Issue: March / April 2025

In recent years, pharmaceutical research has increasingly utilized the conjugation of two molecules (typically an antibody or peptide and a small molecule) as a key strategy for drug development. This technique is based on the use of a linker to bind the two moieties. Although monomers of oligoethylene glycol (OEG) are most widely used in this context, there is interest in repeated amino acid oligomers. Monodisperse polysarcosine (PSar) emerges as an excellent option. Dodeca oligomer peptides of Sarcosine (Sar) were synthesized using Fmoc-Sar-OH, Fmoc-(Sar)2-OH, and Fmoc-(Sar)4-OH, respectively, as building blocks, applying DIC and OxymaPure as coupling reagents. The dodeca target peptide was obtained in all three cases; however, small impurities accompanying the main product peak precluded its direct use as linker for conjugation chemistry in drug discovery. Previous studies by our group indicated that ETT works well in combination with DIC for the coupling of steric-hindered amino acids. We therefore proceeded to prepare (Sar)12 using DIC/ETT as coupling reagents. We observed that the use of Fmoc-Sar-OH and Fmoc-(Sar)2-OH to grow the peptide chain led to a mixture containing the desired dodeca peptide along with an additional Sar attachment, i.e., one extra Sar residue in the case of Fmoc-Sar-OH and two extra ones for Fmoc-(Sar)2-OH, detectable only by MS. However, Fmoc-(Sar)4-OH yielded the desired peptide without any additional Sar attachments.