Synthesis of both enantiomers of hydroxypipecolic acid derivatives equivalent to 5-azapyranuronic acids and evaluation of their inhibitory activities against glycosidases

Bioorg Med Chem. 2008 Sep 1;16(17):8273-86. doi: 10.1016/j.bmc.2008.06.016. Epub 2008 Jun 13.


We have synthesized 3-hydroxy- and 3,4,5-trihydroxypipecolic acid derivatives corresponding to 5-aza derivatives of uronic acids and evaluated their inhibitory activities against various glycosidases including beta-glucuronidase. Compounds 4 and 5 were chosen as common intermediates for the synthesis of 3,4,5-trihydroxypipecolic acids and 3-hydroxypipecolic acids as well as for 3-hydroxybaikiain, a unique natural product isolated from a toxic mushroom. Cross aldol reaction of N-Boc-allylglycine derivative with acrolein followed by the ring-closing metathesis gave 4 and 5 as a mixture of diastereomers which could be separated by silica gel column chromatography. By employing lipase-catalyzed kinetic resolution, the synthesis of both L- and D-isomers of 3,4,5-trihydroxy- and 3-hydroxypipecolic acids was achieved. None of the compounds tested showed inhibitory activity against alpha- and beta-glucosidases. On the other hand, L-23 and L-29 were found to have potent inhibitory activity against beta-glucuronidase. In addition, it is interesting that some uronic-type azasugar derivatives showed moderate inhibitory activities against beta-N-acetylglucosaminidase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aza Compounds / chemical synthesis
  • Aza Compounds / chemistry
  • Aza Compounds / pharmacology*
  • Cattle
  • Chickens
  • Dose-Response Relationship, Drug
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Glycoside Hydrolases / antagonists & inhibitors*
  • Humans
  • Molecular Structure
  • Pipecolic Acids / chemical synthesis
  • Pipecolic Acids / chemistry
  • Pipecolic Acids / pharmacology*
  • Stereoisomerism
  • Structure-Activity Relationship
  • Temperature
  • Time Factors
  • Uronic Acids / chemical synthesis*
  • Uronic Acids / chemistry
  • Uronic Acids / pharmacology*


  • Aza Compounds
  • Enzyme Inhibitors
  • Pipecolic Acids
  • Uronic Acids
  • Glycoside Hydrolases