We report here the discovery and development of boron-assisted oxime formation as a powerful connective reaction for chemical biology.

Here we show as even-step chemical synthesis of aD NA-encoded macrocycle library (DEML) on DNA. Inspired by polyketide and mixed peptide-polyketide natural products,t he library was designed to incorporate rich backbone diversity.Achievingt his diversity,h owever,c omes at the cost of the custom synthesis of bifunctional building block libraries.T his study outlines the importance of careful retrosynthetic design in DNA-encoded libraries,w hile revealing areas where new DNAs ynthetic methods are needed.

We use kinetic data, photophysical properties, and mechanistic analyses to compare recently developed high-rate constant oxime and hydrazone formations. We show that when Schiff base formation between aldehydes and arylhydrazines is carried out with an appropriately positioned boron atom, then aromatic B-N heterocycles form irreversibly. These consist of an extended aromatic structure amenable to the tailoring of specific properties such as reaction rate and fluorescence. The reactions work best in neutral aqueous buffer and can be designed to be fluorogenic - properties which are particularly interesting in bioconjugation.

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DNA-encoded library (DEL) technology uses DNA tags to track the synthetic history of individual members in a split-and-pool combinatorial synthesis scheme. DEL synthesis hinges on robust methodologies that tolerate combinatorial synthesis schemes while not destroying the information in DNA. We introduce here a DEL-compatible reaction that assembles a boron-containing pyridazine heterocycle. The heterocycle is unique because it can engage in reversible covalent interactions with alcoholsa feature that, until now, has not been deliberately engineered into DELs