2-Chlorotrityl chloride resin

2-Chlorotrityl chloride resin
2-Chlorotrityl chloride polystyrene resin (2-chlorotriphenylmethyl chloride resin, 2-CTC); 100–200 mesh

A trityl chloride resin for anchoring the first residue as a very acid-labile ester. Stir the Fmoc-amino acid with DIPEA in dichloromethane and the carboxylate displaces chloride at the trityl carbon; because the amino acid itself is never activated, the activation step that racemizes the first residue is avoided, which is the main reason this resin is chosen for a C-terminal cysteine or histidine. Cap the unreacted sites afterwards, usually with methanol and DIPEA, and take the loading from the Fmoc released on the first deprotection. The bulky linker can also reduce diketopiperazine loss for sequences that begin with proline or glycine.

The ester is cleaved by dilute acid: 1% TFA in dichloromethane, or mixtures such as acetic acid/trifluoroethanol/DCM or HFIP/DCM, release the peptide acid with its Boc and tert-butyl side-chain protection still in place, which is how protected fragments and precursors for solution-phase cyclization are made. Trityl groups are more acid-sensitive and can be partly lost under these conditions, His(Trt) especially, so check the fragment by analysis. 95% TFA with scavengers instead removes the acid-labile side-chain groups (Boc, tert-butyl, trityl, Pbf) as it releases the peptide acid. Keep the resin dry, since the trityl chloride hydrolyzes to the alcohol and hydrolyzed sites will not load.

Applications

• Low-racemization anchoring of a C-terminal cysteine, histidine or other sensitive residue
• Protected peptide fragments for convergent synthesis and solution-phase cyclization
• Sequences prone to diketopiperazine loss on alkoxybenzyl ester resins
• Peptide acids by standard Fmoc SPPS

Storage
Store refrigerated (2–8 °C) and dry, in a tightly closed container.

Published research using P3 BioSystems material

• Gamage K et al. O-GlcNAc Modification of α-Synuclein Can Alter Monomer Dynamics to Control Aggregation Kinetics. ACS Chemical Neuroscience 2024. doi:10.1021/acschemneuro.4c00301
• Zhu Y et al. Activating hidden signals by mimicking cryptic sites in a synthetic extracellular matrix. Nature Communications 2023. doi:10.1038/s41467-023-39349-w
• Ballantine RD et al. Linearization of the Brevicidine and Laterocidine Lipopeptides Yields Analogues That Retain Full Antibacterial Activity. Journal of Medicinal Chemistry 2023. doi:10.1021/acs.jmedchem.3c00308
• Low SA et al. Bone-targeted acid-sensitive doxorubicin conjugate micelles as potential osteosarcoma therapeutics. Bioconjugate Chemistry 2014. doi:10.1021/bc500392x

References

1. Barlos K et al. 2‐Chlorotrityl chloride resin. Studies on anchoring of Fmoc‐amino acids and peptide cleavage. International Journal of Peptide and Protein Research 1991, 37, 513–520. doi:10.1111/j.1399-3011.1991.tb00769.x
2. Fujiwara Y et al. Racemization-Free Synthesis of C-Terminal Cysteine-Peptide Using 2-Chlorotrityl Resin. Chemical and Pharmaceutical Bulletin 1994, 42, 724–726. doi:10.1248/cpb.42.724
3. Pedroso E et al. Diketopiperazine formation in solid phase peptide synthesis using p-alkoxybenzyl ester resins and Fmoc-amino acids. Tetrahedron Letters 1986, 27, 743–746. doi:10.1016/s0040-4039(00)84089-7

For research use only. Not for human or veterinary use.