An alternative and efficient synthesis of MLN4924, a selective NEDD8 inhibitor

Abstract

An efficient synthesis of MLN4924, a small molecule inhibitor of NEDD8-activating enzyme (NAE) in clinical trial as an anticancer agent, has been accomplished via regioselective α-alkoxy removal by Al(Hg) and stereoselective reduction based on the conformational study as key steps. The present synthesis was achieved through a versatile cyclopentanone intermediate, which is expected to provide an easy access to structural analogues of MLN4924 for further exploration as a biologically privileged template.