Synthesis of Nonnatural Helical Polypeptide via Asymmetric Polymerization and Reductive Cleavage of N–O Bond

Herein, we present
a novel synthetic strategy, to amino-acid-free
peptide synthesis based on postpolymerization conversion, for chiral
nonnatural polypeptides. Optically active poly-N-alkoxyamides
were prepared by our asymmetric polymerization as precursors of polypeptides,
and the reductive cleavage of N–O bonds using a SmI2–THF complex was carried out. The reaction proceeded smoothly
with quantitative conversion to afford a nonnatural polypeptide. The
resulting polypeptide adopted a one-handed stable helical structure
in solution, which was established by circular dichroism (CD) and
theoretical calculations using density functional theory (DFT). The
simulated spectra by time-dependent (TD) DFT methods clearly indicated
the validity of the proposed structure. The synthetic approach is
a promising candidate for the synthesis of nonnatural polypeptides.