Macrocyclization of linear peptides enabled by amphoteric molecules.
There has been enormous interest in both naturally occurring and synthetic cyclic peptides as scaffolds that preorganize a given amino acid sequence into a rigid conformation. Such molecules have been employed as nanomaterials, imaging agents, and therapeutics. Unfortunately, the laboratory synthesis of cyclic peptides directly from linear precursors is afflicted by several thermodynamic and kinetic challenges, resulting in low chemical yields and poor chemo- and stereoselectivities. Here we report that amphoteric amino aldehydes can be used for efficient syntheses of cyclic peptides in high yields and selectivities starting from alpha-amino acids or linear peptides. The cyclizations effectively operate at unusually high molar concentrations (0.2 M), while side processes such as epimerization and cyclodimerization are not observed. The products are equipped with sites that allow for a highly specific, late-stage structural modification. The overall efficiency of the macrocyclization is due to the coexistence of nucleophilic and electrophilic reaction centers in amphoteric amino aldehydes.
Hili
Ryan
R
Davenport Research Laboratories, Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario, Canada M5S 3H6.
Rai
Vishal
V
Yudin
Andrei K
AK
D000596:Amino Acids / Q000737:chemistry; D003500:Cyclization; D008968:Molecular Conformation; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry; D010879:Piperazines / Q000737:chemistry; D013237:Stereoisomerism
D000596:Amino Acids; D010456:Peptides, Cyclic; D010879:Piperazines