Synthesis and Sequential Deprotection of Triblock Copolypept(o)ides Using Orthogonal Protective Group Chemistry

The synthesis of triblock copolymers based on polysarcosine, poly‐ N ‐ε‐ t ‐butyloxycarbonyl‐ l ‐lysine, and poly‐ N ‐ε‐ t ‐trifluoroacetyl‐ l ‐lysine by ring‐opening polymerization of the corresponding α‐amino acid N ‐carboxyanhydrides (NCAs) is described. For the synthesis of N ‐ε‐ t ‐butyloxycarbonyl‐ l ‐lysine (lysine(Boc)) NCAs, an acid‐free method using trimethylsilylchloride/triethylamine as hydrochloric acid (HCl) scavengers is presented. This approach enables the synthesis of lysine(Boc) NCA of high purity (melting point 138.3 °C) in high yields. For triblock copolypept(o)ides, the degree of polymerization (X n ) of the polysarcosine block is varied between 200 and 600; poly‐ N ‐ε‐ t ‐butyloxycarbonyl‐ l ‐lysine and poly‐ N ‐ε‐ t ‐trifluoroacetyl‐ l ‐lysine blocks are designed to have a X n in the range of 10–50. The polypeptide‐polypeptoid hybrids (polypept(o)ides) can be synthesized with precise control of molecular weight, high end group integrity, and dispersities indices between 1.1 and 1.2. But more important, the use of tert ‐butyloxycarbonyl‐ and trifluoroacetyl‐protecting groups allows the selective, orthogonal deprotection of both blocks, which enables further postpolymerization modification reactions in a block‐selective manner. Therefore, the presented synthetic approach provides a versatile pathway to triblock copolypept(o)ides, in which functionalities can be separated in specific blocks.