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

Abstract

β-Sheet forming polypeptides are one of the least explored synthetic systems due to their uncontrolled precipitation in the ring-opening polymerization (ROP) synthetic methodology. Here, a new t-butylbenzene functionalization approach is introduced to overcome this limitation by sterically controlling the propagating polymer chains, and homogeneous polymerization with good control over chain growth was accomplished. New bulky N-carboxyanhydride monomers were designed having t-butylbenzene pendant by multistep organic synthesis, and N-heterocyclic carbene was explored as a catalyst to make high-molecular-weight and narrow polydisperse soluble polypeptides. This ROP process was successfully demonstrated for two β-sheet forming polypeptides such as poly(l-serine) and poly(l-cysteine). These new t-butylbenzene-functionalized polypeptides were found to be readily soluble in tetrahydrofuran, chloroform, and so forth, and they were produced in high molecular weights having Mn = 32 kDa with dispersity D̵ ≤ 1.3. ROP kinetics were studied by real-time Fourier transform infrared and 1H NMR to determine the actual content of the secondary structures in the propagating chains. These studies established that the α-helical conformational front in the propagation chain was speeding up the polymerization kinetics with good degree of control in the ROP process. Reversible-conformational transitions in the post-polymerization deprotection were found to restore the β-sheet secondary structures in poly(l-serine)s. The newly developed t-butylbenzene-substituted steric-hindrance approach is valuable in yielding soluble polymers, and this approach could be useful for exploring new polypeptide architectures for long-term impact.