Novel β-amino Amide Organocatalysts for the Synthesis of Pharmaceutically Relevant Oxindoles

Mariana Gavendova, Claire M. Lennon, Lee Coffey, Panagiotis Manesiotis, Michael Kinsella

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

In this work, a series of novel organocatalysts derived from unique unnatural β-amino acid scaffold were synthesized and further developed to enhance the desired catalytic properties. Their evaluation was carried out in the asymmetric crossed-aldol condensation of isatin and enolizable ketone donors. Following a systematic study of the reaction parameters including variations of additive, solvent, temperature, catalyst loading and substrate scope, (1R,2R)-2-amino-N-((R)-1-phenylethyl)cyclohexane carboxamide 9 proved particularly successful, affording the corresponding 3-hydroxy-3-alkyl-2-oxindole in excellent yield (>99%) and distereoselectivity (>99% dr) with good enantioselective control (up to 52% ee) in the presence of p-nitrophenol and EtOH in <24 h. An added benefit of this catalyst was its catalytic activity and selectivity at room temperature eliminating the requirement of reduced reaction temperatures. This scaffold, comprising of β-amino amide, has not yet been applied in organocatalysis, thus, this is the first reported in this growing area. In mechanistic studies, direct infusion ESI-MS proved a valuable tool forproposal of the catalytic cycle, confirming the formation of 2 key reaction intermediates.

Original languageEnglish
Pages (from-to)8246-8254
Number of pages9
JournalChemistrySelect
Volume4
Issue number28
Early online date25 Jul 2019
DOIs
Publication statusPublished - 31 Jul 2019

Keywords

  • aldol
  • covalent organocatalysis
  • oxindole
  • primary amine
  • β-amino amide

ASJC Scopus subject areas

  • Chemistry(all)

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