Changing permanent protecting groups for avoiding tert-butylation in solid-phase peptide synthesis of somatostatinamide

The most widely used synthetic scheme for peptide synthesis is the so-called Fmoc/tBu SPPS strategy. tBu for the side-chains of Ser, Thr, Tyr (as ethers), Asp, Glu (as esters), and Lys, Trp (as carbamates, Boc). During the final global deprotection, tert-butylated cations and other tert-butyl-containing species are formed that, even in the presence of scavengers, can lead to tert-butylation of sensitive amino acids such as Met, Trp, Cys, and even Ser. Obviously, the best way to eliminate a side reaction is to eliminate the reagent or the moiety that produces it. In this context, herein, we have studied the substitution of the tBu protecting groups of Ser and Thr by Thp or Trt and of the Boc of Lys by Mtt. As a proof of concept, the synthesis of Somatostatinamide has been carried out because the synthesis of this peptide, which contains two Cys and one Trp with tBu-based protecting groups, yields almost 20 % of tert-butylated side-products. • Avoiding tert- butylation side-reaction. • Improving atom economy. • Easy to synthesize protecting group. • Non-aromatic protecting group. • Greening the solid-phase peptide synthesis process.