An Expeditious Multigram‐Scale Synthesis of Lysine Dendrigraft (DGL) Polymers by Aqueous N‐Carboxyanhydride Polycondensation

Abstract The synthesis and characterisation of new arborescent architectures of poly( L ‐lysine), called lysine dendrigraft (DGL) polymers, are described. DGL polymers were prepared through a multiple‐generation scheme (up to generation 5) in a weakly acidic aqueous medium by polycondensing N ε ‐trifluoroacetyl‐ L ‐lysine‐ N ‐carboxyanhydride (Lys(Tfa)‐NCA) onto the previous generation G( n −1) of DGL, which was used as a macroinitiator. The first generation employed spontaneous NCA polycondensation in water without a macroinitiator; this afforded low‐molecular‐weight, linear poly( L ‐lysine) G1 with a polymerisation degree of 8 and a polydispersity index of 1.2. The spontaneous precipitation of the growing N ε ‐Tfa‐protected polymer (G n P) ensures moderate control of the molecular weight (with unimodal distribution) and easy work‐up. The subsequent alkaline removal of Tfa protecting groups afforded generation G n of DGL as a free form (with 35–60 % overall yield from NCA precursor, depending on the DGL generation) that was either used directly in the synthesis of the next generation (G( n +1)) or collected for other uses. Unprotected forms of DGL G1–G5 were characterised by size‐exclusion chromatography, capillary electrophoresis and 1 H NMR spectroscopy. The latter technique allowed us to assess the branching density of DGL, the degree of which (ca. 25 %) turned out to be intermediate between previously described dendritic graft poly( L ‐lysines) and lysine dendrimers. An optimised monomer (NCA) versus macroinitiator (DGL G( n −1)) ratio allowed us to obtain unimodal molecular weight distributions with polydispersity indexes ranging from 1.3 to 1.5. Together with the possibility of reaching high molecular weights (with a polymerisation degree of ca. 1000 for G5) within a few synthetic steps, this synthetic route to DGL provides an easy, cost‐efficient, multigram‐scale access to dendritic polylysines with various potential applications in biology and in other domains.