SYNTHETIC APPROACHES TO CYCLOPROPYL PEPTIDOMIMETICS AS 20S PROTEASOME INHIBITORS

Abstract

Proteasome inhibitors are a relatively new class of chemotherapeutics with only three drugs currently on the market. Belactosin A, a natural product found in Streptomyces sp., possesses anti-tumor effects due to its proteasome inhibition properties, however it is not used clinically due to its toxicity. This led to several syntheses of belactosin A analogs in hopes of similar efficacy and lower toxicity. Most reported syntheses require a substantial number of steps to synthesize the cyclopropyl backbone and the b-lactone warhead of belactosin A. An efficient stereoselective cyclopropanation of amino acid enones that undergo a Michael-induced ring closure is reported here with the use of cinchona alkaloids as a catalysts, and lactonization of L-threonine to afford the a-substituted b-lactone warhead. The proposed synthetic route of the L-threonine-derived b-lactone analog of belactosin A is significantly more efficient compared to alternative analogs reported in literature.