A New Architecture for DNA‐Templated Synthesis in Which Abasic Sites Protect Reactants from Degradation

The synthesis of artificial sequence‐defined polymers that match and extend the functionality of proteins is an important goal in materials science. One way of achieving this is to program a sequence of chemical reactions between precursor building blocks by means of attached oligonucleotide adapters. However, hydrolysis of the reactive building blocks has so far limited the length and yield of product that can be obtained using DNA‐templated reactions. Here, we report an architecture for DNA‐templated synthesis in which reactants are tethered at internal abasic sites on opposite strands of a DNA duplex. We show that an abasic site within a DNA duplex can protect a nearby thioester from degradation, significantly increasing the yield of a DNA‐templated reaction. This protective effect has the potential to overcome the challenges associated with programmable, sequence‐controlled synthesis of long non‐natural polymers by extending the lifetime of the reactive building blocks. An abasic site within a DNA duplex reduces hydrolysis of a colocalised DNA‐thioester. This forms the basis for an architecture for DNA‐templated synthesis which protects DNA‐tagged building blocks until a DNA strand exchange reaction removes the protective site and colocalizes a second reactive group.