Direct Catalytic Asymmetric Mannich-Type Reaction of α- And β-Fluorinated Amides

Lennart Brewitz, Fernando Arteaga Arteaga, Liang Yin, Kaliyamoorthy Alagiri, Naoya Kumagai, Masakatsu Shibasaki

Research output: Contribution to journalArticlepeer-review

72 Citations (Scopus)

Abstract

The last two decades have witnessed the emergence of direct enolization protocols providing atom-economical and operationally simple methods to use enolates for stereoselective C-C bond-forming reactions, eliminating the inherent drawback of the preformation of enolates using stoichiometric amounts of reagents. In its infancy, direct enolization relied heavily on the intrinsic acidity of the latent enolates, and the reaction scope was limited to readily enolizable ketones and aldehydes. Recent advances in this field enabled the exploitation of carboxylic acid derivatives for direct enolization, offering expeditious access to synthetically versatile chiral building blocks. Despite the growing demand for enantioenriched fluorine-containing small molecules, α- and β-fluorinated carbonyl compounds have been neglected in direct enolization chemistry because of the competing and dominating defluorination pathway. Herein we present a comprehensive study on direct and highly stereoselective Mannich-type reactions of α- and β-fluorine-functionalized 7-azaindoline amides that rely on a soft Lewis acid/hard Brønsted base cooperative catalytic system to guarantee an efficient enolization while suppressing undesired defluorination. This protocol contributes to provide a series of fluorinated analogs of enantioenriched β-amino acids for medicinal chemistry.

Original languageEnglish
Pages (from-to)15929-15939
Number of pages11
JournalJournal of the American Chemical Society
Volume137
Issue number50
DOIs
Publication statusPublished - 2015 Dec 23
Externally publishedYes

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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