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 (E1), has been accomplished using catalytic asymmetric α 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 E1 inhibitors, RKTS‐80, ‐81, and ‐82. A key step in the asymmetric total synthesis of (+)‐panepophenanthrin (3), an inhibitor of ubiquitin‐activating enzyme (E1), is the catalytic asymmetric α aminoxylation of 1,4‐cyclohexanedione monoethylene ketal (1) to give α‐aminoxy ketone 2, followed by several diastereoselective reactions. The investigation of the biological properties of new derivatives of 3 allowed the development of new cell‐permeable E1 inhibitors.