Regioselective and Efficient Synthesis of Nonsymmetric Cyclic Peptides via a Stapling Reaction of 2-Acetyl-thiophene-3-carboxaldehyde with Primary Amine and Thiol.

In this work, 13 nonsymmetric cyclic peptides with a thieno[2,3-c]pyrrole bridge were efficiently and regioselectively synthesized by a stapling reaction of the primary amine (from lysine (Lys) side chain and peptide N-terminus), thiol (from cysteine (Cys) side chain), and 2-acetyl-thiophene-3-carboxaldehyde (ATA). A single regioisomeric thieno[2,3-c]pyrrole staple was formed, generating the thieno[2,3-c]pyrrole-bridged peptide. The stapling reaction can be carried out in various solvents. Moreover, the obtained nonsymmetric cyclic peptides were stable in PBS solution. Furthermore, three bicyclic peptides containing both an acetone-like bridge and the thieno[2,3-c]pyrrole bridge were synthesized via two stapling strategies: (1) a symmetric stapling reaction of 1,3-dichloroacetone (DCA) with two Cys residues, and (2) a nonsymmetric stapling reaction of ATA with Lys and Cys residues. Satisfied yields of the bicyclic peptides were achieved. The positions of the two bridges determined the synthetic accessiblity of the bicyclic peptides. Certainly, a wide variety of thieno[2,3-c]pyrrole-bridged nonsymmetric cyclic peptides can be designed, thus entrenching the methodologies in peptide cyclization. The strategy is applied conveniently to the synthesis of nonsymmetric cyclic peptides with a large structural diversity.