[Venky0287]

We are synthesising a peptide (SPPS) conjugated with lipids having a secondary alcohol attached to it. We are facing a problem while cleaving peptide off resin as the TFA used for cleavage is reacting with the secondary alcohol in lipid structure thereby forming trifluoroacetylated product of the peptide. Can you please suggest us regarding how we can avoid this reaction of TFA and -OH group of lipid or else do you suggest any special condition or cleavage cocktail which can avoid such type of reaction.

[pgk]

If you use the Fmog solid synthesis, you can cleave with Piperidine 20%/DMF at room temperature that leads to the formation of piperidinium trifluoroacetate, which cannot esterify the secondary alcohols.
If you use the Boc solid synthesis, you can cleave with HCl saturating an oxygen containing solvent that fits to you (e.g. MeOH, THF, dioxane, glyme, etc.) at room temperature.
If you use any other type of peptides solid synthesis, please specify.

[pgk]

Clarification:
If you use the Fmoc solid-phase synthesis, you can cleave with Piperidine 20%/DMF at room temperature, which is basic and cannot favor alcohol dehydration. If working with TFA is necessary (e.g. preliminary removing other co-existing protecting groups at room temperature), then you can remove Fmoc with Piperidine 20%/DMF at room temperature that leads to the formation of piperidinium trifluoroacetate that cannot esterify (secondary) alcohols.
PS: I apologize if my previous post led to any confusion.

[kriggy]

did you try lower concentration of TFA in cleaving cocktail? I know friends of mine used as low as 1% TFA in DCM