Total synthesis of the ubiquitin-activating enzyme inhibitor (+)-panepophenanthrin.

In 2002, the first natural product inhibitor of ubiquitin activating enzyme, panepophenanthrin (1), was isolated from the mushroom strain Panus rudis Fr. IFO8994. In 2003, we completed the first total synthesis of (+)-panepophenanthrin utilizing a highly stereoselective Diels-Alder dimerization of an epoxyquinol dienol monomer. Our retrosynthetic route for panepophenanthrin is depicted in Figure 1. Epoxyquinol 1 may be derived from hemiacetal formation of hydroxy ketone precursor 2. The propensity for epoxyquinol derivatives to form both hydrates and hemiacetals by reaction of water and alcohols with the electrophilic carbonyl has been documented. Open-form precursor 2 may be derived from exo-Diels Alder dimerization of epoxyquinol monomer 3, the conjugated diene isomer of the natural product panepoxydon 4. Reports by Shotwell et al have documented the facile rearrangement of 4 to conjugated isomers such as 3 under mildly acidic conditions. 4 Epoxyquinol diene monomer 3 may be derived from transformations of chiral, nonracemic epoxy ketone 5, including a Heck-type coupling to install the dienol. Compound 5 may be prepared in either antipode using tartrate-mediated asymmetric nucleophilic epoxidation of a quinone monoketal precursor.