The Development of an Aza-C-Glycoside Library Based on a Tandem Staudinger/Aza-Wittig/Ugi Three-Component Reaction

T. Wennekes, K.M. Bonger, K. Vogel, S.A. van den Berg, A. Strijland, W.E. Donker-Koopman, J. Aerts, A. van der Marel, H.S. Overkleeft

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Abstract

We report the tandem Staudinger/aza-Wittig/Ugi three-component reaction mediated synthesis of a 64-member compound library of aza-C-glycosides. The library is composed of four pyrrolidine and three piperidine scaffolds, onto which a number of functional groups is grafted to form seven sublibraries. Variation in the library is achieved by transformation of two pentoses and a hexose into the corresponding 4-azidopentanal and 5-azidohexanal derivatives as precursors for the Staudinger/aza-Wittig process. Further variation is achieved by using different isocyanides as well as protective- and functional-group manipulations on the fully protected Ugi-3CR intermediates. Preliminary biological evaluation of the compound library revealed several low micromolar inhibitors of human acid glucosylceramidase
Original languageEnglish
Pages (from-to)6420-6454
JournalEuropean Journal of Organic Chemistry
Volume2012
Issue number32
DOIs
Publication statusPublished - 2012

Keywords

  • ugi 4-component condensation
  • gaucher-disease
  • multicomponent reactions
  • nonlysosomal glucosylceramidase
  • functionalized pyrrolidines
  • pharmacological chaperones
  • n-butyldeoxynojirimycin
  • combinatorial libraries
  • bicyclic scaffolds
  • storage disorders

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    Wennekes, T., Bonger, K. M., Vogel, K., van den Berg, S. A., Strijland, A., Donker-Koopman, W. E., Aerts, J., van der Marel, A., & Overkleeft, H. S. (2012). The Development of an Aza-C-Glycoside Library Based on a Tandem Staudinger/Aza-Wittig/Ugi Three-Component Reaction. European Journal of Organic Chemistry, 2012(32), 6420-6454. https://doi.org/10.1002/ejoc.201200923