Applications and limitations of the I2-mediated carbamate annulation for the synthesis of piperidines: five- versus six-membered ring formation

J Org Chem. 2013 Oct 4;78(19):9791-802. doi: 10.1021/jo401512h. Epub 2013 Sep 19.

Abstract

A protecting-group-free synthetic strategy for the synthesis of piperidines has been explored. Key in the synthesis is an I2-mediated carbamate annulation, which allows for the cyclization of hydroxy-substituted alkenylamines into piperidines, pyrrolidines, and furans. In this work, four chiral scaffolds were compared and contrasted, and it was observed that with both d-galactose and 2-deoxy-d-galactose as starting materials, the transformations into the piperidines 1-deoxygalactonorjirimycin (DGJ) and 4-epi-fagomine, respectively, could be achieved in few steps and good overall yields. When d-glucose was used as a starting material, only the furan product was formed, whereas the use of 2-deoxy-d-glucose resulted in reduced chemo- and stereoselectivity and the formation of four products. A mechanistic explanation for the formation of each annulation product could be provided, which has improved our understanding of the scope and limitations of the carbamate annulation for piperidine synthesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Deoxynojirimycin / analogs & derivatives*
  • 1-Deoxynojirimycin / chemistry
  • Carbamates / chemistry*
  • Cyclization
  • Fucose / chemistry*
  • Imino Pyranoses / chemistry
  • Molecular Structure
  • Piperidines / chemical synthesis*
  • Piperidines / chemistry
  • Stereoisomerism

Substances

  • Carbamates
  • Imino Pyranoses
  • Piperidines
  • 1-Deoxynojirimycin
  • Fucose
  • fagomine
  • piperidine
  • migalastat