Uniform soluble support for the large-scale synthesis of sequence-defined macromolecules

Herein, a monodisperse soluble support is explored and used as an effective tool for the large-scale, liquid-phase synthesis of sequence-defined macromolecules. This support, based on a benzyl derivative with three long hydrophobic alkyl chains, combines the advantages of solid-phase and soluble support- based synthesis by allowing a straightforward workup after each coupling step and a direct characterisation of the intermediates, without prior cleavage from the support. While the soluble support is used for the multi-gram synthesis of thiolactone-based sequence-defined macromolecules, it can be applied for numerous other synthetic strategies too. Additionally, as it is uniform, it leads to a single peak in mass spectrometry and thus not to a molecular weight distribution as typically observed for standard polymeric soluble supports, thus facilitating the characterisation. To demonstrate the potential for the synthesis of sequence-defined macromolecules on a scale that is sufficient for their introduction in bulk material synthesis, a hexamer is prepared on a 14 g scale. Furthermore, two different cleavable linkers have been attached to the uniform soluble support, hence emphasizing the versatility of this strategy.