An Atom-Economic Inverse Solid-Phase Peptide Synthesis Using Bn or BcM Esters of Amino Acids

Abstract

An atom-economic N-to-C-directed solid-phase peptide synthesis is reported that uses benzyl (Bn) or (benzhydryl-carbamoyl)-methyl (BcM) esters of amino acids as the building blocks, which facilitate efficient hydrazinolysis, convenient conversion to acyl azide, and robust amidation with the next amino acid ester. This method is free of coupling reagents and free of protection on the side-chain OH, CO2H, CONH2, etc., therefore exhibiting a significantly improved atom economy compared to those of BOC- or Fmoc-based C-to-N-directed approaches.

Sustainability in peptide chemistry: current synthesis and purification technologies and future challenges

“…Recently, Li and coworkers shed light on the possibility of applying an inverse solid-phase peptide synthesis (ISPPS) protocol, in which N-to-C direct SPPS is performed. 140 According to the authors, by using this approach, it is possible to replace the conventional Fmoc/ t Bu strategy with an atom-economic method free from coupling reagents and side-chain protections. However, the process is based on the use of highly toxic chemicals and the formation of potentially explosive intermediates.…”

Super silyl-based stable protecting groups for both the C- and N-terminals of peptides: applied as effective hydrophobic tags in liquid-phase peptide synthesis

“…In SPPS, resins installed at the C-terminal are well developed while those installed at the N-terminal to synthesize peptides in the reverse direction (N to C) are not widely used. 22 In LPPS, researchers focused on developing different structures of tags at the C-terminal and using these tags to conduct the peptide synthesis in a linear or convergent way. 6–11 Epimerization and diketopiperazine (DKP) formation are the major reasons why peptide synthesis in the reverse direction is not widely used.…”

Protecting Group-Minimum, Practical N-to-C Peptide Synthesis

“…N-to-C peptide elongation (Figure 1-b) is less explored than C-to-N elongation due to difficulty in suppressing epimerization of the C-terminus amino acid residue's stereocenter. [24][25][26][27][28][29][30][31][32] Because the two amino groups, one in the elongating peptide strand and the other in the amino acid to be introduced, are already differentiated as amide and amine groups, respectively, this strategy is potentially advantageous in improving both atom and step efficiency by minimizing protecting group manipulations. Here we report an iterative and practical N-to-C peptide synthesis in liquid phase, in which epimerization is minimal.…”