Unconventional cleavage

While solid phase peptide synthesis has reached impressive heights over the years, the predominant way of preparing peptides continues to be through the so-called C-to-N route. In this procedure, an amino acid is anchored to the solid support via its C- terminus. Subsequent steps amount to iterative coupling reactions with interspersed protection/deprotection steps. There are many advantages to the other mode of synthesis, which goes in the opposite direction: from N to C terminus. However, the corresponding methods are considerably less developed. I enjoyed reading the article published by Masurier and co-workers, wherein advances in the so-called pipecolic linker technology, were described. In the graphic below, I am showing a representative example showcasing this idea. To me, the most exciting part of this and related linkers is conceptual in nature. It is good to see methods that proceed through amide bond cleavage that is triggered by one of the amides (in this case, that of piperidine amide). This example underscores that under appropriate conditions, nearby amides can “bite” each other. For those of us who try to make peptides, this process is normally to be avoided. However, it can apparently be brought to good use. There’s something special about this pipecolic linker.


2 thoughts on “Unconventional cleavage

  1. I have seen somewhat related amide cleavage when attempting to make peptoid-aldehydes on acetal-linked polymer support. RCON(R)CH2CON(R)CH2C(OMe)O-Polymer would upon acidolytic cleavage (formic acid) cyclize to oxazolidinium salt, which hydrolyzes with loss of N-alkyl-glycinaldehyde. For us it was a complication because we wanted C-terminal aldehydes, so I had to replace the first peptoid piece with N(R)CH2CH2SO2 sulfonamide unit, and that solved the problem.

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s