N,O‐Benzylidene Acetal Dipeptides (NBDs) Enable the Synthesis of Difficult Peptides via a Kinked Backbone Strategy

Abstract

Proteins with highly hydrophobic regions or aggregation‐prone sequences are typically difficult targets for chemical synthesis at the current stage, as obtaining such type of peptides via solid‐phase peptide synthesis requires sophisticated operations. Herein, we report N,O‐benzylidene acetal dipeptides (NBDs) as robust and effective building blocks to allow the direct synthesis of difficult peptides and proteins via a kinked backbone strategy. The effectiveness and easy accessibility of NBDs have been well demonstrated in our chemical syntheses of various challenging peptides and proteins, including chemokine, therapeutic hormones, histone, and glycosylated erythropoietin.

Robust Chemical Synthesis of “Difficult Peptides” via 2-Hydroxyphenol-pseudoproline (ψ2-hydroxyphenolpro) Modifications

“…We want to address these issues by introducing different functional groups in the C(5) position of the oxazolidine ring. Serine/threonine ligation (STL), developed by Li and co-workers, is an effective strategy in synthetic peptide/protein chemistry. – The possible mechanism of this reaction is to form an N , O -benzylidene acetal intermediate, which can be readily restored to the natural peptidic linkage by acidolysis. ,, Very recently, Li and co-workers reported an N , O -benzylidene acetal dipeptide-based method for the synthesis of “difficult peptides”, in which the N , O -benzylidene acetal intermediates were prepared from 4-methoxysalicylaldehyde esters of different AAs (except for Pro) . Almost simultaneously, we have also developed a novel strategy in which a series of 2-hydroxyphenol-pseudoproline (ψ 2‑hydroxyphenyl pro) building blocks (Figure ) have been designed, efficiently synthesized, and successfully applied in the preparation of “difficult peptides”.…”

“…11,13,14 Very recently, Li and co-workers reported an N,O-benzylidene acetal dipeptidebased method for the synthesis of "difficult peptides", in which the N,O-benzylidene acetal intermediates were prepared from 4-methoxysalicylaldehyde esters of different AAs (except for Pro). 15 Almost simultaneously, we have also developed a novel strategy in which a series of 2-hydroxyphenolpseudoproline (ψ 2-hydroxyphenyl pro) building blocks (Figure 1) have been designed, efficiently synthesized, and successfully applied in the preparation of "difficult peptides". Different from Li's work, the salicylaldehyde esters of AAs with various side chains have been studied, including proline residues.…”