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

Abstract

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 α-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 (^NBnMe-G) and N-(4-ethylphenyl)methyl glycine (^NBnEt-G) NCAs, can be polymerized to give peptoid oligomers, P(^NBnMe-G)₁₀ and P(^NBnEt-G)₁₀. Also, the corresponding diblock copolypeptoids, mPEG₄₅-b-P(^NBnMe-G)₁₂ and mPEG₄₅-b-P(^NBnEt-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 α-amino acids towards the functional polypeptoids.