Sequence-Defined Oligomers from Hydroxyproline Building Blocks for Parallel Synthesis Applications

The functionality of natural biopolymers has inspired significant effort to develop sequence‐defined synthetic polymers for applications including molecular recognition, self‐assembly, and catalysis. Conjugation of synthetic materials to biomacromolecules has played an increasingly important role in drug delivery and biomaterials. We developed a controlled synthesis of novel oligomers from hydroxyproline‐based building blocks and conjugated these materials to siRNA. Hydroxyproline‐based monomers enable the incorporation of broad structural diversity into defined polymer chains. Using a perfluorocarbon purification handle, we were able to purify diverse oligomers through a single solid‐phase extraction method. The efficiency of synthesis was demonstrated by building 14 unique trimers and 4 hexamers from 6 diverse building blocks. We then adapted this method to the parallel synthesis of hundreds of materials in 96‐well plates. This strategy provides a platform for the screening of libraries of modified biomolecules. Another link in the chain: A controlled synthesis of novel oligomers from hydroxyproline‐based building blocks was developed. The hydroxyproline‐based monomer allows the incorporation of diverse side chains, and high‐throughput purification can be achieved by fluorous solid‐phase extraction. This method is adaptable to high‐throughput synthesis in multiwell plates, thus allowing hundreds of novel oligomer structures to be synthesized in parallel.