doubt the procedure they describe. They used the material in next step but reported high yields on multigram scale. I tried the next step with the bis-selenylated material to see if they maybe made a wrong compound but it doesnt work (not surprising)

Offline phth

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Re: Enolate alkylation troubles
« Reply #6 on: January 26, 2022, 12:35:07 AM »
phth: do you have a reference for that paper?

I made it work in the end by the lit. conditions but I got fresh base. Still, the yield is <30% and is a mixture of multiple products.

rolnor: Its a mixture of diastereomers that might be the reason for it but yeah, its very strange and makes me doubt the procedure they describe. They used the material in next step but reported high yields on multigram scale. I tried the next step with the bis-selenylated material to see if they maybe made a wrong compound but it doesnt work (not surprising)

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