Sequence-controlled polymerizations, such as DNA replication and transcription, are essential in biological systems. However, replicating these mechanisms in laboratories remains a challenge. From biological systems, much has been learned and applied in biological contexts, such as for the autocatalytic self-replication of peptides. Beyond the scope of biology, sequence-controlled polymers have yielded advanced materials for digital data storage, among other applications. Given the importance of biological and biomimetic polymers in both biological and non-biological arenas, this work makes progress towards the synthesis of sequence-controlled polypeptides with repeating units comprised of multiple amino acids. Glycine- and proline-containing tetrapeptides, identified by theory-based calculations, were prepared using solid phase peptide synthesis and then ring closed to generate the corresponding N-carboxyanhydride monomers. The tetrapeptides, Gly-Gly-Gly-Gly, Gly-Gly-Pro-Gly, and Gly-Pro-Pro-Gly, were obtained in 20-55% yields and the structures were confirmed by electrospray ionization mass spectrometry (ESI MS) and nuclear magnetic resonance (NMR) spectroscopy. High-performance liquid chromatography (HPLC) experiments demonstrated the high purity of the tetrapeptides. Following reaction of the tetrapeptides with triphosgene to form the corresponding N-carboxyanhydride monomers, solubilization of the resulting products in organic solvents is suggestive of successful ring-closing reactions, though further syntheses on a larger scale are needed for detailed characterization studies to confirm the chemical structures. These experiments provide a foundation for future scale-up and optimization of the synthesis of multi-amino acid-containing N-carboxyanhydrides and for the synthesis of sequence-controlled polymers to enable technologies in a variety of fields, including medicine and engineering, among others.

Synthesis towards sequence-controlled polypeptides

255th National Meeting (2018)

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