Schiff base and reductive amination reactions of -amino acids: a facile route toward N-alkylated amino acids and peptoid synthesis

Polypeptoids are a promising class of peptidomimetic polymers for applications in biotechnology, but the polymers prepared by solution polymerization have limited side-chain functionalities due to synthetic difficulty. Synthetic versatility still remains challenging. Herein, we demonstrate a facile approach to prepare N-substituted amino acids and peptoid polymers via Schiff base and reductive amination reactions from readily available natural -amino acids. These N-substituted amino acids can be easily converted into the corresponding N-substituted N-carboxy anhydrides (NNCAs), which subsequently undergo ring-opening polymerization (ROP) to prepare polypeptoids. Two NNCA monomers, i.e., N-(4-methylphenyl)methyl glycine ((BnMe)-Bn-N-G) and N-(4-ethylphenyl)methyl glycine ((BnEt)-Bn-N-G) NCAs, can be polymerized to give peptoid oligomers, P((BnMe)-Bn-N-G)(10) and P((BnEt)-Bn-N-G)(10). Also, the corresponding diblock copolypeptoids, mPEG(45)-b-P((BnMe)-Bn-N-G)(12) and mPEG(45)-b-P((BnEt)-Bn-N-G)(10), were successfully synthesized via methoxypolyethylene glycol amine (mPEG-NH2) initiated ROP. The thermal properties of these oligopeptoids and diblock copolymers were investigated. The synthetic strategy represents a new methodology to directly install N-substituents onto -amino acids towards the functional polypeptoids.