Science of Synthesis

Franzini, R. M., Science of Synthesis: DNA-Encoded Libraries, (2024) 1, 425.

In summary, the conjugation of building blocks to protected DNA that is linked to a solid support is an effective strategy to attach molecules that are otherwise difficult to introduce. However, there are limitations to this approach; reactions involving strong nucleophiles are not suitable for on-support modifications, because both the linker attaching the DNA to the support (e.g., a succinic ester) and the amine-protecting groups used in standard DNA synthesis are sensitive to nucleophiles (‌Scheme 1‌). DNA attachment linkers based on orthogonal chemistry have been described. Similarly, different protecting groups could be used if desired and, importantly, thymine does not require protecting groups, so oligo-T sequences are therefore unproblematic from this standpoint.[‌4‌] A second challenge is that chemical structures may be unstable under DNA deprotection/cleavage conditions[‌3‌] and care is needed to ensure that the appended molecule has the anticipated structure.

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