Usage of Trityl Linkers

The convergent (or fragment condensation) method for the solid phase synthesis of peptides and large amounts of pharmaceutical grade peptides, is rapidly becoming the method of choice (1).

Using Fmoc/tBu protected amino acids, in combination with the 2-chlorotrityl chloride resin, confers certain advantages for the synthesis of protected peptide fragments. The linkage is particularly acid label even to fluorinated alcohols and is cleaved rapidly with hexafluoroisopropanol (HFIP) in dichloromethane (DCM) (1:4 v/v)(2). HFIP-DCM is a weak acid but strong enough to facilitate cleavage without causing de-protection of the peptide. Each step in the assembly can readily be optimized and therefore very high purity peptides can result. Protected peptides are obtained within a few minutes.


The procedure offers the following advantages:

  • Avoids the use of carboxylic acids which can be troublesome if all traces are not removed before further condensation reactions.
  • Peptides are indistinguishable from those cleaved with TFA or AcOH mixtures.
  • The HFIP is a good solvent even for hydrophobic peptide fragments.
  • Side chain Boc and tBu groups are stable to HFIP.
  • Peptides containing C-terminal His and Phe are cleaved with less than 1% racemization.


2-CTC resin, as well as Fmoc protected amino acids, are readily available from CBL from the small to large scale. Both 2-chlorotrityl chloride polystyrene or, preferentially, with the first amino acid already attached are available.


1. Bray, B. L. Nat. Rev. Drug Discuss. 2003, 2, 587.

2. Bollhagen, R.; Schmiedberger, M.; Barlos, K.; Grell. E. J Chem Soc Chem Commun 1994, 2559–2560


















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