Synthesis of cyclopropene analogues of ceramide and their effect on dihydroceramide desaturase

J Org Chem. 2003 Dec 26;68(26):9924-32. doi: 10.1021/jo030141u.


The synthesis of several analogues of the N-[(1R,2S)-2-hydroxy-1-hydroxymethyl-2-(2-tridecyl-1-cyclopropenyl)ethyl]octanamide (GT11), the first reported inhibitor of dihydroceramide desaturase, as well as their effects on this enzyme, are described. Modifications of the parent structure include variations on the cyclopropene ring, the N-acyl chain length, the configuration of the stereocenters, and the hydroxyl group at C1. The key intermediates for the synthesis are the products resulting from the addition of suitable organolithium compounds to either Garner's aldehyde or its enantiomer. The final products are obtained by TMSTf-induced cleavage of the protecting groups and N-acylation, both under specific conditions. An alternative method for N-Boc deprotection is also reported that allows us to obtain the cyclopropene analogue of sphingosine 12a, which can be transformed into GT11 upon acylation. The procedure consists of the conversion of the Garner aldehyde addition products into the bicyclic dihydrooxazolo[3,4,0]oxazol-3-ones 19 by transesterification in basic medium of the tert-butyl group with the hydroxyl function at C3. Mild cleavage of the N,O-isopropylidene cyclic acetal present in 19 affords the oxazolidin-2-one 20, which gives 12a upon saponification. Furthermore, compound 20 is also the key intermediate in the synthesis of the terminal deoxy, methoxy, and fluoro derivatives 9, 10, and 11, respectively. Determination of dihydroceramide desaturase activity in vitro showed that GT11 was a competitive inhibitor (Ki = 6 microM) and that its analogues with N-hexanoyl (6) and N-decanoyl (7) moieties inhibited the enzyme with similar potencies (IC50 = 13 and 31 microM, respectively). No decrease in dihydroceramide desaturase activity was observed with any of the other compounds tested.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding, Competitive
  • Ceramides / chemical synthesis*
  • Ceramides / chemistry
  • Ceramides / pharmacology*
  • Cyclopropanes / chemical synthesis
  • Cyclopropanes / chemistry*
  • Cyclopropanes / pharmacology*
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Microsomes, Liver / enzymology
  • Oxidoreductases / antagonists & inhibitors*
  • Oxidoreductases / metabolism
  • Rats
  • Stereoisomerism


  • Ceramides
  • Cyclopropanes
  • Enzyme Inhibitors
  • cyclopropene
  • Oxidoreductases
  • dihydroceramide desaturase