Enantio- and diastereoselective total synthesis of (+)-panepophenanthrin, a ubiquitin-activating enzyme inhibitor, and biological properties of its new derivatives

The asymmetric total synthesis of (+)-panepophenanthrin, an inhibitor of ubiquitin-activating enzyme (El), has been accomplished using catalytic asymmetric alpha aminoxylation of 1,4-cyclohexanedione monoethylene ketal as a key step, followed by several diastereoselective reactions. The biomimetic Diels-Alder reaction of a monomer precursor was found to proceed efficiently in water. The investigation of the biological properties of new derivatives of (+)-panepophenanthrin enabled us to develop new cell-permeable El inhibitors, RKTS-80, -81, and -82.