From nickel-catalyzed reductive coupling to cyclic peptide synthesis

Abstract

This dissertation is focused on nickel-catalyzed reductive cross couplings of amine derivatives via C-N activation and their application in peptide macrocyclization. ☐ Chapter 1 focuses on the development of a deaminative reductive cross coupling to prepare noncanonical amino acids in perfect enantiopurity. Natural amino acid lysine and its analogues were used to synthesize pyridinium salts as coupling partners. This method has good tolerance of many distinct functional groups. And this reaction has been used in peptide late-stage functionalization to help with pharmaceutical studies. ☐ Chapter 2 focuses on the development of a peptide macrocyclization via reductive cyclization of two amino acid pyridinium salts. This method gives high yield with broad functional group tolerance in making alkyl-alkyl tethered cyclic peptides. Various macrocyclization strategies beyond the sidechain-to-sidechain linkage are possible with a wide range of ring sizes. Notably, the pyridinium salt building block and the linear peptide substrate can be easily synthesized. Solid phase peptide synthesis works very well with the amino acid pyridinium salts. In addition, a natural bicyclic peptide analogue was synthesized with the new method in good yield. ☐ Chapter 3 focuses on the development of a peptide macrocyclization via reductive cross coupling of amino acid pyridinium salts with aryl bromides. This method provides high yield in the construction of an alkyl-aryl linkage. Solid phase peptide synthesis can be used to prepare the substrates to accelerate scope exploration. So far, up to 89% yield has been obtained, and the scope exploration is ongoing.