An Improved Strategy For Solid Phase Peptide Synthesis In N-to C-Direction

Objective:Peptides are commonly used in biology,biochemistry,chemical biology,peptide-based medicinal chemistry,and many other research areas.Among all those chemical methods for peptide synthesis,besides classic method of solid-phase peptide synthesis(SPPS),inverse solid-phase peptide synthesis(ISPPS)has also attracted the interest of many researchers.Most of the development of the ISPPS method has focused on finding a temporary protective groups for carboxyl groups.However,the application of limited by the disadvantages of unstable,difficult to prepare and low deprotection efficiency and the coupling method will cause racemization.Therefore,we want to realize the synthesis of the peptide N-terminal to the C-terminal and modification of the peptide C-terminal by developing a transient protecting group for the amino acid carboxyl group and acyl azide coupling method.Methods:Our previous work have demonstrated that the amino acid benzyl ester can be converted to acyl azide efficiently.We envisioned Nto C-directed ISPPS can be conducted with commercial amino acid benzyl ester by means of acyl azide strategy.We reported this improved azide ISPPS methodology,in which only two low-cost inorganic reagents(hydrazine,sodium nitrite)were needed to realize the coupling process and no racemization occurred as expected.Result:An improved azide strategy for N-to C-directed solid-phase peptide synthesis was accomplished in much mild condition,which allowed straightforward access to C-terminally modified peptides.The highlights of this method were emphasized by commercially available amino acid building blocks,low-cost inorganic reagents and no racemization.Furthermore,the synthesis of two medicinal short peptides(Ac-SLV-OH,Suc-AKPL-pNA)and one long-chain peptide containing all kinds of 20 natural amino acids demonstrated its practical utility.Moreover,we have developed a method to achieve ISPPS in the green solvent guanidine hydrochloride.Conclusion:We have developed an ISPPS new strategy by which OBg esters were used as temporary protective groups for carboxyl groups to achieve peptide chain extension by acyl azide,and this method is compatible with water systems to achieve green polypeptide chemical synthesis.The method has mild conditions and good compatibility and universality for 20 amino acid blocks.