p‐Nitrobenzyloxycarbonyl (pNZ) as a Temporary N^α‐Protecting Group in Orthogonal Solid‐Phase Peptide Synthesis – Avoiding Diketopiperazine and Aspartimide Formation

Abstract

Keywords: Amino protecting group / Nitro reduction / SnCl 2 reduction / PNZ group in SPPS / Combinatorial chemistry / Side reactions p-Nitrobenzyloxycarbonyl (pNZ) was used as a temporary protecting group for α-amino functionalities in solid-phase peptide synthesis. The corresponding derivatives are readily synthesized solids that perform well on solid phase. The pNZ moiety is orthogonal with the most common protecting groups used in peptide chemistry, and is removed under neutral conditions in the presence of catalytic amounts of acid.

Fmoc‐2‐mercaptobenzothiazole, for the introduction of the Fmoc moiety free of side‐reactions

“…arbamates such as Boc, 1,2 Fmoc, 3 Z, 4 and to a lesser extent Alloc, 5,6 pNZ, 7 and Troc 8 are the most efficient way to mask the nucleophilicity of the amino function during peptide synthesis. 9,10 The introduction of the alkoxycarbonyl moiety was first carried out under weakly basic conditions via the Schotten-Baumann reaction, by using the corresponding chloroformates (also known as chlorides).…”

Oxathiocoraline: Lessons to be Learned from the Synthesis of ComplexN‐Methylated Depsipeptides

“…b) To minimize the risk of DKP formation by: i) avoiding Cys(Me) as the C terminus because it is very prone to give DKPs as a result of the acidity of its β-proton, ii) using Alloc and pNZ groups instead of the Fmoc group, [19,20] iii) using CTC resin, which because of its steric hindrance gives better results than Wang resin, [15,16] and iv) restricting the flexibility of the peptide chain by, for example, using the dimerization approach. [4] c) To choose the chemistry carefully after the ester bond has been formed.…”

“…A number of general precautions have been described, such as the use of highly steric hindered resins (e.g., CTC resin, which protects the carboxylic function [14][15][16] ) or protecting groups that are removed under acidic or almost neutral conditions. [17][18][19][20] In depsipeptide syntheses, the presence of labile ester bonds in the peptide chain provides another potential point for DKP formation. This process is favoured by the flexibility of the growing chain together with the absence of protection from the solid-support steric hindrance.…”

“…For Wang resin, Alloc-Cys(Me)-OH (Scheme 2, a) was introduced as the first amino acid, and the pNZ group was used for protection of the amino group of the second residue, Cys(Acm), to keep the amino group protonated and therefore to minimize DKP formation. [20] AllocGly-OH was introduced as a third amino acid, and finally Fmoc--Ser(Trt)-OH completed the tetrapeptide. In this approach, cleavage of the Fmoc group was used to quantify the resin loading.…”

Convergent Approaches for the Synthesis of the Antitumoral Peptide, Kahalalide F. Study of Orthogonal Protecting Groups

“…pNZ-Orn(Boc)-OH was prepared as described previously 29 and Alloc-amino acids as essentially described […”