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

Abstract

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. File list (2) download file view on ChemRxiv strained_allenes-preprint.pdf (184.62 KiB) download file view on ChemRxiv strained_allenes-SI.pdf (2.14 MiB)

DNA-encoded libraries (DELs): a review of on-DNA chemistries and their output

“… 71 Schreiber's group developed [2 + 2], [3 + 2], and [4 + 2] reactions on DNA. 72 The DNA-tagged silyl derivatives underwent the cycloaddition reaction with 1,3-dipoles, olefins, and N -substituted pyrroles under the CsF catalysis. The yield of most products was above 90% ( Table 6 entry 3).…”

Allenes in Diels–Alder Cycloadditions

“…The bourgeoning field of bioorthogonal reactions, of which uncatalyzed cycloadditions already play an important role, would benefit significantly from utilizing certain allenic precursors and their Diels–Alder processes. 114…”

Leveraging Fleeting Strained Intermediates to Access Complex Scaffolds

“…For example, Schreiber and co-workers have recently harnessed heterocyclic allene chemistry for the synthesis of DNA-encoded libraries. 194 …”

“…With regard to diastereoselectivity, reactions proceed with endo selectivity with respect to the unreactive cyclic allene double bond. , Given the synthetic utility of this methodology and the ability to understand the regiochemical and stereochemical outcomes, we expect this methodology will see increased usage in chemical synthesis. For example, Schreiber and co-workers have recently harnessed heterocyclic allene chemistry for the synthesis of DNA-encoded libraries …”