Abstract
Polypeptides have broad applications and can be prepared via ring-opening polymerization of α-amino acid N-carboxyanhydrides (NCAs). Conventional initiators, such as primary amines, give slow NCA polymerization, which requires multiple days to reach completion and can result in substantial side reactions, especially for very reactive NCAs. Moreover, current NCA polymerizations are very sensitive to moisture and must typically be conducted in a glove box. Here we show that lithium hexamethyldisilazide (LiHMDS) initiates an extremely rapid NCA polymerization process that is completed within minutes or hours and can be conducted in an open vessel. Polypeptides with variable chain length (DP = 20–1294) and narrow molecular weight distribution (Mw/Mn = 1.08–1.28) were readily prepared with this approach. Mechanistic studies support an anionic ring opening polymerization mechanism. This living NCA polymerization method allowed rapid synthesis of polypeptide libraries for high-throughput functional screening.
Highlights
Polypeptides have broad applications and can be prepared via ring-opening polymerization of α-amino acid N-carboxyanhydrides (NCAs)
We report the discovery that lithium hexamethyldisilazide (LiHMDS) initiates very rapid ring-opening NCA polymerization to generate polypeptides with low dispersity, over a wide range of average chain length
Our data clearly establish the superiority of LiHMDS-initiated polymerizations, those conducted with high NCA:initiator ratios
Summary
Polypeptides have broad applications and can be prepared via ring-opening polymerization of α-amino acid N-carboxyanhydrides (NCAs). Other efforts have included the use of a thiourea organocatalyst[45], and the exploration of modified reaction conditions such as low temperature[46,47], high vacuum[48,49,50], and nitrogen flow[51] Despite these innovations, NCA polymerization is still challenging due to its high sensitive to moisture and generally need to operate in a glove box. We report the discovery that lithium hexamethyldisilazide (LiHMDS) initiates very rapid ring-opening NCA polymerization to generate polypeptides with low dispersity, over a wide range of average chain length. We identify potent and broad-spectrum polymers that target antibiotic-resistant strains of Pseudomonas aeruginosa (P. aeruginosa) and methicillin-resistant Staphylococcus aureus (MRSA)
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