Water-Compatible Cycloadditions of Oligonucleotide-Conjugated Strained Allenes for DNA-Encoded Library Synthesis

• Published in: Journal of the American Chemical Society Vol. 142; no. 17; pp. 7776 - 7782
• Main Authors: Westphal, Matthias V, Hudson, Liam, Mason, Jeremy W, Pradeilles, Johan A, Zécri, Frédéric J, Briner, Karin, Schreiber, Stuart L
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 29-04-2020
• Subjects: Alkadienes - chemistry; Cycloaddition Reaction - methods; Gene Library; Humans; Oligonucleotides - metabolism; Small Molecule Libraries - chemistry
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/jacs.9b13186

DNA-encoded libraries of small molecules are being explored extensively for the identification of binders in early drug-discovery efforts. Combinatorial syntheses of such libraries require water- and DNA-compatible reactions, and the paucity of these reactions currently limit the chemical features of resulting barcoded products. The present work introduces strain-promoted cycloadditions of cyclic allenes under mild conditions to DNA-encoded library synthesis. Owing to distinct cycloaddition modes of these reactive intermediates with activated olefins, 1,3-dipoles, and dienes, the process generates diverse molecular architectures from a single precursor. The resulting DNA-barcoded compounds exhibit unprecedented ring and topographic features, related to elements found to be powerful in phenotypic screening.