Diversity‐Oriented Synthesis (DOS) of On‐DNA Peptidomimetics from Acid‐Derived Phosphonium Ylides

Abstract

The DNA-encoded library (DEL) technology represents a revolutionary drug-discovery tool with unprecedented screening power originating from the association of combinatorial chemistry and DNA barcoding. The chemical diversity of DELs and its chemical space will be further expanded as new DNA-compatible reactions are introduced. This work introduces the use of DOS in the context of on-DNA peptidomimetics. Wittig olefination of aspartic acid-derived on-DNA Wittig ylide, combined with a broad substrate scope of aldehydes, led to formation of on-DNA a,b-unsaturated ketones. The synthesis of on-DNA multi-peptidyl-ylides was performed by incorporating sequential amino acids onto a monomeric ylide. Di-, tri-and tetrameric peptidyl-ylides were validated for Wittig olefination and led to on-DNA a, b-unsaturated-based peptidomimetics, an important class of intermediates. One on-DNA aryl Wittig ylide was also developed and applied to Wittig olefination for synthesis of on-DNA chalcone-based molecules. Furthermore, DOS was used successfully with electron-deficient peptidomimetics and led to the development of different heterocyclic cores containing on-DNA peptidomimetics.

Impact of organic chemistry conditions on DNA durability in the context of DNA-encoded library technology

“…This headpiece structure is similar to the one typically used as a starting piece in DEL field except that we used 3 nucleotide overhangs. 18 , 59 , 60 Briefly, the two DNA strands are covalently linked with a spacer that carries a free functional group (e.g., NH 2 ) for chemical addition. The headpiece allows for cohesive DNA ligation with a subsequent DNA fragment (3′-OH and 5′-phosphate), it also allows for ethanol precipitation, and it is short enough (MW 6517) to be compatible with a clear LCMS resolution following deconvolution.…”

More than just Alkene Construction – Re‐Using Wittig Reactions/Reagents in Biomacromolecular Labeling, Imaging, Sequencing and Modification

“…This strategy can avoid the influence of secondary structure and the number of coupling steps on the reaction efficiency [13] . These methodologies not only enable the synthesis of linear molecules but also facilitate the production of large cyclic compounds, which are typically challenging to prepare in synthetic chemistry [14–16] …”