A Synthesis Platform Technology for gamma / delta / macro-Lactones Serving as Potential Drug Candidates

Tsvelikhovsky Dmitry, HUJI, School of Medicine - IMRIC, School of Pharmacy- Institute for Drug Research



  • Methylene lactone structures are frequently observed as scaffold segments of various biochemical compounds.
  • These architectures have been identified as building blocks of numerous terpenoids, as well as other families of diverse and often remotely related metabolites.  
  • A hydroxyalkenoic acid scaffold has the potential to serve as operational, collective key precursor for methylene lactone construction via controlled intramolecular cyclizations.

Our Innovation

A novel method that links a simple hydroxy acid with diverse, methylene lactone architectures.

  • A streamlined, synthetic methodology allowing for the rapid composition of multiple methylene lactone derivatives, using a single, common precursor.
  • Collective and regioselective synthesis of gamma-, delta- and macro-lactones from hydroxyalkenoic acid.
  • A suppressed condensation of the hydroxyalkenoic acid precursor.
  • Formation of differently substituted methylene lactones.
  • Successful construction of medium-sized lactones via a Tsuji–Trost type transformation


  • A Palladium-catalyzed Tsuji–Trost-like allylation reaction using unprotected alcohols and free carboxylic acids as nucleophiles was developed. It affords methylene lactones of various ring sizes.
  • The designed precursors were subjected to Pd-catalyzed cyclization conditions to provide a range of δ –lactones in good yields.
  • All the acids, proved to undergo regioselective allylation,
  • No detectable amounts of condensation or other side products were formed.
  • The cyclization was found to be dependent on the electronic nature of substituted substrate.
  • The rapid composition of key– hydroxyalkenoic acid scaffold yields an assembly of oxocanones, oxepanones, and pyranones in a regioselective and stereodirected fashion.
  • This method of collective synthesis of medium-sized methylene lactones via palladium catalyzed cyclization controlled cyclizations of easily accessible collective precursors was demonstrated in our labs.


Fig. 1: Products from diverse biological origins share methylene lactone cores


Fig. 2: Optimization of the Pd promoted δ-lacomization of hydroxyalkenoic acid: suppression of condensation


Fig. 3: Regioselective formation of γ-lactones



The synthesis platform technology could be used for the creation of new drug candidates

Patent Status

Granted US 10,844,050

Contact for more information:

Keren-Or Amar
VP, Business Development, Healthcare
Contact ME: