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A series of novel N‐alkyl linkers that connect small‐molecule library members with their encoding DNA oligonucleotides has been developed. In comparison with the standard amide linker (usually constructed with oligo‐AOP‐NH2), the N‐alkyl linker is not only more chemically stable, but also provides better structural diversity at the linkage point. Chemical variety in the vicinity of the polyglycol terminus, in particular, could affect binding interactions with the target protein. It could have been neglected in previous DNA‐encoded chemical library (DEL) synthesis and screening studies due to the limited linkage alternatives. With these linkers, one can produce versatile key intermediates as Cycle 1 products directly amenable to Cycle 2 chemistry without the use of protecting groups. As a result, a DEL synthesis process that uses the fewest chemical conversions, such as 3‐step, 3‐cycle DELs, can achieve higher synthetic efficiency while creating less DNA tag degradation, resulting in higher quality DELs. [ABSTRACT FROM AUTHOR]

Here we show a seven‐step chemical synthesis of a DNA‐encoded macrocycle library (DEML) on DNA. Inspired by polyketide and mixed peptide‐polyketide natural products, the library was designed to incorporate rich backbone diversity. Achieving this diversity, however, comes at the cost of the custom synthesis of bifunctional building block libraries. This study outlines the importance of careful retrosynthetic design in DNA‐encoded libraries, while revealing areas where new DNA synthetic methods are needed. [ABSTRACT FROM AUTHOR]