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