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Abstract Base‐filling, i. e., post‐synthetic furnishing of an oligonucleotide scaffold with base moieties or their analogues, is an interesting alternative to the conventional approach of sequential coupling of building blocks (modified or otherwise). Reversible attachment of the base moieties is particularly attractive as it allows the use of dynamic combinatorial chemistry and usually leads to higher fidelity. This concept article summarizes the various backbones and coupling reactions used for base‐filling over the past fifteen years, discusses the impact of base stacking and pairing on efficiency and fidelity and highlights potential and realized applications.

Abstract Hairpin oligodeoxynucleotides incorporating a (2R,3S)‐4‐(methoxyamino)butane‐1,2,3‐triol residue in the middle of the double‐helical stem and opposite to either one of the canonical nucleobases or an abasic 2‐(hydroxymethyl)tetrahydrofuran‐3‐ol spacer were synthesized. Under mildly acidic conditions, aromatic aldehydes reacted reversibly with these oligonucleotides, converting the (2R,3S)‐4‐(methoxyamino)butane‐1,2,3‐triol unit into a 2‐aryl‐N‐methoxy‐1,3‐oxazinane nucleoside analogue. The equilibrium of this reaction was found to be dependent on both the aldehyde and the nucleobase opposite to the modified residue. 9‐Formyl‐9‐deazaadenine, combining a large stacking surface with an array of hydrogen bond donors and acceptors, showed the highest affinity as well as selectivity consistent with the rules of Watson‐Crick base pairing. 5‐Formyluracil or indole‐3‐carbaldehyde, lacking in either stacking or hydrogen bonding ability, were incorporated with a much lower affinity and selectivity.