Diversity‐Oriented Synthesis (DOS) of On‐DNA Peptidomimetics from Acid‐Derived Phosphonium Ylides. Issue 11 (18th January 2023)

• Record Type: Journal Article
• Authors: Krishna Sunkari, Yashoda; Kumar Siripuram, Vijay; Flajolet, Marc
• Is Part Of: Chemistry. Volume 29:Issue 11(2023)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2023-01-18
• Subjects: DNA-encoded library (DEL) -- diversity-oriented synthesis (DOS) -- peptidomimetics -- peptidyl-ylides -- Wittig olefination reactions; Chemistry -- Periodicals; 540
• DOI: 10.1002/chem.202203037
• Languages: English
• ISSNs: 0947-6539

Abstract

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 α ${\alpha }$, β ${\beta }$ ‐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 α ${\alpha }$, β ${\beta }$ ‐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. Abstract : On‐DNA ! Aspartic acid‐derived Wittig ylides were generated onto DNA and have been validated for Wittig olefination with various aldehydes to develop on‐DNA α ${\alpha }$, β ${\beta }$ ‐unsaturated peptidomimetics. These were further converted into heterocyclic core‐containing peptidomimetics through diversity‐oriented synthesis (DOS).