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

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 the N,O-benzylidene acetal dipeptides (NBDs) as robust and effective building blocks to allow direct synthesis of difficult peptides/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/proteins, including chemokine, therapeutic hormones, histone and glycosylated erythropoietin.