Tertiary-Butylbenzene Functionalization as a Strategy for β-Sheet Polypeptides.

Area of Science:

• Polymer Chemistry
• Organic Synthesis
• Biomaterials Science

Background:

• β-Sheet forming polypeptides are challenging to synthesize due to uncontrolled precipitation during ring-opening polymerization (ROP).
• Existing synthetic methods lack control over chain growth and solubility for these important biomaterials.

Purpose of the Study:

• To introduce a novel t-butylbenzene functionalization strategy to enable controlled synthesis of soluble β-sheet polypeptides.
• To overcome precipitation issues in ROP and achieve high molecular weights with narrow dispersity.

Main Methods:

• Design and synthesis of bulky N-carboxyanhydride monomers with t-butylbenzene pendants.
• Utilizing N-heterocyclic carbene catalysis for ring-opening polymerization.
• Employing real-time Fourier transform infrared and 1H NMR spectroscopy to study ROP kinetics and secondary structures.

Main Results:

• Achieved homogeneous polymerization with controlled chain growth for poly(l-serine) and poly(l-cysteine).
• Synthesized soluble polypeptides in high molecular weights (Mn = 32 kDa) with narrow dispersity (Đ ≤ 1.3).
• Demonstrated that α-helical conformational fronts in propagating chains accelerate ROP kinetics.

Conclusions:

• The t-butylbenzene-substituted steric-hindrance approach successfully yields soluble, high-molecular-weight polypeptides.
• This method provides a valuable platform for exploring new polypeptide architectures and applications.
• Reversible conformational transitions can restore β-sheet structures post-deprotection, offering further control over material properties.