Synthesis of Substituted γ‐ and δ‐Lactams through Mannich‐Type Reactions of Solid‐Supported N‐Acyliminium Ions

Vitaly V. Komnatnyy, Kennedy M. Taveras, Nitin Subhash Nandurkar, Sebastian Thordal Le Quement, Michael Christian Givskov, Thomas Eiland Nielsen

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

We report the results of our recent investigations into the reactivity of cyclic solid‐supported N‐acyliminium ions. An intermolecular Mannich‐type transformation of these intermediates was used to generate libraries of substituted lactams. Masked aldehyde building blocks were readily prepared and coupled to peptides immobilized on PEGA800(polyethylene glycol dimethyl acrylamide) resin through an HMBA [4‐(hydroxymethyl)benzoic acid] linker. When treated with acid, the aldehyde was cleanly released and condensed with the amide backbone to form a hydroxylactam/N‐acyliminium ion, which underwent intermolecular reactions with a series of nucleophilic heterocycles, such as substituted indoles, thiophenes, furans, and electron‐rich benzenes. The resulting lactams were formed within a few minutes and in high purities (typically >85 %).
Original languageEnglish
JournalEuropean Journal of Organic Chemistry
Volume2015
Issue number16
Pages (from-to)3524-3530
Number of pages7
ISSN1434-193X
DOIs
Publication statusPublished - 2015

Keywords

  • Solid‐phase synthesis
  • Nitrogen heterocycles
  • Lactams
  • N‐Acyliminium ions
  • Aromatic substitution

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