Consider the synthesis of the dipeptide Glu–Ala (image). The amino acid Glu (glutamic acid) has two carboxyl groups, where one of them should reacts with the amine group from the other amino acid. Does the side chain carboxyl group in Glu have to be protected also, or do we just assume that it does not react?

Synthesis of Glu-Ala
  • 2
    $\begingroup$ You should protect it. $\endgroup$
    – Zhe
    Jan 27 at 1:04
  • $\begingroup$ If it is in aqueous solution, no reaction would occur (neither the one desired one nor the two undesired ones). $\endgroup$ Jan 27 at 3:34
  • $\begingroup$ Murphy's Law applies. If it can possibly react it will $\endgroup$
    – Waylander
    Jan 27 at 7:29
  • $\begingroup$ Well our profesor said that we need to draw the mescanism and just assume it reacts. But thank you for your answers:) $\endgroup$
    – xxx
    Jan 27 at 7:57
  • $\begingroup$ related: chemistry.stackexchange.com/q/125224/102629 $\endgroup$
    – cngzz1
    Jan 30 at 9:11

Yes, the side chain carboxylic acid requires protection.

The two most commonly used peptide coupling strategies use Boc or Fmoc on the amide.

The side-chain carboxylate is typically protected as a tBu ester in case of Fmoc synthesis (the compound is commercially available under CAS 71989-18-9) or as a benzyl ester in case of Boc synthesis (as before, CAS 13574-13-5).

Not protecting these side chains would give coupling mixtures as both carboxylic acids can and will react with the coupling reagents.


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